O-TMS-α,α-diphenyl-(S)-prolinol modified with an ionic liquid moiety: A recoverable organocatalyst for the asymmetric michael reaction between α,β-enals and dialkyl malonates

Article abstract of DOI:10.1002/ejoc.200900807

O-TMS-α,β-diphenyl-(S)-prolinol derivative bearing an ionic liquid fragment was synthesized for the first time and proven to be an efficient catalyst for the asymmetric Michael reaction of aromaticα,β- unsaturated aldehydes with dialkyl malonates. The pre

Full text of DOI:10.1002/ejoc.200900807

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200900807
O-TMS-α,α-diphenyl-(S)-prolinol Modified with an Ionic Liquid Moiety:
A Recoverable Organocatalyst for the Asymmetric Michael Reaction between
α,β-Enals and Dialkyl Malonates
Oleg V. Maltsev,[a] Alexandr S. Kucherenko,[a] and Sergei G. Zlotin*[a]
Keywords: Organocatalysis / Michael addition / Ionic liquids / Supported catalysts / Sustainable chemistry
O-TMS-α,α-diphenyl-(S)-prolinol derivative bearing an ionic
liquid fragment was synthesized for the first time and proven
to be an efficient catalyst for the asymmetric Michael reac-
tion of aromatic α,β-unsaturated aldehydes with dialkyl mal-
onates. The prepared catalyst can be recovered four times
and used in the same reaction without a decrease in activity
or a decrease in the enantioselectivity of the reaction.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
nated catalyst could only be achieved by means of expensive
fluorinated silica gel.[11a] A weak point of a dendritic cata-
lyst is its sophisticated synthesis,[11b] and a polymer-sup-
ported catalyst becomes deactivated after the first regenera-
tion.[11c]
In this paper we report a synthesis of the first representa-
tive of a new family of recoverable prolinol-type organocat-
alysts modified with ionic liquid (IL) moieties. IL-sup-
ported α-amino acid derivatives with unmodified carboxylic
groups were applied earlier as recoverable organocatalysts
for asymmetric aldol reactions.[12] Yet, to the best of our
knowledge, this approach has never been used to regenerate
compounds with a prolinol unit.
Introduction
The organocatalytic asymmetric 1,4-conjugate addition
of nucleophilic reagents to electron-deficient alkenes is one
of the most powerful tools for the stereocontrolled forma-
tion of carbon–carbon and carbon–heteroatom bonds,[1]
which is widely applied for the synthesis of biologically
active compounds and natural products.[2] The reaction is
efficiently catalyzed by a number of organocatalysts in par-
ticular by (S)-proline,[3] imidazolidine,[4] and thiourea[5] de-
rivatives, and by some other chiral compounds.[1] α,α-Di-
arylprolinol silyl ethers are among the most active and
enantioselective catalysts.[6] Yet, these compounds synthe-
sized from proline in several synthetic steps[7,8] are usually
lost during the isolation of Michael adducts like a majority
of other organocatalysts. Therefore, the development of im-
mobilized versions of α,α-diarylprolinol ethers is an impor-
tant issue both from economical and from green chemistry
standpoints.
Recoverable organocatalysts bearing an (S)-proline unit
at the active site have been well documented and re-
viewed.[9] There are successful examples of supported proli-
nol-type catalysts with a free OH group mainly applied for
α,β-enone reductions.[10] Though only a few immobilized
catalysts containing prolinol silyl ether moieties to include
compounds modified with perfluoroalkyl,[11a] dendritic,[11b]
or polymeric[11c] groups have been reported so far. These
catalysts have certain drawbacks. The recovery of a fluori-
Results and Discussion
α,α-Diphenylprolinol derivatives 4a–c with an imid-
azolium cation and bromide or hexafluorophosphate
anions were synthesized by a sequence of reactions, which
includes the esterification of (3R,5S)-1-benzyl-5-(hydroxy-
diphenylmethyl)pyrrolidin-3-ol (1)[13] with 5-bromopenta-
noic acid in the presence of DCC/DMAP, alkylation of 1-
methylimidazole with bromoester 2, catalytic hydrogenation
of imidazolium salt 3, followed by the transformation of
bromide 4a into hexafluorophosphate 4b or its O-TMS de-
rivative 4c by anion metathesis and silylation reactions
(Scheme 1). Total yields of compounds 4a–c were 68–77%.
Prepared compounds 4a–c were examined in a reaction
of α,β-unsaturated aldehydes with dialkyl malonates, which
is used for synthesizing chiral biologically active com-
pounds.[14] It should be mentioned that the immobilized O-
TMS-α,α-diphenylprolinol derivatives were only applied as
catalysts for epoxidation reactions[11c] and for 1,4-addition
reactions between aldehydes and nitroalkenes[11a–11c] pro-
[a] Zelinsky Institute of Organic Chemistry, Russian Academy of
Sciences,
119991 Moscow, Russia
Fax: +7-499-135-5328
E-mail: zlotin@ioc.ac.ru
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900807.
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Eur. J. Org. Chem. 2009, 5134–5137

Recoverable Organocatalyst for Asymmetric Michael Reactions
Table 1. Catalysts screening in the reaction between dimethyl ma-
lonate 6a and trans-cinnamaldehyde (5a).[a]
Entry Catalyst
Solvent
Conversion[b]
[%]
Yield[c]
[%]
ee[d]
[%]
1
2
3
4[g]
5
4a
4b
4c
4c
4c
4c
EtOH
EtOH
EtOH
26
15
Ͼ99
47
96
80
–
–
–
–
93 (85[e], 90[f]) 96 (94[e], 96[f])
EtOH
–
92
73
–
92
92
H2O (50 equiv.)
neat
6
[a] Unless otherwise specified, all reactions were carried out with
trans-cinnamaldehyde (5a; 1 mmol), dimethyl malonate (6a;
0.5 mmol), and the solvent (0.5 mL) in the presence of the catalyst
(10 mol-%) at 4 °C for 24 h. [b] The conversion of 6a into 7a was
estimated by 1H NMR spectroscopy. [c] Isolated yield. [d] Deter-
mined by chiral HPLC analysis of the isolated product. [e] Yield
according to ref.[14] [f] Yield according to ref.[16] [g] The reaction
was carried out in the presence of 1 mol-% of 4c.
Scheme 1. Synthesis of α,α-diphenylprolinol derivatives 4a–c bear-
ing an ionic liquid fragment.
ceeding via the formation of enamine-type intermediates
comprised of a catalyst and an aldehyde donor[1c,15]
(Scheme 2, A).
Product 7a was obtained in aqueous media in 92% yield,
but the enantioselectivity appeared to be slightly lower
(92%ee; Table 1, Entry 5). In contrast to compound 4c,
α,α-diphenyl(or hexyl)-(S)-prolinol silyl ethers without IL
groups catalyzed this reaction in water only in the presence
of acidic additives,[8,16] which indicates an important role of
the IL moiety. Under neat conditions, product 7a was pre-
pared in as low as 73% yield after 24 h, whereas the
enantioselectivity remained at the same level (92%ee;
Table 1, Entry 6).
Scheme 2. Enamine A and iminium B intermediates in organocata-
lytic reactions of carbonyl compounds.
The most efficient procedure (4c: 10 mol-%, 96% EtOH,
The immobilized catalysts have never been employed in 4 °C) was applied in reactions of trans-cinnamaldehyde (5a)
reactions that involve iminium ion B formation from a chi- and its derivatives 5b–e bearing donor (i.e., 5d) or acceptor
ral catalyst and an aldehyde acceptor[15] Ϫ the reaction class (i.e., 5b,c,e) groups in the aromatic ring with dimethyl, di-
where unimmobilized prolinol ether organocatalysts exhibit ethyl, and dibenzyl malonates (i.e., 6a,b,c, respectively;
high efficacy.[6a,14,15d]
Table 2). In most cases, corresponding adducts 7a–j were
First of all, we examined compounds 4a–c in a reaction produced in yields (up to 98%) higher than those produced
of trans-cinnamaldehyde (5a) with dimethyl malonate (6a) in the presence of the known catalysts[8,14,16] and with com-
where unimmobilized α,α-diaryl-(S)-prolinol exhibited parable ee values (up to 96%ee). Furthermore, catalyst 4c
good activity and enantioselectivity.[14] The reactions were increased the yield (from 72 to 94%) and enantiomeric ex-
carried out in the presence of 1–10 mol-% of catalyst at 4 °C cess (from 86 to 96%ee) of fluorinated adduct 7j, which
for 24 h in 96% EtOH. It was found that in the presence of is the key intermediate for the synthesis of the prospective
compounds 4a and 4b with free hydroxy groups the yield antidepressant (–)-paroxetine, as compared with the re-
of adduct 7a did not exceed 26% (Table 1, Entries 1 and 2, ported data[14] (Table 2, Entry 10).
respectively), whereas in the presence of 4c, 93% yield was
The recoverability of catalyst 4c was studied in a reaction
attained along with 96%ee (Table 1, Entry 3). Remarkably, of 5a with 6a (Table 3). Upon completion of the reaction,
the unimmobilized analogue of compound 4c gave compar- EtOH was evaporated, the products were extracted with
able results only after a noticeably longer reaction time Et2O, and fresh portions of reagents 5a, 6a, and ethanol
(96 h).[14] By decreasing the loading of catalyst 4c to 1 mol- were added to the residue. The catalyst could be recovered
%, a lower conversion of 6a was observed (47%; Table 1, three times and used in the same reaction without any de-
Entry 4).
crease in its activity or decrease in the enantioselectivity of
We examined next a reaction between compounds 5a and the reaction. Yet, upon the fourth regeneration (fifth cycle),
6a in water and under neat conditions in the presence of the conversion after 24 h dropped down to 70%, and at the
catalyst 4c, which exhibited higher efficacy in 96% EtOH. sixth cycle it was necessary to extend the reaction time to
Eur. J. Org. Chem. 2009, 5134–5137
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O. V. Maltsev, A. S. Kucherenko, S. G. Zlotin
SHORT COMMUNICATION
Table 2. Enantioselective Michael reactions between dialkyl malonates 6a–c and substituted trans-cinnamaldehydes 5a–e catalyzed by
4c.[a]
Entry
R
R1
Time [d]
Product, yield[b] [%]
ee[c] [%]
1
2
3
Ph
Ph
Ph
Me
Et
1
2
3
2
3
3
2
3
2
3
7a, 93 (85[e], 90[f])
96 (94[e], 96[f])
7b, 98 (42[e])
95 (89[e])
Bn
Me
Bn
Bn
Me
Bn
Me
Bn
7c, 81 (80[e], 93[f], 77[g]
7d, 97
)
92 (91[e], 95[f], 96[g]
91
)
)
4
4-ClC6H4
4-ClC6H4
4-O2NC6H4
4-MeOC6H4
4-MeOC6H4
4-FC6H4
4-FC6H4
5
7e, 95 (85[e])
88 (86[e])
6[d]
7
7f, 97
82
7g, 97 (73[e], 81[f])
76 (90[e], 91[f])
89 (92[e], 96[f], 99[g]
92 (97[f])
8
9
10
7h, 98 (93[e], 88[f], 74[g]
7i, 95 (78[f])
)
7j, 94 (72[e])
96 (86[e])
[a] Unless otherwise specified, reactions were carried out by using substituted trans-cinnamaldehyde 5 (0.664 mmol), dialkyl malonate 6
(0.332 mmol), and EtOH (0.3 mL) in the presence of catalyst 4c (10 mol-%) at 4 °C. [b] Isolated yield. [c] Determined by chiral HPLC
analysis of the isolated product. [d] The reaction was carried out by using 0.6 mL of EtOH. [e] Yield according to ref.[14] [f] Yield according
to ref.[16] [g] Yield according to ref.[8]
96 h to reach the same conversion as that obtained in the formation, by modifying α,α-diarylprolinol silyl ethers with
fifth cycle. Despite the deactivation of the catalyst, the ionic liquid moieties. In the presence of synthesized catalyst
enantioselectivity of the reaction remained the same or ever 4c the reaction of dialkyl malonates 6a–c with trans-cinn-
slightly increased (up to 98%ee). Possibly, the catalyst deac- amaldehyde (5a) and its derivatives 5b–e proceeded under
tivation could be explained by its leaching into the organic mild conditions to afford the respective adducts in high
solvent (Et2O) or by its transformation into catalytically in- yields (up to 98%) and high enantioselectivities (up to
active or less-active compounds (e.g., into compound 4b 98%ee). Unlike the known prolinol-type catalysts, com-
through hydrolysis of the TMS group[11c]). We suppose that pound 4c could be used four times without any decrease
optimization of the catalyst structure (substituents in the in its activity or decrease in the enantioselectivity of the
pyrrolidine ring, IL cation and anion) would allow these reaction.
undesirable processes to be suppressed, which would extend
the catalytic system operation period.
Experimental Section
Table 3. Recycling of catalyst 4c in the asymmetric Michael reac-
tion between dimethyl malonate (6a) and trans-cinnamaldehyde
(5a).[a]
Cycle
General Procedure for the Michael Reactions: A mixture of catalyst
4a–c (0.03 mmol, 10 mol-%), α,β-unsaturated aldehyde 5a–e[17]
(0.66 mmol, 2 equiv.), dialkyl malonate 6a–c (0.33 mmol, 1 equiv.),
and 96% EtOH (0.3 mL) was stirred at 4 °C for the indicated time
(Table 2). The solvent was evaporated under reduced pressure; the
products were extracted with Et2O (2ϫ1 mL). The combined ex-
tract was evaporated under reduced pressure. Compounds 7 were
isolated by column chromatography (TLC monitoring by using 2,4-
diphenylhydrazine for visualization). If appropriate, the catalyst
was reused.
Time [h]
Conversion[b] [%]
ee[c] [%]
1
2
3
4
5
6
24
24
24
24
24
96
Ͼ99
Ͼ99
Ͼ99
96
70
70
95
94
94
95
98
98
[a] Unless otherwise specified, all reactions were carried out with
trans-cinnamaldehyde (5a; 0.332 mmol), dimethyl malonate (6a;
0.166 mmol), and EtOH (0.15 mL) at 4 °C in the presence of 4c
(10 mol-%). After the indicated time catalyst 4c was separated from
the products by the addition of ether (2ϫ1 mL) and reused. [b] The
Catalyst Recycling:
A solution of compounds 5a (88 mg,
0.66 mmol) and 6a (44 mg, 0.33 mmol) in 96% EtOH (0.3 mL) was
added to the catalyst, which remained after the extraction of prod-
uct 7a, and the reaction was carried out as described above.
1
conversion of 6a into 7a was estimated by H NMR spectroscopy.
[c] Determined by chiral HPLC analysis of the isolated product.
Supporting Information (see footnote on the first page of this arti-
cle): Synthetic procedures and analytical data of compounds 1–7.
Conclusions
Acknowledgments
In summary, we have proposed a new promising ap-
proach to the development of recoverable organocatalysts
We gratefully acknowledge financial support of the Russian Foun-
for asymmetric Michael reactions, involving iminium ion dation of Basic Research (grant No. 09-03-00384 and 09-03-12164).
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Eur. J. Org. Chem. 2009, 5134–5137

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Received: July 18, 2009
Published Online: September 11, 2009
Eur. J. Org. Chem. 2009, 5134–5137
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5137