Ionic polymer-supported O-trimethylsilyl-α,α-diphenyl-(S)- prolinols as recoverable organocatalysts for the asymmetric Michael reactions of carbon acids with α,β-enals

Article abstract of DOI:10.1016/j.mencom.2011.04.011

A recyclable organocatalyst bearing O-trimethylsilyl-α,α- diphenyl-(S)-prolinol unit tagged to the imidazolium cation and poly(4-styrenesulfonate) anion in the reaction of CH-acids with α,β-enals provided the respective Michael adducts in high yields (up

Full text of DOI:10.1016/j.mencom.2011.04.011

Mendeleev
Communications
Mendeleev Commun., 2011, 21, 146–148
Ionic polymer-supported O-trimethylsilyl-a,a-diphenyl-(S)-
prolinols as recoverable organocatalysts for the asymmetric
Michael reactions of carbon acids with a,b-enals
Oleg V. Maltsev,a,b Alexander S. Kucherenkoa and Sergei G. Zlotin*a
a N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 495 135 5328; e-mail: zlotin@ioc.ac.ru
b D. I. Mendeleev University of Chemical Technology of Russia, 125047 Moscow, Russian Federation
DOI: 10.1016/j.mencom.2011.04.011
A recyclable organocatalyst bearing O-trimethylsilyl-a,a-diphenyl-(S)-prolinol unit tagged to the imidazolium cation and poly(4-styrene-
sulfonate) anion in the reaction of CH-acids with a,b-enals provided the respective Michael adducts in high yields (up to 99%) and
with high enantioselectivities (up to 98% ee).
O-Trimethylsilyl-protected a,a-diarylprolinols (O-TMS-a,a-diaryl-
prolinols) and their derivatives are widely applied as chiral organo-
catalysts in asymmetric reactions of carbonyl compounds,1 in par-
ticular, on the key steps of the synthesis of some natural products
and medicines.2(a),(b) However, the industrial application of these
catalysts as well as of a majority of other modern organocatalysts
having rather complicated structure requires developing their
recyclable immobilized versions.3,4(a)–(c) A few immobilization
strategies by tagging O-TMS-a,a-diarylprolinol unit to poly-
mer,5(a)–(e) dendritic,6 perfluoroalkyl,7 paramagnetic8 or ionic
groups9(a)−(e) have been developed so far. The latter one is advan-
tageous since it allows tuning catalyst properties by varying the
cation and/or anion structure and monitoring the catalyst syn-
thesis by NMR spectroscopy.Yet, some O-TMS-a,a-diarylprolinol
derivatives bearing ionic groups9(c) are moderately soluble in
organic solvents and partly can be washed out during work-up.10
The catalysts containing PF6− anion are poorer soluble in organic
phase, however, they are less resistant to moisture for their sus-
ceptibility to release the fluoride anion,11(a),(b) which promotes
hydrolysis of the O–Si bond.
We assumed that the modification of the ionic catalyst with
an ionic polymer (polyelectrolyte) as a support or a counter-ion
would diminish the influence of these unfavorable factors. To
verify this hypothesis, we prepared the systems A and B by the
reactions of O-TMS-a,a-diphenyl-(S)-prolinols 1 or 29(a)–(c) with
available poly(diallyldimethylammonium hexafluorophosphate) 3
or poly(sodium 4-styrenesulfonate) 4 (Scheme 1). We supposed
that in the system A the catalyst 2 would be linked with the ionic
polymer 3 by ion–ion interaction forces because a similar system
(S)-proline/polyelectrolyte 3 [one molecule of (S)-proline per two
monomer units of the polyelectrolyte 3] can be easily recovered
and retains its activity for several cycles in the asymmetric aldol
reaction.12 The catalyst B, in which the ions incorporated into a
chiral inductor (the imidazolium cation) and into a polyelectro-
lyte chain (the sulfonate anion) have opposite charges, should
be even more robust. The imidazolium13 and quinuclidinium14
PF6
PF6
N
PF6
PF6
n
O
N
N
N
N
N
Me
Me Me Me Me
Me Me Me Me
O
O
4
3
Ph
N
N
PF6
Me
MeOH, 15 min
100%
O
4
Ph
N
Ph
Ph
H
OTMS
PF6
N
2
H
OTMS
n
A
see ref. 9(a)
i, Me3SiCl, Et3N, CH2Cl2,
room temperature, 18 h
O
ii, poly(sodium 4-styrenesulfonate) 4,
H2O, room temperature, 10 min
N
N
Me
O
4
O
SO3
Ph
Ph
65% overall
N
N
Br
Me
O
4
N
Ph
H
OH
Ph
OTMS
1
N
H
n
B
Scheme 1
© 2011 Mendeleev Communications. All rights reserved.
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Mendeleev Commun., 2011, 21, 146–148
Table 1 The regeneration of ionic catalysts 2, A and B in the reaction of
solvent for this reaction.‡,9(b) After reaction completion (TLC-
monitoring) MeOH was evaporated, the product was extracted
with Et2O, fresh portions of reactants 5a and 6a were added to
the recovered catalyst A or B, and the reaction was re-performed.
The activity and recoverability of supported catalyst A appeared
to be similar to that of hexafluorophosphate 2, but the enantio-
selectivity was somewhat lower (Table 1, entries 1 and 2). The
best results were achieved in the reactions catalyzed by the poly-
styrene system B containing moisture-resistant sulfated polymeric
anions, in which conversions and enantioselectivities remained
extremely high at least for four reaction cycles (Table 1, entry 3).
Moreover, the poorly soluble in organic phase catalyst B was
hardly ‘washed-out’ during the product extraction: the loss of
its mass over five cycles was less than 5% [for compound 2,
~20%9(b)]. However, after the fourth regeneration a gradual de-
activation of the system B was observed, which is characteristic
of all O-TMS-prolinol-type organocatalysts.
Next, we examined the catalytic properties of polyelectrolyte
B (10 mol%) in the asymmetric Michael reactions of trans-cin-
namaldehyde derivatives 5 with various carbon acids 6 (nitro-
methane 6a, dimethyl malonate 6b, and dibenzyl malonate 6c) in
96% aqueous MeOH. In all cases respective enantiomers of Michael
adducts [(S)- for 7a–e and (R)- for 7f–h] were obtained, yields
and ee values of the products were comparable with or even higher
than those attained with the use of PF6-containing catalyst 29(a),(b)
(Table 2). The synthesized compounds 7a, 7b, 7e, and 7f (or 7g) are
the intermediates for the preparation of chiral medicines Phenibut,9(b)
Baclofen,15(a),(b) Rolipram,15(c) and Paroxetin,16(a),(b) respectively.
Unlike other organocatalysts bearing ionic groups,9(a),(b) the catalyst
B remains solid (does not ‘liquify’) during the recovery and does
not contain moisture-sensitive and corrosion-dangerous fluorinated
anions, which would be undesirable in neoteric organocatalytic
technologies for the preparation of chiral medications.
trans-cinnamaldehyde 5a with nitromethane 6a.a
NO2
CHO
CHO
Catalyst (10 mol%)
+
MeNO2
96% aqeous MeOH,
20 °C, 24 h
5a
6a
7a
eec (%) (cycle)
Entry
1d
Catalyst
Conversionb (%) (cycle)
29(a)
100 (1); 100 (2); 100 (3);
89 (4); 70 (5)
95 (1); 94 (2); 94 (3);
94 (4); 94 (5)
2
3
A
B
100 (1); 100 (2); 100 (3);
95 (4); 74 (5)
100 (1); 100 (2); 100 (3);
100 (4); 80 (5)
92 (1); 92 (2); 92 (3);
92 (4); 92 (5)
95 (1); 96 (2); 95 (3);
95 (4); 94 (5)
aAll reactions were carried out using trans-cinnamaldehyde 5a (26 mg,
0.2 mmol) and nitromethane 6a (37 mg, 0.6 mmol) in 96% aqueous MeOH
(0.4 ml) in the presence of the indicated catalyst (10 mol% per monomer) at
room temperature for 24 h. bEstimated by 1H NMR. cEstimated by a chiral
HPLC. dAccording to ref. 9(b).
salts with the poly(4-styrenesulfonate) anions have been prepared
recently, however, O-TMS-a,a-diarylprolinol derivatives modified
with polyelectrolytes have not been reported so far.
The system A was prepared by mixing of hexafluorophos-
phate 2 with polyelectrolyte 3 in MeOH followed by the solvent
evaporation. The catalyst B was synthesized by the reaction
sequence including the silylation of the hydroxy group in com-
pound 1 and bromide-anion exchange with poly(sodium 4-styrene-
sulfonate) 4.†
We examined the systems A and B in the asymmetric Michael
reaction between trans-cinnamaldehyde 5a and nitromethane 6a
in 96% aqueous MeOH which is known to be the most efficient
†
NMR spectra were recorded in DMSO-d6 solutions on a BrukerAM300
Preparation of polyelectrolyte B. Chlorotrimethylsilane (326 mg, 384 ml,
3 mmol) was added dropwise to a solution of 3-{5-[(3R,5S)-5-(hydroxy-
phenylmethyl)pyrrolidin-3-yloxy]-5-oxopentyl}-1-methyl-1H-imidazol-
3-ium bromide 19(a) (772 mg, 1.5 mmol) and Et3N (455 mg, 606 ml, 4.5 mmol)
in CH2Cl2 (5 ml) at 4°C. The reaction mixture was stirred at room tem-
perature for 15 h. The solvent was removed in vacuo (15 Torr) and the
residue was dissolved in water (10 ml). To the obtained aqueous solution,
a solution of poly(sodium 4-styrenesulfonate) 4 (619 mg, 3 mmol per
monomer) in water (15 ml) was added dropwise with stirring. After 5 min,
the water phase was decanted, the remaining oil was dissolved in CH2Cl2
(50 ml), washed with distilled water (2×10 ml) and dried over anhydrous
Na2SO4. The solvent was evaporated in vacuo (15 Torr) and the residue
was dried under reduced pressure (2 Torr) at 35°C to afford 671 mg (65%)
of catalyst B as a reddish solid. According to NMR data, the polyelec-
trolyte B contained one imidazolium cation unit per one sulfated poly-
styrene anion unit. 1H NMR (25°C) d: –0.14 (s, 9H, SiMe3), 1.43 (m, 3H,
4-H, CH2CH2CH2COO), 1.74 [m, 3H, 4-H, CH2(CH2)2COO], 2.28 (m,
2H, CH2COO), 2.56 (m, 2H, ArCHCH2), 2.88 (m, 3H, 2-H, ArCHCH2),
3.70 (s, 3H, Me), 4.11 (m, 1H, NCH2), 4.33 (m, 1H, 5-H), 4.79 (m, 1H,
3-H), 7.13–7.38 (m, 12H, HPh, NCHCHN, HAr), 7.44 (m, 2H, HPh), 7.67
(m, 2H, HPh), 9.12 (s, 1H, NCHN). 13C NMR (25°C) d: 2.4, 20.8, 28.7,
32.8, 33.9, 35.5, 41.2, 48.2, 52.8, 54.9, 62.5, 74.7, 82.2, 122.1, 123.5, 126.6,
127.4, 127.6, 127.8, 136.6, 145.5, 146.1, 172.3. Found (%): C, 64.51; H, 6.74,
N, 6.25. Calc. for C37H47N3O6SSi (689.94) (%): C, 64.41; H, 6.87, N, 6.09.
spectrometer (300 MHz for 1H, 75 MHz for 13C, 282 MHz for 19F,
121 MHz for 31P). HPLC was performed on a Stayer chromatograph
equipped with an UV detector using a DAICEL Chiralpak® AD–H column.
Silica gel 0.035–0.070 (Acros) was used for a column chromatography.
4-Chloro- (5b), 4-nitro- (5c), 4-methoxy- (5d), 4-fluoro- (5f) (E)-cinnam-
aldehydes17 and 3-cyclopentyloxy-4-methoxy-(E)-cinnamaldehyde (5e)15(c)
were prepared according to the literature procedures. Poly(diallyldimethyl-
ammonium hexafluorophosphate) 3 was prepared from commercially
available poly(diallyldimethylammonium chloride) (Aldrich, average
MW 400000–500000, CAS26062-79-3).12 (E)-Cinnamaldehyde and poly-
(sodium 4-styrenesulfonate) 4 (Acros, average MW 70000, CAS25704-18-1)
were obtained from commercial sources and used without further puri-
fication.
Preparation of supported catalyst A. A mixture of poly(diallyl-
dimethylammonium hexafluorophosphate) 3 (38 mg, 0.14 mmol per
monomer), 3-(5-{(3R,5S)-5-[diphenyl(trimethylsilyloxy)methyl]pyrro-
lidin-3-yloxy}-5-oxopentyl)-1-methyl-1H-imidazol-3-ium hexafluoro-
phosphate 29(a) (46 mg, 0.07 mmol), and methanol (5 ml) was stirred at
room temperature for 30 min. The solvent was removed in vacuo (15 Torr)
and the residue was dried under reduced pressure (2 Torr) at 35°C to afford
84 mg (100%) of catalyst A. According to NMR data, the system A con-
tained one molecule of compound 2 per two monomer units of polyelec-
trolyte 3. 1H NMR (28°C) d: –0.11 (s, 9H, SiMe3), 1.26 [m, 14H, 4-H,
(CH2)2CH2COO, MeN+CH2CHCH2], 1.77 (m, 4H, MeN+CH2CHCH2),
2.30 (m, 2H, CH2COO), 2.87 (m, 2H, 2-H), 3.08 (s, 12H, MeN+CH2CHCH2),
3.72 (s, 8H, MeN+CH2CHCH2), 3.85 (s, 3H, Me), 4.16 (m, 1H, NCH2),
4.30 (m, 1H, 5-H), 4.80 (m, 1H, 3-H), 7.25 (m, 8H, HPh, NCHCHN), 7.44
(m, 2H, HPh), 7.69 (d, 2H, HPh, J 13.2 Hz), 9.06 (s, 1H, NCHN). 13C NMR
(28°C) d: 2.3, 20.8, 26.3–26.6 (polymer), 28.7, 32.7, 34.0, 35.7, 37.3–37.9
(polymer), 48.4, 51.4–54.8 (polymer), 52.7, 62.6, 69.2–69.6 (polymer),
74.6, 82.2, 122.2, 123.6, 126.5, 126.7, 127.4, 127.7, 127.8, 136.5, 145.4,
147.0, 172.3. 19F NMR (28°C) d: –70.8 (d, J 710 Hz). 31P NMR (28°C)
d: –143.3 (hept., J 710 Hz). Found (%): C, 45.59; H, 6.00; N, 5.63. Calc.
for C45H72F18N5O3P3Si (1194.06) (%): C, 45.26; H, 6.08, N, 5.87.
‡
Michael reaction and recycling procedure. A mixture of a,b-enal 5,
CH-acid 6, catalyst B (10 mol% per monomer), and 96% aqueous MeOH
was stirred for the indicated time at the indicated temperature (Table 2).
The solvent was evaporated under reduced pressure (15 Torr) and the
Michael adduct was extracted with Et2O (2×1 ml). The combined organic
extracts were concentrated in vacuo and purified by column chromato-
graphy using a mixture EtOAc/n-hexane (1:5–1:2) as an eluent. If appro-
priate, the catalyst that remained after the extraction of the product with
Et2O was reused by adding fresh portions of the reagents and the solvent.
All analytical data of the prepared compounds 7 were identical to the
reported ones.9(a),(b)
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Mendeleev Commun., 2011, 21, 146–148
Table 2 The reactions of a,b-enals 5 with carbon acids 6 in the presence
of polyelectrolyte B.a
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R4
R3
CHO
CHO
Catalyst B
(10 mol%)
R3
R2
R2
+
96% aqueous
MeOH
R4
R1
R1
5
6
7a–h
a R1 = R2 = R3 = H, R4 = NO2
b R1 = Cl, R2 = R3 = H, R4 = NO2
c R1 = NO2, R2 = R3 = H, R4 = NO2
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e R1 = MeO, R2 = cyclo-C5H9O, R3 = H, R4 = NO2
f R1 = F, R2 = H, R3 = R4 = COOBn
g R1 = F, R2 = H, R3 = R4 = COOMe
h R1 = R2 = H, R3 = R4 = COOMe
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Product Time/h
Yieldb (lit.,9(b)) (%)
eec (lit.9(b)) (%)
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1
2
3
4
7a
7b
7c
7d
7e
7f
24
24
24
48
24
48
48
48
83 (84)
90 (91)
68 (64)
72 (87)
76 (80)
94 (93)
93 (95)
99 (93)
95 (94)
91 (90)
98 (93)
92 (93)
91 (90)
87 (96)
92 (92)
93 (96)
5
6d
7d
8d
7g
7h
aUnless otherwise specified, all reactions were carried out using aldehydes 5
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(1 ml) in the presence of catalyst B (34 mg, 0.05 mmol per monomer) at
20°C for the indicated time. bIsolated yield. cEstimated by a chiral HPLC.
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In conclusion, we have synthesized for the first time O-TMS-
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polyelectrolyte units and evaluated their efficacy as recoverable
organocatalysts in the asymmetric Michael reactions between
a,b-enals and carbon acids. In the presence of ionic catalyst B
bearing the sulfated polystyrene anions, the reactions afforded
the corresponding Michael adducts in high yields (up to 99%)
and with high enantioselectivity (up to 98% ee) which retained
over 4 cycles. The advantages of developed catalyst B are its
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This work was supported by the Ministry of Education and Science
of the Russian Federation (contract no. 02.740.11.0630) and by the
Russian Foundation of Basic Research (grant no. 09-03-00384).
Received: 31st January 2011; Com. 11/3679
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