Organocatalysis in Ionic Liquids: Highly Efficient L-Proline-Catalyzed Direct Asymmetric Mannich Reactions Involving Ketone and Aldehyde Nucleophiles

Article abstract of DOI:10.1055/s-2003-41483

Proline-catalyzed direct asymmetric Mannich reactions of N-PMP protected α-imino ethyl glyoxylate with various aldehydes and ketones in ionic liquids afforded both α- and β-amino acid derivatives with excellent yields and enantioselectivities, providing f

Full text of DOI:10.1055/s-2003-41483

1906
CLUSTER
Organocatalysis in Ionic Liquids: Highly Efficient L-Proline-Catalyzed Direct
Asymmetric Mannich Reactions Involving Ketone and Aldehyde Nucleophiles
O
rganocatalysis in
a
Ionic
L
iqu
i
ids du S. Chowdari, D. B. Ramachary, Carlos F. Barbas III*
The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037,
USA
Fax +1(858)7842583; E-mail: carlos@scripps.edu
Received 4 June 2003
In recent years, ionic liquids have attracted a great deal of
Abstract: Proline-catalyzed direct asymmetric Mannich reactions
attention from synthetic chemists as novel green reac-
of N-PMP protected a-imino ethyl glyoxylate with various alde-
tion media.7 This is mainly due to their nonvolatile nature,
hydes and ketones in ionic liquids afforded both a- and b-amino
tunable polarity and high thermal stability. The insolubil-
acid derivatives with excellent yields and enantioselectivities,
providing facile product isolation, catalyst recycling, and signifi- ity of ionic liquids in some solvents and their ability to
cantly improved reaction rates, ca 4- to 50-fold. Three component
dissolve catalysts, particularly transition metal catalysts,
Mannich reactions involving other imines also worked well in ionic
has made them attractive with respect to both solvent and
liquids. Significant advantages and limitations of ionic liquid sol-
catalyst recycling. Herein, we report the unique favorable
vents in this reaction have been revealed.
features as well as the limitations of proline-catalyzed
direct asymmetric Mannich reactions in ionic liquids
(Scheme 1).
Key words: proline, enamine, Mannich reaction, ionic liquids,
green chemistry
In the 91 years since its invention, the Mannich reaction
has established itself as one of the most important carbon-
carbon bond-forming reaction in organic synthesis.1 Dur-
ing this time, substantial efforts have been devoted to op-
timizing this reaction since the b-amino ketones and
aldehydes it provides are key intermediates in the synthe-
sis of natural products and bioactive products in medicinal
chemistry. Of late, particular emphasis has been devoted
to the development of asymmetric versions of this type of
transformation. These studies have culminated in the de-
velopment of approaches that affect the direct catalytic
Scheme 1 L-Proline-catalyzed direct asymmetric Mannich reac-
tions in [bmim][BF4]
Table 1 Catalyst and Ionic Liquid Solvent Recycling in the L-Pro-
addition of unmodified ketones2 and most recently alde- line Catalyzed Direct Asymmetric Mannich Reaction of Cyclohex-
hydes.3 In considering the optimization of a reaction,
anone with N-PMP Protected a-Imino Ethyl Glyoxylate
attention must also be paid to the practical aspects of
the reaction that go beyond the products themselves; i.e.
solvent, apparatus, and recycling of non-consumed ma-
terials. Ideally such optimization takes into account envi-
ronmental safety as an important element of the overall
economy of the process.4 In 1997 we initiated compara-
Run
1
Yield (%)
dra
ee (%)b
>99
tive studies of aldolase antibodies with proline5 and this
research effort has led to the development of a number of
organocatalytic reactions as well as additional catalysts.
The reactions include asymmetric aldol, Michael,
Mannich, Diels–Alder and related reactions based on ex-
ploiting enamines and imines generated in a catalytic
fashion.2c,d,3,6 Organocatalysis of direct asymmetric Man-
nich reactions involving ketone nucleophiles and,
more significantly, aldehyde nucleophiles promises to
have an impact on the practice of this important reaction.
99
92
87
83
>19:1
>19:1
>19:1
>19:1
2
>99
3
>99
4
>99
a Determined by 1H NMR analysis of unpurified products.
b Determined by HPLC analysis using Chiralpk AS column.
We initially studied8 the Mannich reaction of N-PMP pro-
tected a-imino ethyl glyoxylate with cyclohexanone using
a catalytic amount of L-proline (5 mol%) in [bmim]BF4 at
room temperature (Table 1). We were delighted to find
that the reaction was complete within 30 minutes and
SYNLETT 2003, No. 12, pp 1906–1909
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9
.0
9
.2
0
0
3
Advanced online publication: 19.09.2003
DOI: 10.1055/s-2003-41483; Art ID: Y00403ST
© Georg Thieme Verlag Stuttgart · New York

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Organocatalysis in Ionic Liquids
1907
provided the Mannich product in quantitative yield with aromatic and aliphatic aldehydes were employed in this
excellent ee (>99%) and diastereoselectivity (>19:1). In three component Mannich reaction affording the products
order to study catalyst and solvent recycling, the product with good yields and ee’s. Interestingly, reactions involv-
was extracted with Et2O. The recovered ionic liquid con- ing 5-hexene 2-one afforded a single regioisomer. The re-
taining L-proline was then used for the next reaction run. actions involving aliphatic aldehydes were faster (1 h)
Again, the Mannich product was obtained in excellent (Table 3, entry 5 and 6) than those involving aromatic al-
yield and ee’s. Following four consecutive reaction cycles dehydes (6 h). These results are comparable with respect
there was no diminution in ee and a slight decrease in to yield and enantioselectivity with the reactions conduct-
yield when the 30 minutes reaction time was strictly main- ed in organic solvents,2c,e though again the reaction rates
tained. The use of another ionic liquid, [bmim]PF6, as re- are significantly faster. In entry 6 the product yield and
action solvent also afforded the Mannich products with ee’s are superior to those reported using traditional sol-
identical yields and ee’s.
vent (82% yield and 75% ee).2e
Encouraged by these promising results we next studied
the Mannich reaction using various aldehydes and ketones
as nucleophiles or donors in this reaction.2d,3a In all cases,
the reactions were complete within 30 minutes to furnish
various functionalized amino acids with excellent yields
and ee’s. In most of the cases (Table 2, entries 1–3 and 5–
6) the amino acid derivatives were obtained as single
enantiomers with excellent diastereoselectivity (>19:1).
The use of aldehyde donors, possible only through orga-
nocatalysis, afforded the corresponding a- and b-amino
acid derivatives. Reducing the catalyst loading to 1 mol%
using ionic liquid solvent did not compromise the enanti-
oselectivity of the reaction but required a longer, albeit
reasonable, 2 hour reaction time (Table 2, entry 6). These
results demonstrate that the use of ionic liquids as solvents
for these reactions leads to higher yields and markedly ac-
celerated reactions. Our original disclosure of these reac-
tions involving traditional organic solvents required 2–24
h reaction times with 5–20 mol% catalysts.
Table 3 L-Proline-Catalyzed Asymmetric Three Component Man-
nich Reactions in [bmim][BF4]
Entry
1
R1
H
R2
Yield (%)
54
ee (%)
95
2
H
63
82
3
4
allyl
allyl
60
52
87
93
With this success next we investigated the three compo-
nent Mannich reaction in ionic liquids (Table 3).9 Various
Table 2 L-Proline-Catalyzed Direct Asymmetric Mannich Reac-
tions in [bmim][BF4]
5
6
H
H
80
98
43
93
Entry R1
R2
Yield dra
(%)
ee
(%)b
Limitations on the Use of Ionic Liquids in the
Proline-Catalyzed Mannich Reaction
1
2
3
H
H
H
n-Bu
87
96
95
13:1
>99
>19:1 >99
>19:1 >99
n-Pent
The first significant limitation we noted concerned Man-
nich reactions involving hydroxyacetone as a nucleophile.
Hydroxyacetone is a unique donor whose properties we
initially described in the context of our studies of aldolase
antibodies.10 Here we studied the hydroxyacetone Man-
nich reaction under a variety of reaction conditions pre-
sented in Table 4. While the desired amino alcohol
products were obtained with excellent yield, the diastereo-
and enantioselectivity of the reaction was severely com-
promised as compared to the same reaction in organic sol-
vents, e.g. DMSO or DMF. In these solvents we had
obtained products with ee’s of 99% and dr’s of > 19:1. In-
deed, it was hydroxyacetones’ characteristic of acting as a
4
H
i-Pr
90
77
99
80
5:1
93
5
Me
Me
>19:1 >99
>19:1 >99
6c
7
-(CH2)2- -(CH2)2-
Me
H
–
97
a Determined by 1H NMR analysis of reaction mixtures.
b Determined by HPLC analysis using Chiralpk AS or Chiralpk AD
columns.
c With 1 mol% of L-proline the reaction was complete in 2 h.
Synlett 2003, No. 12, 1906–1909 © Thieme Stuttgart · New York

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N. S. Chowdari et al.
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nucleophilic enamine to generate products with excep- In summary, proline-catalyzed direct asymmetric Man-
tional enantio- and diastereoselectivity that made this ke- nich reactions in ionic liquids are substantially faster than
tone an exceptional donor in our antibody studies and later the corresponding reactions in standard organic solvents,
in organocatalysis. To determine if the poor performance ca 4–50 times faster. We speculate that enhanced rates re-
of hydroxyacetone in ionic liquids was a general phenom- sult from ionic liquid-based activation of the imine elec-
enon, we studied the aldol reaction shown in Scheme 2. trophiles. These results are noteworthy compared to the
Contrary to the results we obtained in the Mannich reac- proline-catalyzed aldol reactions involving unsubstituted
tion, the Aldol reaction using hydroxyacetone afforded ketones in ionic liquids, where the reactivity, yields and
the desired product with excellent diastereo- and enanti- ees are comparable or inferior as compared to the reac-
oselectivity. (Scheme 2) In accord with studies of simple tions performed in standard organic solvents.11 Limita-
unsubstituted ketones in proline catalyzed aldol reactions tions include poor performance in hydroxyacetone
in ionic liquids,11 no increase in the reaction rate was Mannich reactions and in SMP-catalyzed anti-Mannich
noted in the special case of hydroxyacetone.
reactions. Together these results go a long way to creating
a ‘green’ class of Mannich reactions wherein both solvent
and catalyst are readily recycled and reaction times are
minimized thereby significantly improving the overall
economy of this reaction. The catalyst itself is edible.
These reactions can be performed on a multi-gram scale
under operationally simple and safe conditions. Further
studies aimed at exploring the scope of organocatalytic
reactions in ionic liquids are ongoing.
Scheme 2 L-Proline-catalyzed aldol reaction of hydroxyacetone in
[bmim][BF4]
Acknowledgment
The next limitation we noted came in the context of our
recently developed catalytic direct asymmetric anti-selec-
tive Mannich reaction. The (S)-2-methoxymethylpyrroli-
dine (SMP)-catalyzed3b reaction of isovaleraldehyde with
This study was supported in part by the NIH (CA27489) and the
Skaggs Institute for Chemical Biology.
N-PMP protected a-imino ethyl glyoxylate in References
[bmim][BF4] provided the desired anti-Mannich product
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albeit in only 20% yield and 33% ee (Scheme 3). With
dioxane as the solvent, this reaction provides the product
in 48% yield with an ee of 69% and a dr >10:1.
(b) Kleinmann, E. F. Comprehensive Organic Synthesis,
Vol. 2; Trost, B. M.; Fleming, I., Eds.; Pergmon Press: New
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55, 8857. (b) Juhl, K.; Gathergood, N.; Jorgensen, K. A.
Angew. Chem. Int. Ed. 2001, 40, 2995. (c) Notz, W.;
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Scheme 3 (S)-2-Methoxymethylpyrrolidine (SMP)-catalyzed syn-
thesis of anti-Mannich product in [bmim][BF4]
Table 4 L-Proline-Catalyzed Direct Asymmetric Mannich Reactions in [bmim][BF4] with Hydroxyacetone
Entry
Ionic liquid
[bmim][BF4]
[bmim][BF4]
[bmim][BF4]
[bmim][PF6]
Temperature (°C)
Time (min)
Yield (%)
dr
ee (%) (syn/anti)
1
2
3
4
22
0
30
180
180
30
97
50
20
93
68:32
67:33
67:33
58:42
3/24
0/25
2/39
3/37
–20
22
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Organocatalysis in Ionic Liquids
1909
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Barbas, C. F. III J. Am. Chem. Soc. 2002, 124, 1866.
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(8) General experimental procedure: To a glass vial charged
with L-proline (3 mg, 0.025 mmol) was added [bmim]BF4 (1
mL) followed by a-imino ethyl glyoxylate (104 mg, 0.5
mmol), aldehyde (1.5 equiv) or ketone (1 mL) and the
reaction was stirred at r.t. for 30 min. After completion of the
reaction (as monitored by TLC), the product was isolated by
extraction with Et2O (4 × 5 mL). The combined Et2O
extracts were concentrated to obtain the Mannich product.
The ionic liquid containing L-proline was dried under
vacuum prior to reuse.
(9) General experimental procedure for three component
Mannich reaction (Table 3): To a glass vial charged with
L-proline (3 mg, 0.025 mmol) were added [bmim]BF4 (1
mL), p-anisidine (68mg, 0.55 mmol), aldehyde (0.5 mmol)
and ketone (1 mL) and the reaction was stirred at r.t. After
completion of the reaction (as monitored by TLC), the
product was isolated by extraction with Et2O (4 × 5 mL). The
combined ether extracts were concentrated and
chromatographed to obtain the Mannich product.
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Synlett 2003, No. 12, 1906–1909 © Thieme Stuttgart · New York