Poly(methylhydrosiloxane)-supported chiral imidazolinones: New versatile, highly efficient and recyclable organocatalysts for stereoselective Diels-Alder cycloaddition reactions

Article abstract of DOI:10.1039/c2cc17919a

Poly(methylhydrosiloxane) (PMHS) supported organic catalysts promoted the Diels-Alder reaction of dienes with α,β-unsaturated aldehydes, also in pure water, in yields and enantiomeric excesses comparable to those observed with the non-supported catalysts

Full text of DOI:10.1039/c2cc17919a

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COMMUNICATION
Poly(methylhydrosiloxane)-supported chiral imidazolinones: new
versatile, highly efficient and recyclable organocatalysts for
stereoselective Diels–Alder cycloaddition reactionswz
a
a
b
Stefania Guizzetti, Maurizio Benaglia* and Jay S. Siegel*
Received 19th December 2011, Accepted 26th January 2012
DOI: 10.1039/c2cc17919a
Poly(methylhydrosiloxane) (PMHS) supported organic catalysts
promoted the Diels–Alder reaction of dienes with a,b-unsaturated
aldehydes, also in pure water, in yields and enantiomeric excesses
comparable to those observed with the non-supported catalysts
and insoluble in a few other solvents, like hexanes, thus allowing us
to run a catalyzed reaction under homogeneous conditions and to
isolate and recover the catalyst as if it were bound to an insoluble
polymer. PMHS is a well known, cheap, atoxic, widely used
7
(
up to 93% ee). Recycling of the catalysts was performed with no
reducing agent; however quite surprisingly its use as support for
loss of enantioselectivity for at least five reaction cycles.
the immobilization of chiral catalysts remained almost unexplored.
Only recently one of us reported the use of PMHS-anchored
cinchona alkaloid derivatives to obtain recyclable ligands for
Supporting catalysts and reagents on polymer backbones offer
8
the Sharpless dihydroxylation reaction.
several engineering advantages with respect to the goals of
1
‘Green’’ chemistry. In systems like grafted polyHDMS,
Here we describe for the first time the synthesis of PMHS-
supported chiral organic catalysts derived from MacMillan’s
imidazolidin-4-ones and a study of their behaviour in the
stereoselective Diels–Alder cycloaddition.
‘
where the final macromolecular properties strongly reflect the
nature of the grafts, one can anticipate control over solubility,
isolability and even stability through judicious tuning of graft
composition and proportion. In the area of ‘‘Organocatalysis’’,
these tailored macromolecules maintain low equivalent weight
and good solubility characteristic of lower molecular weight
The protonated phenylalanine-derived imidazolidinone 1
9
developed by MacMillan has found widespread use in a
number of relevant organocatalytic processes. Given its popularity,
it is not surprising that it has been covalently immobilized on
‘
‘homogenous’’ embodiments while providing easy catalyst
1
0–15
different supports.
confinement and recovery methods, which address separation,
2
recycling and waste management issues. In the present context,
Despite this variety of proposed solutions, however, the
development of an easily available, inexpensive, recyclable and
truly chemical and stereochemical efficient MacMillan catalyst
still has to be realized. Among the major drawbacks still to be
properly addressed and solved we can mention the lower
enantioselectivities with respect to that of the non-supported
system and the issue of the recyclability.
grafting of imidazolium based catalysts (ala MacMillan) to
polyHDMS produces catalysts with sustainable high-level
performance across a variety of conditions.
The immobilization of organocatalysts seems particularly
attractive, because these metal free systems obviate classical
3
leaching problems and lend themselves to batch or flow processes.
4
In principle, the immobilization of imidazolidin-4-ones such
as 1 (Fig. 1) can be performed using two different handles for
polymer attachment: the amide nitrogen at position 3, and the
aryl residue at the stereogenic centre; both of them were
explored as connecting points to PMHS in this work.y
Starting from (S)-tyrosine methyl ester hydrochloride,
imidazolidinone 2 was easily obtained in 77% overall yield by
N-butyl amide formation, treatment with acetone, and reaction
with allyl bromide in acetonitrile in the presence of Cs CO .
In this context the choice of the support plays a crucial role.
Polymers of discreet solubility can be extremely convenient because
they allow us to realize a ‘‘monophase’’ (that is, homogeneous)
5
,6
catalysis while still enjoying the advantage of biphase separations.
We have recently turned our attention to polymethylhydrosiloxane
PMHS) that presents several positive features such as low cost,
(
commercial availability, easy fuctionalization, and very favourable
solubility profile. Indeed, PMHS is soluble in many organic solvents
2
3
a
The introduction of the allyl double bond was instrumental to
Dipartimento di Chimica Organica e Industriale,
Universita` di Milano, via Venezian 21, 20133, Milano, Italy.
E-mail: Maurizio.Benaglia@unimi.it; Fax: +390250314159;
Tel: +390250314171
Organisch-Chemisches Institut, Universita¨t Zu¨rich,
Winterthurerstrasse 190, CH-8057 Zu¨rich, Switzerland.
b
E-mail: jss@oci.uzh.ch; Fax: +410446356888; Tel: +410446354281
w This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
z Electronic supplementary information (ESI) available. See DOI:
1
0.1039/c2cc17919a
Fig. 1 MacMillan catalyst.
3
188 Chem. Commun., 2012, 48, 3188–3190
This journal is c The Royal Society of Chemistry 2012

the isolated compounds; ees were obtained by HPLC analysis.
As can be seen from the reported data, roughly 50 : 50 mixtures
of endo and exo cycloadducts were typically obtained.
Preliminary experiments with PMHS-supported catalyst 5
showed that preformed salts gave better results than in situ
prepared catalysts.z The use of trifluoroacetic acid led to
chemically and stereochemically more efficient processes than
with HCl (see entries 3–4 vs entries 1–2 of Table 1). However in
a 95/5 MeOH/water mixture as reaction solvent best results
were obtained with HBF
4
salts. Under the best conditions
(
entry 6) the cycloadduct was isolated in 67% yield as a 52/48
mixture of exo and endo isomers, both having 91% ee. PMHS-
immobilized catalyst 3, derived from (S)-tyrosine, catalyzed the
Diels–Alder reaction with lower stereoselectivity.8 Noteworthily
tetrafluoroborate salt of PMHS-supported imidazolinone 5
performed well in different solvent systems, promoting the
cycloaddition in up to 93% enantioselectivity also in aqueous
dichloromethane or acetonitrile.
Scheme 1 Synthesis of PMHS-supported chiral imidazolinones.
The behavior of chiral imidazolinone 5 in aqueous reaction
media was further investigated (Table 2). It was discovered that the
perform catalyst immobilization by platinum catalyzed hydro-
silylation, a reaction that led to the isolation of the PMHS-
4
PMHS-supported HBF salt of 5 promoted the cycloaddition in
8
supported catalyst 3 in 90% yield (Scheme 1).
different methanol/water mixtures always with enantioselectivities
higher than 90%. Even at 25 1C the product was isolated in 87%
yield and 90% ee. The reaction in pure methanol proceeded
with a good stereoselectivity but definitely in lower yield (entry 7,
Table 2). With dichloromethane best results were observed with a
On the other hand the condensation of (S)-phenyl alanine
with allyl amine followed by reaction with acetone gave in
8
3% yield the imidazolinone 4 that was anchored to PMHS to
give 5. Conversion of these compounds to the catalytically
active species involved the addition of an equimolar amount of a
protic acid. In situ protonated supported catalysts and pre-formed
catalysts were both investigated and their behavior was compared.
The Diels–Alder cycloaddition of cyclopentadiene (5 mol equiv.)
with trans-cinnamaldehyde (1 mol equiv.) carried out in the
presence of 0.1 mol equiv. of various salts of 3 and 5 at different
temperatures was used to evaluate the performance of the
supported catalysts (Table 1). Yields were determined based
on the isolated products; endo/exo ratios were determined by
1/1 DCM/water mixture, when the two isomers of the cycloadduct
were isolated in 91% and 95% ee (entry 9, Table 2). Remarkably
PMHS-supported catalyst 5 promoted the Diels–Alder reaction in
pure water. In this medium, not only at 0 1C but even at room
4
temperature the use of HBF salt of 5 led to the formation of the
cycloadducts in almost quantitative yield and enantioselectivities
16
constantly higher than 90% (entries 10–11, Table 2).
In addition to facilitating the separation of the catalyst from
the reaction products, catalyst immobilization on a polymer
should allow simple recovery and recycling. In this work,
the separation of the catalyst was easily obtained by concen-
trating the reaction mixture under vacuum, dissolving
the residue in a very small amount of dichloromethane
1
H NMR analysis of the crude products and confirmed based on
Table 1 Enantioselective Diels–Alder reaction catalyzed by catalyst 5
ꢀ
1
(
2 mL g of catalyst), and adding hexanes to the mixture
Table 2 Enantioselective Diels–Alder cycloaddition promoted by
catalyst 5 in aqueous reaction medium
exo ee
Yield exo/endo (endo ee)
exo ee
Yield exo/endo (endo ee)
b
c
d
b
c
a
Entry Acid
a
Entry Acid Solvent
Solvent
(%)
(%)
(%)
(%)
(%)
(%)
e
1
2
3
4
5
6
7
8
9
1
1
HCl
HCl
TFA
TFA
TFA
HBF
95 : 5 MeOH : H
neat
95 : 5 MeOH : H
neat
neat
2
O
O
51
67
85
98
48
48/52
51/49
52/48
52/48
52/48
52/48
52/48
52/48
58/42
48/52
55/45
55 (45)
51 (23)
84 (80)
83 (82)
86 (83)
91 (91)
84 (82)
80 (79)
61 (61)
91 (93)
92 (93)
1
2
3
4
5
6
7
8
9
HBF
4
95 : 5 MeOH : H
neat (+7 equiv. H
95 : 5 MeOH : H
2
95 : 5 MeOH : H O
2
O
2
O) 43
O
67
52/48
55/45
53/47
55/45
53/47
52/48
53/47
52/48
50/50
52/48
52/48
91 (91)
77 (76)
90 (89)
93 (93)
91 (91)
91 (91)
90 (91)
83 (71)
91 (95)
92 (91)
91 (90)
e
e
e
HBF
HBF
HBF
4
4
d
e
2
2
87
41
68
81
31
15
65
95
98
4
HBF
HBF
HBF
HBF
4
4
4
4
85 : 15 MeOH : H
65 : 35 MeOH : H
MeOH
2
O
O
4
2
95 : 5 MeOH : H O 67
2
CH
CF
HBF
3
SO
3
H 95 : 5 MeOH : H
2
O
O
31
45
33
3
SO
3
H 95 : 5 MeOH : H
neat
2
95 : 5 DCM : H
2
O
4
HBF
HBF
HBF
4
4
4
50 : 50 DCM : H O
2
0
1
HBF
HBF
4
85 : 15 DCM : H
2
O 45
CN : H O 65
10
11
H
H
2
O
O
d
4
95 : 5 CH
3
2
2
a
b
a
b
Reaction run at 0 1C. Yields determined after chromatographic
purification. Diastereoisomeric ration determined by NMR on the crude
Reaction run at 0 1C. Yields determined after chromatographic
purification; diastereoisomeric ration determined by NMR on the
c
d
reaction mixture. Enantiomeric excess determined by HPLC on the
c
crude reaction mixture. Enantiomeric excess determined by HPLC.
d
e
e
alcohols obtained by NaBH
4
reduction of adducts. Reaction run at 25 1C.
Reaction run at 25 1C. Reaction run at ꢀ20 1C.
This journal is c The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 3188–3190 3189

Table 3 Recycle of the HBF
4
salt of PMHS-supported catalyst 5
exo ee
d
di molecole funzionali’’; JSS thanks the Swiss National Fund
for financial support.
b
c
Recycles
Yield exo/endo (endo ee)
a
Entry nr.
Notes and references
Solvent
(%)
(%)
(%)
n
y Commercial PMHS is available from Aldrich with M = 1900–3200.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
2
3
4
1
2
3
1
2
3
4
5
6
H
H
H
H
2
2
2
2
O
O
O
O
95
90
65
21
65
61
18
O 65
O 60
O 58
O 60
O 55
O 53
52/48
52/48
52/48
52/48
50/50
50/50
50/50
55/45
52/48
52/48
52/48
52/48
52/48
92 (91)
91 (91)
81 (80)
z Typically the Diels–Alder cycloadditions run in the presence of an
in situ generated salt led to the products in lower yields and enantio-
selectivities 10–20% lower than the corresponding reactions promoted
by a preformed salt.
n.d. (n.d.)
91 (95)
91 (93)
86 (87)
92 (93)
90 (92)
90 (91)
90 (91)
90 (93)
90 (91)
50 : 50 DCM : H
50 : 50 DCM : H
50 : 50 DCM : H
95 : 5 CH
95 : 5 CH
95 : 5 CH
95 : 5 CH
95 : 5 CH
95 : 5 CH
2
2
2
O
O
O
8
For example the cycloaddition promoted by HBF
4
salt of 3 in the
9
5/5 MeOH/H O mixture at 0 1C led to the formation of the product
2
in 38% yield, 55/45 exo/endo ratio, 81% ee for the exo isomer and 72%
ee for the endo isomer.
3
3
3
3
3
3
CN : H
2
2
2
2
2
2
CN : H
CN : H
CN : H
CN : H
CN : H
*
* In very preliminary experiments PMHS-supported catalyst 5
0
1
2
3
showed to be able to efficiently catalyze the enantioselective reduction
of b-methyl cynnamic aldehyde with Hantzsch ester; the results will be
reported in due course.
a
b
1 P. T. Anastas and J. C. Warner, Green Chemistry: Theory and Practice,
Oxford University Press, New York, 1998; See: P. T. Anastas, Green
Chemistry Textbook, Oxford University Press, New York, 2004.
Reaction run at 0 1C. Yields determined after chromatographic
purification. Diastereoisomeric ration determined by NMR on the
c
d
crude reaction mixture. Enantiomeric excess determined by HPLC.
2
Handbook of Asymmetric Heterogeneous Catalysts, eds. K. J. Ding
and F. J. K. Uozomi, Wiley-VCH, Weinheim, 2008; M. Benaglia,
Recoverable and Recyclable Catalysts, ed. M. Benaglia, John Wiley
and Sons, 2009; N. Haraguchi and S. Itsuno, Polymeric Chiral Catalyst
Design and Chiral Polymer Synthesis, John Wiley & Sons, 2011.
Review: A. F. Trindade and C. A. M. Afonso, Chem. Rev., 2009,
109, 3401–3429.
(50 mL of hexanes per mL of dichloromethane). The precipitated
PMHS-supported catalyst was then isolated by centrifugation and
filtration in 85–95% yield and the organic phase was worked-up
to obtain the products. The recovered catalyst was then shortly
3
4
5
17
M. Benaglia, A. Puglisi and F. Cozzi, Chem. Rev., 2003, 103,
3401–3429. See also F. Cozzi, Adv. Synth. Catal., 2006, 348, 1367–1390.
dried under vacuum to remove traces of solvent and recycled.
The methodology afforded remarkable results both as
chemical yield and stereocontrol in water; therefore the recycle
of 5 in water was studied at first. However already in the third
run the catalytic systems showed a diminished chemical efficiency
M. Benaglia, Recoverable organic catalysts, in Recoverable and
Recyclable Catalysts, ed. M. Benaglia, John Wiley and Sons, 2009.
6 M. Benaglia, New J. Chem., 2006, 30, 1525–1533.
7
For a review on PMHS see: N. J. Lawrence, M. D. Drew and
S. M. Bushell, J. Chem. Soc., Perkin Trans. 1, 1999, 3381–3391. For
recent contributions see J. Gajewy, J. Gawronski and M. Kwit,
Org. Biomol. Chem., 2011, 9, 3863–3870 and references cited.
M. S. DeClue and J. S. Siegel, Org. Biomol. Chem., 2004, 2, 2287–2298.
K. A. Ahrendt, C. J. Borths and D. W. C. MacMillan, J. Am.
Chem. Soc., 2000, 122, 4243–4244. For a review see: G. Lelais and
D. W. C. MacMillan, Aldrichimica Acta, 2006, 39, 79–92.
18
that decreased dramatically in the third recycle. The same trend
was observed working in aqueous dichloromethane (entries 5–7).
Gratifyingly we found that a 95/5 acetonitrile/water mixture
was the ideal solvent system to guarantee the recycle of the
PMHS-supported catalyst. The tetrafluoroborate salt of 5 was
reused five times with only marginal loss of chemical activity
8
9
10 M. Benaglia, G. Celentano, M. Cinquini, A. Puglisi and F. Cozzi, Adv.
Synth. Catal., 2002, 344, 149–152. See also: M. Benaglia, G. Celentano,
M. Cinquini, A. Puglisi and F. Cozzi, Eur. J. Org. Chem., 2004, 567–573.
(
yield from 65% to 53%) and with no appreciable decrease of
stereo and enantiocontrol, affording both exo and endo isomers
with enantioselectivity always higher than 90%. The PMHS-
supported MacMillan catalyst 5 favorably compares to other
immobilized imidazolinones, for which the recycle was realized
1
¨ ¨
1 S. A. Selkala, J. Tois, P. M. Pihko and A. M. P. Koskinen,
Adv. Synth. Catal., 2002, 344, 941–945.
12 T. Mitsudome, K. Nose, T. Mizugaki, K. Jitsukawa and
K. Kaneda, Tetrahedron Lett., 2008, 49, 5464–5467.
3 Y. Zhang, L. Zhao, S. S. Lee and J. Y. Ying, Adv. Synth. Catal.,
006, 348, 2027–2031.
1
1
0–13
only on two or three reruns
or the observed enantio-
2
selectivities were lower than those obtained with the non-
1
supported MacMillan catalyst (Table 3).
14 H. Hagiwara, T. Kuroda, T. Hoshi and T. Suzuki, Adv. Synth.
Catal., 2010, 352, 909–916.
4,15
1
5 J. Y. Shi, C. A. Wang, Z. J. Li, Q. Wang, Y. Zhang and W. Wang,
Chem.–Eur. J., 2011, 17, 6206–6213.
In conclusion, it was shown that catalysts derived from PMHS-
supported imidazolidinone 5 and different acids can be conveni-
ently employed to promote Diels–Alder cycloadditions of
a,b–unsaturated aldehydes with cyclopentadiene. The supported
catalysts behaved very similarly to their non-supported counter-
parts in terms of enantioselectivity.** The immobilization on the
polymer greatly simplified the catalyst recovery. Recycling experi-
ments showed that the supported catalyst maintains its stereo-
chemical efficiency for up to five reaction cycles. The use of
poly(methyl-hydrosiloxane) as support for the development of
recyclable organic catalysts opens interesting perspectives and
intriguing possibilities; for example since it is possible to synthesize
multifunctional polymers bearing two different organic residues, it
could be possible in principle to design novel materials and fine
1
6 While we were working on the manuscript another group described
the use of a supported catalyst in water (see ref. 15). However with
that silica gel-supported MacMillan catalyst enantioselectivities
between 62% and 81% were typically observed.
1
7 Different from the Diels–Alder cycloadditions promoted by PEG-
10
supported catalysts in which recycling was more efficient if the
recycled catalyst was treated in situ with a fresh equimolecular
amount of acid before adding the reagents, acid addition resulted
in lower yields and stereoselection when applied to the PMHS-
anchored imidazolinones.
18 Any attempt to maintain the chemical efficiency was unsuccessful;
for example the addition of a further equivalent of HBF to the
4
recovered catalyst allowed the authors to recycle 5 three times, with
erosion of chemical yield (from 98% to 68%) and of stereo-
selectivity (from 91% ee to 77% ee for the exo isomer).
19 For the synthesis of bifunctional polymers resulting in different
and tunable physico-chemical properties see ref. 8. The synthesis of
bifunctional PMHS, bearing a chiral imidazolinone and a second
organic moiety able to modify the solubility of the polymeric
material is already under active investigation in our group.
19
tuning the properties of the polymer-supported chiral catalyst.
MB thanks MIUR (Rome) within the national project
‘Nuovi metodi catalitici stereoselettivi e sintesi stereoselettiva
‘
3
190 Chem. Commun., 2012, 48, 3188–3190
This journal is c The Royal Society of Chemistry 2012