Asymmetric synthesis of polyfunctionalized pyrrolidines via a thiourea catalyzed domino Mannich/aza-Michael reaction

Article abstract of DOI:10.1002/adsc.201000658

The domino Mannich/aza-Michael reaction of γ-malonate-substituted α,β-unsaturated esters with N-protected arylaldimines has been achieved. Catalyzed by bifunctional thioureas, 2,5-cis-configured polysubstituted pyrrolidines are obtained in good to excellent yields (76-99%), enantioselectivities (75-94%) and excellent diastereoselectivities (de >95%). The pure stereoisomers are available by crystallization and removal of the racemates. Copyright

Full text of DOI:10.1002/adsc.201000658

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DOI: 10.1002/adsc.201000658
Asymmetric Synthesis of Polyfunctionalized Pyrrolidines via a
Thiourea Catalyzed Domino Mannich/Aza-Michael Reaction
Dieter Enders,a,* Dominik P. Gçddertz,a Christian BeceÇo,a and Gerhard Raabea
a
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax : (+49)-241-809-2127; e-mail: enders@rwth-aachen.de
Received: August 23, 2010; Published online: November 17, 2010
Dedicated to Professor Gꢀnter Helmchen on the occasion of his 70th birthday.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000658.
Abstract: The domino Mannich/aza-Michael reac-
tion of g-malonate-substituted a,b-unsaturated
esters with N-protected arylaldimines has been
achieved. Catalyzed by bifunctional thioureas, 2,5-
cis-configured polysubstituted pyrrolidines are ob-
tained in good to excellent yields (76–99%), enan-
tioselectivities (75–94%) and excellent diastereose-
lectivities (de >95%). The pure stereoisomers are
available by crystallization and removal of the race-
mates.
sis and have been applied successfully in many orga-
nocatalytic reactions.[9]
Many syntheses of substituted pyrrolidines have
been developed, with initial approaches including the
hydrogenation of pyrroles[10] and the Hofmann–
Lçffler–Freytag cyclization.[11] Current synthetic ap-
proaches have significantly broadened the stereoselec-
tivity and diversity in the formation of such nitrogen-
containing heterocycles. For instance, pyrrolidines
have been obtained by the asymmetric [3+2]-cyclo-
addition of azomethine ylides to alkenes[12] and by
ring-closure of pre-synthesized chiral linear mole-
cules.[13]
Recently, highly stereoselective Mannich additions
of malonic esters to N-protected aryl aldimines have
been reported.[14] These reactions are usually cata-
lyzed by bifunctional thioureas, although they have
also been achieved in the presence of chiral metal-
Keywords: bifunctional thioureas; domino reaction;
Mannich/aza-Michael reaction; organocatalysis;
pyrrolidines
In the last decade the research area of asymmetric or- ligand complexes and phase-transfer organocatalysts.
ganocatalysis has grown rapidly and became a third Even though the stereoselective addition of a-methyl-
brand of asymmetric catalysis besides the well estab- substituted malonates to imines has been described in
lished bio- and metal catalysis.[1] Recently, organoca- the literature, the use of malonates with other sub-
talytic domino/cascade reactions came into focus al- stituents in similar reactions has still remained unsol-
lowing the synthesis of complex molecules economi- ved.[14f,i]
cally in fewer steps.[2] Applying this strategy to nitro-
In the course of our ongoing research on organoca-
gen-containing heterocycles, such structural motifs as talytic cascade reactions[15] we envisaged an asymmet-
piperidines[3] and isoquinuclidines[4] have been effi- ric synthesis of polyfunctionalized pyrrolidines via a
ciently generated via sequential Mannich/aza-Michael thiourea-catalyzed domino Mannich/aza-Michael re-
reactions.
action of N-protected aryl aldimines with g-malonate-
Due to the involvement of pyrrolidine structures in substituted a,b-unsaturated esters (Scheme 1). The
many physiological processes such as in interactions latter have already been used in tandem Michael re-
with enzymes[5] and receptors[6], the synthesis of these actions to generate substituted cyclopentanes.[16]
compounds is the focus of much current research. In
Therefore we screened a number of a,b-unsaturat-
addition, pharmacological studies of the antiviral[7] ed esters 2[17] with carbamate-protected benzaldimines
and analgesic[8] activities of pyrrolidine derivatives 1[18] to gauge the potential of the novel pyrrolidine
have led to a demand for additional synthetic strat- synthesis (Table 1).
egies towards these heterocycles. In addition, proline
In the first instance we chose the catalysts 4a and
and its derivatives play a central role in organocataly- 4b[19] for the Mannich reaction owing to their excel-
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Table 1. Enantioselective Mannich reaction.[a]
Entry
Product
Imine
Malonate
Catalyst
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
3a
1a
1b
1c
1a
1a
1a
1a
2a
2a
2a
2b
2c
2d
2a
4a
4a
4a
4a
4a
4a
4b
95
95
94
92
56
61
50
83
58
15
85
85
84
68
[a]
Reaction conditions: 1 (1.6 mmol), 2 (0.8 mmol), absolute DCM (4 mL), 4 (10 mol%), 5 d, room temperature.
Yield of isolated 3.
Determined by chiral stationary phase HPLC analysis.
[b]
[c]
such as K2CO3, Cs2CO3, DBU, DBN either gave no
product or resulted in complex mixtures.Therefore we
decided to enhance the electrophilicity of the Michael
system by introducing an additional ester function to
the double bond. The required g-malonate-substituted
a,b-unsaturated methyl ester 7 was prepared using
standard synthetic procedures starting from commer-
Scheme 1. Envisaged domino Mannich/aza-Michael reac-
tion.
cially available dimethyl allylmalonate 5 (Scheme 2).
Ozonolysis and subsequent acetal protection fur-
nished dimethyl 2,2-dimethoxy
ACHTUNGERTNeNUNG thylmalonate 6. After
treatment with TFA followed by a proline-catalyzed
lent results in the previously published organocatalyt- Knoevenagel condensation with dimethyl malonate
ic Mannich reactions between N-protected arylald- the tetramethyl ester 7 was obtained.
ACHTUNGTRENNUNG
imines and malonates.[14b,e]
We found that the Takemoto catalyst 4a allowed
the formation of the Mannich products 3 in moderate
to very good yields and good enantiomeric excesses,
whereas the more bulky cinchonine-thiourea catalyst
4b showed both lower enantioselectivity and activity
(Table 1, entry 7). The N-Boc-protected benzaldimine
and g-malonate-substituted a,b-unsaturated ester 2
bearing small methyl ester groups turned out to be
the best substrate combination for the desired Man-
nich reaction (Table 1, entries 1 and 4).
Even though it was not possible to isolate the envis-
aged pyrrolidine derivatives, the Mannich reaction
could be performed efficiently. It was assumed that
the Michael acceptor nature of 2 was not sufficiently
electrophilic to enable a direct subsequent aza-
Michael addition with the generated secondary
Scheme 2. Synthesis of the g-malonate-substituted a,b-unsa-
amine. The attempt to cyclize products 3 with bases turated methyl ester 7.
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Asymmetric Synthesis of Polyfunctionalized Pyrrolidines
Table 3. Optimization of the catalyst loading.[a]
In the first test reactions between the N-protected
benzaldimines 1 and the g-malonate-substituted a,b-
unsaturated ester 7 we were able to isolate the
domino Mannich/aza-Michael product 8 exclusively
(Table 2). To our delight, excellent diastereoselectivi-
ties along with moderate to good enantioselectivities
and yields were achieved. The best result with regard
to reaction time, yield and stereoselectivity was ob-
tained using the Takemoto catalyst 4a and the N-Boc-
protected benzaldimine 1a (Table 2, entry 1) in ac-
cordance with the previous results (Table 1). Catalyst
4b, cinchonine 4c and the tryptophan-derived thiourea
4d[14g] were not as selective or active as catalyst 4a
(Table 2, entries 4–6).
Entry
4a [mol%]
Time [d]
Yield[b] [%]
ee[c] [%]
1
2
3
20
10
5
1
–
4
5
5
6
94
95
93
57
–
83
84
82
82
–
4
5[d]
10
[a]
The de of every product was found to be >95% as deter-
mined by H NMR spectroscopy.
Yield of isolated 8a.
Determined by chiral stationary phase HPLC analysis.
1
[b]
[c]
[d]
Carried out without the addition of any catalyst.
Based on these first results we investigated the op-
timal catalyst loading. Increasing the catalyst loading
to 20 mol% showed no further improvement, while
lowering it to 5 mol% caused a slight drop in stereo-
selectivity and yield. The use of only 1 mol% showed
the same enantiomeric excess of 82% with a signifi-
cantly lower yield though.
Running the reaction without catalyst proved that a
possible background reaction could be excluded
(Table 3, entry 5). All following reactions were per-
formed with a catalyst loading of 10 mol%. The
screening of several solvents showed that the reaction
tolerates other solvents besides dichloromethane,
such as THF, toluene and chloroform, without any no-
ticeable change in reaction time, yield or stereoselec-
tivity (Table 4, entries 1–4). Interestingly, the addition
of molecular sieves (3 ꢂ) caused a significant drop of
the enantiomeric excess to 53% (Table 4, entry 5).
Therefore we set out to verify the proposed catalytic
activity of the molecular sieves in the same reaction
and obtained product 8a in good yield as a racemate
(Table 4, entry 6). Decreasing the temperature to 28C
Table 4. Influence of the solvent on the Mannich/aza-
Michael reaction.[a]
Entry
Solvent
Time [d]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
THF
5
5
6
5
6
4
5
13
94
93
89
95
89
85
71
38
84
82
83
84
53
–
toluene
CHCl3
DCM
DCM[d]
DCM[e]
DCM[f]
DCM[g]
85
91
[a]
The de of every product was found to be >95% as deter-
mined by H NMR spectroscopy.
Yield of isolated 8a.
Determined by chiral stationary phase HPLC analysis.
3 ꢂ molecular sieves were added.
3 ꢂ molecular sieves were added without the presence of
a catalyst.
The reaction was performed at 28C.
The reaction was performed at À268C.
1
[b]
[c]
[d]
[e]
[f]
[g]
Table 2. Screening of protecting groups and catalysts for the Mannich/aza-Michael reaction.[a]
Entry
Product
Catalyst
Imine
Time [d]
Yield[b] [%]
ee[c] [%]
1
2
3
4
5
6
8a
8b
8c
8a
8a
8a
4a
4a
4a
4b
4c
4d
1a
1b
1c
1a
1a
1a
5
7
6
6
6
6
95
52
89
95
39
33
84
70
60
78
À69
À79
[a]
1
The de of every product was found to be >95% as determined by H NMR spectroscopy.
Yield of isolated 8.
Determined by chiral stationary phase HPLC analysis.
[b]
[c]
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Table 5. Substrate scope of the organocatalytic domino
Mannich/aza-Michael reaction.[a,b]
Entry Product Aryl
Substituent
Time Yield
[d]
ee
[%][c,d] [%][e,f]
1
2
3
4
5
6
7
8a
8d
8e
8f
8g
8h
8i
Phenyl
5
6
5
5
11
3
4
95 (76) 84 (99)
91 (77) 75 (99)
91 (75) 83 (>99)
99 (75) 78 (>99)
85 (77) 83 (97)
2-Me-C6H4
4-F-C6H4
4-MeO-C6H4
1-naphthyl
2-furyl
95
76
94
83
2-thiophenyl
[a]
The de of every product was found to be >95% as deter-
mined by H NMR spectroscopy.
Reaction conditions: 1 (0.7 mmol), 7 (0.7 mmol), absolute
DCM (3 mL), 4a (10 mol%), room temperature.
Yield of isolated 8.
1
[b]
[c]
[d]
The values in brackets are the yields after removal of the
racemate.
[e]
[f]
Determined by chiral stationary phase HPLC analysis.
The values in brackets refer to the enantiomeric excesses
after removal of crystalline racemate.
led to a slightly higher ee but a notably lower yield
(Table 4, entry 7). The highest ee of 91% was ob-
tained at À268C albeit with a significantly lower yield
(Table 4, entry 8).
Figure 1. X-ray crystal structure of (R,R)-8d. The Flack pa-
rameter[21] for the data collected at 100 K is 0.01(15).
Next we investigated the substrate scope using dif-
ferent N-Boc-protected aryl aldimines 1a, d–i[18] under
The virtually pure single stereoisomers are avail-
the optimized conditions. The results are presented in able by removal of the crystalline racemates.
Table 5. Thus, we were able to synthesize a variety of
polysubstituted pyrrolidines in good to excellent
yields (76–99%), enantiomeric excesses (75–94%) and Experimental Section
excellent diastereoselectivities (de>95%). In the case
of product 8g a longer reaction time was necessary, General Procedure for the Mannich Reaction
likely due to the bulky naphthyl substituent (entry 5).
A faster reaction was observed using five-membered
In a dry, argon-flushed one-necked flask, the carbamate-pro-
tected benzaldimine 1 (1.6 mmol), the g-malonate-substitut-
heterocycles, with product 8h formed after 3 days in
excellent yield and stereoselectivity. In several cases
the virtually stereoisomerically pure pyrrolidines 8
(de>95%, ee=97 to >99%) were obtained by crys-
tallization of the racemates from n-heptane and di-
chloromethane and removal of the crystals.
The relative configuration of the product pyrroli-
dines could be determined to be 2,5-cis by X-ray
structure analyses in the case of rac-8a and 8d. The
latter allowed us to assign the absolute configuration
as (2R,5R) (Figure 1).[20]
ed a,b-unsaturated methyl ester 2 (0.8 mmol) and the thio-
urea catalyst 4 (10 mol%) were dissolved in absolute di-
chloromethane (4 mL) and stirred at room temperature for
5 days. After removal of the solvent under vacuum the mix-
ture was dissolved in toluene and purified via flash chroma-
tography over silica gel (diethyl ether/n-pentane=1:3 to
1:1). The Mannich products 3 were obtained as colourless
oils. Racemic samples were prepared using a 1:1 mixture of
cinchonine:cinchonidine as catalysts applying the same reac-
tion conditions.
In conclusion, we have developed an efficient
domino Mannich/aza-Michael reaction between car-
bamate-protected aryl aldimines and g-malonate-sub-
stituted a,b-unsaturated methyl esters promoted by a
bifunctional thiourea catalyst. The new method
furnishes 2,5-cis-configured polysubstituted pyrroli-
dines in good to excellent yields, enantioselectivities
and excellent diastereoselectivities.
General Procedure for the Domino Mannich/Aza-
Michael Reaction
In a dry, argon-flushed one-necked flask, the carbamate-pro-
tected aryl aldimine 1 (0.7 mmol), the g-malonate-substitut-
ed a,b-unsaturated methyl ester 7 (0.7 mmol) and the cata-
lyst 4 (10 mol%) were dissolved in absolute dichlorome-
thane (3 mL) and stirred at room temperature for 3–11 days.
After removal of the solvent under vacuum the mixture was
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Asymmetric Synthesis of Polyfunctionalized Pyrrolidines
dissolved in toluene and purified via flash chromatography
over silica gel (diethyl ether/n-pentane=1:3 to 1:2). The pyr-
rolidine derivatives 8 were obtained as colourless oils. Race-
mic samples were prepared using tetrabutylammonium fluo-
ride (1M in THF) as catalyst applying the same reaction
conditions.
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Acknowledgements
This work was supported by the Deutsche Forschungsgemein-
schaft (priority program Organocatalysis) and the Fonds der
Chemischen Industrie. We thank BASF AG for the donation
of chemicals.
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