Poly(ethylene glycol)-Supported Chiral Imidazolidin-4-one: An Efficient Organic Catalyst for the Enantioselective Diels-Alder Cycloaddition

Article abstract of DOI:10.1002/1615-4169(200202)344:2<149::AID-ADSC149>3.0.CO;2-U

A tyrosine-derived imidazolidin-4-one was immobilized on a modified poly(ethylene glycol) and converted in situ into a soluble polymer-supported catalyst for the enantioselective Diels-Alder cycloaddition of acrolein to 1,3-cyclohexadiene (up to 92% ee) a

Full text of DOI:10.1002/1615-4169(200202)344:2<149::AID-ADSC149>3.0.CO;2-U

COMMUNICATIONS
Poly(ethylene glycol)-Supported Chiral Imidazolidin-4-one: An
Efficient Organic Catalyst for the Enantioselective Diels Alder
Cycloaddition
Maurizio Benaglia,*,a Giuseppe Celentano,b Mauro Cinquini,a Alessandra Puglisi,a
Franco Cozzi*,a
a
¡
Centro CNR and Dipartimento di Chimica Organica e Industriale, Universita degli Studi di Milano, via Golgi 19, 20133
Milano, Italy
Fax: ( ‡ 39)-02-50314159, e-mail: Franco.Cozzi@unimi.it
b
¡
¡
Istituto di Chimica Organica, Facola di Farmacia, Universita degli Studi di Milano, via Venezian 21, 20133 Milano, Italy
Received: October 11, 2001; Accepted: February 5, 2002
imidazolidin-4-one on a derivative of PEG5000 mono-
methyl ether afforded an efficient and recyclable
catalyst for the enantioselective Diels Alder cycloaddi-
tion.[8]
Abstract: A tyrosine-derived imidazolidin-4-one was
immobilized on a modified poly(ethylene glycol)
and converted in situ into a soluble polymer-
supported catalyst for the enantioselective Diels
Alder cycloaddition of acrolein to 1,3-cyclohexa-
diene (up to 92% ee) and 2,3-dimethyl-1,3-butadiene
(73% ee). Catalyst recycling (up to four cycles) was
accompanied by some loss of the chemical efficiency
and marginal erosion of the enantioselectivity.
Bu-n
O
OH
N
Me
a, b
Me
N
Cl-H3+N
COOMe
H
Keywords: asymmetric catalysis; catalyst immobili-
zation; chiral organic catalysts; Diels Alder cyclo-
additions; soluble polymers.
(S)-1
OH
O
OMs
c
2
O
N
O
O
The immobilization of chiral catalysts on polymer
matrixes has recently emerged as a practical method
which allows easy recovery and recycling of often
expensive catalysts while facilitating product isolation
and purification.[1] In this context, readily functionalized
poly(ethylene glycol)s (PEGs) of Mw > 2000 Da offer
distinctive advantages over other polymers. These
supports, being soluble in many organic solvents and
in water and insoluble in a few other solvents,[2] allow us
to run a catalyzed reaction under homogeneous (and
likely best performing) conditions and to isolate and
recover the catalyst as if it were bound to an insoluble
polymer.[3]
Bu-n
N
H
3
Me
Me
d
H
+
+
CHO
O
CHO
exo-4
CHO
endo-4
Me
Me
Me
e
H
+
O
Me
5
While immobilization of chiral ligands on PEGs has
been reported,[1,3a,4] the synthesis of PEG-supported
catalysts has been much less studied.[1,3b] Chiral organic
(i.e., metal-free) catalysts[5] seem particularly attractive
for supporting on polymer, since they cannot suffer from
metal leaching upon recycling, a major drawback
associated with the use of polymer-bound, metal-based
catalysts.[6] As a part of a project devoted to the
development of PEG-supported organic catalysts,[7] we
= MeO-(CH2CH2O)n-CH2CH2, n = ca. 110.
Reagents and conditions:
a: n-BuNH2 (4 mol equiv), EtOH, RT, 20 h
b: Me2CO (excess), MeOH, cat. PTSA, 60 °C, 20 h;
c: 2 (0.8 mol equiv), Cs2CO3 (3 mol equiv), DMF, 60 °C, 24 h
d: 3/HX (0.1 mol equiv; X = Cl, CF3COO, CF3SO3), CH3CN/H2O, 95/5, 24 °C
e: 3/TFA (0.1 mol equiv), CH3CN/H2O, 95/5, 24 °C
Scheme 1. Synthesis of PEG-supported catalyst precursor 3
now report that immobilization of an enantiopure and enantioselective Diels Alder cycloadditions.
Adv. Synth. Catal. 2002, 344, No. 2
¹ VCH Verlagsgesellschaft mbH, D-69451 Weinheim, 2002 1615-4150/02/34402-149 152 $ 17.50+.50/0
149

Maurizio Benaglia, et al
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Starting from (S)-tyrosine methyl ester hydrochlor-
The efficiency of the non-supported catalyst was
ide, imidazolidin-4-one 1 was easily obtained[8a] in 58% preliminarily established (entries 1 3). Best results
yield (Scheme 1). Reaction of the Cs salt of (S)-1 were obtained using the trifluoroacetate salt of 1-
(1.25 mol-equiv) with the readily available mesylate 2[9] OMe, that, at a 10% molar loading, led to endo-4 in
in DMF (60 8C, 24 h) afforded the supported imidazo- 75% yield, 92/8 diastereoselectivity, and 84% ee. These
lidin-4-one 3 in 87% yield.[10] In situ conversion of this results were inferior to those obtained by MacMillan et
compound to the catalytically active species involved al. working under similar conditions with 5% molar of
the addition of an equimolar amount of different acids (S)-5-benzyl-2,3,3-trimethylimidazolidin-4-one hydro-
(see Table 1). The resulting ammonium salts (0.1 mol- chloride as the catalyst (82% yield, 93/7 diastereoselec-
equiv) were employed, under different conditions, in the tivity, 94% ee).[8a] However, by using the supported
Diels Alder cycloaddition between cyclohexadiene catalyst derived from 3, and by properly selecting the
(1 mol-equiv) and acrolein (3 mol-equiv) to afford reaction parameters (entry 8), results comparable to
mixtures of endo- (largely major) and exo-cycloadducts MacMillan×s were obtained (67% yield, 94/6 diastereo-
4. The results are reported in Table 1, together with selectivity, 92% ee).
those obtained using the non-supported catalysts de-
The acid employed to generate the catalyst was
rived from (S)-1 and its methyl ether (1-OMe). Yields important (entries 4, 6, 7), with 3/HCl securing better
were determined on the isolated products; diastereoiso- yields and 3/TFA higher stereocontrol. Independently
1
meric ratios were determined by 300 MHz H NMR of the catalyst counterion, a longer reaction time
analysis of the crude products, exploiting the CHO increased the yield (entries 4 vs. 5, 7 vs. 8). Decreasing
signals at d ˆ 9.46 (endo) and 9.75 (exo) ppm, and the catalyst loading to 5% molar slowed down the
confirmed on isolated compounds; enantiomeric ex- reaction, but preserved the stereoselectivity (entry 8 vs.
cesses (ee) were obtained by HPLC analysis on a chiral 9). The use of pre-formed catalysts (entries 11 and 12)
stationary phase carried out on the N,N-diphenylhydra- did not improve the efficiency of the process while
zones derived from 4 in > 95% yield; the (R) absolute making it less practical.
configuration of endo-4 was established by reduction to
Finally, the reaction was successfully extended to the
the corresponding alcohol and comparison of the sign of acyclic 2,3-dimethylbutadiene which, when reacted with
optical rotation with the value reported for a sample of acrolein under the conditions of entry 8, afforded cyclo-
known configuration.[11]
adduct 5,[11] [a]D23: ‡ 170.0 (c 0.20, CH2Cl2), in 75% yield
and 73% ee (by HPLC, see above).
Table 1. Catalytic enantioselective synthesis of cycloadduct 4 at 24 8C in CH3CN/H2O(95/5).
Entry
Catalyst
Time [h]
Yield [%][a]
endo/exo[b]
endo ee %[c]
exo ee %[c]
1
2
3
4
5
6
7
8
9
1/HCl
1/TFA
1-OMe/TFA
3/HCl
3/HCl
3/TfOH
3/TFA
22
22
22
22
40
22
22
40
40
40
40
40
40
40
40
35
39
75
63
81
27
50
67
45
10
61
52
61
50
38
90/10
91/9
92/8
91.5/8.5
91/9
94/6
94/6
94/6
94/6
91/9
92/8
93/7
94/6
94/6
94/6
68
82
84
70
73
88
92
92
undetermined
undetermined
undetermined
60
undetermined
84
undetermined
86
3/TFA
3/TFA[d]
3/TFA
90
undetermined
undetermined
undetermined
undetermined
undetermined
undetermined
undetermined
10[e]
11
12
13
14
15
undetermined
3/HCl[f]
3/TFA[f]
3/TFA[g]
3/TFA[h]
3/TFA[i]
70
84
87
87
85
[a]
Yields of isolated products.
[b]
[c]
1
As determined by 300 MHz H NMR spectroscopy on the crude products and confirmed on the isolated products.
As determined by HPLC on a chiral stationary phase on the corresponding N,N-diphenylhydrazones; yields and ee are
average of duplicate experiments.
0.05 mol-equiv of catalyst.
Carried out in MeOH/H2O.
[d]
[e]
[f]
[g]
[h]
[i]
Carried out with a pre-formed sample of catalyst.
Carried out with a catalyst sample recycled after use in entry 8.
Carried out with a catalyst sample recycled after use in entry 8 and 13.
Carried out with a catalyst sample recycled after use in entry 8, 13, and 14.
150
Adv. Synth. Catal. 2002, 344, 149 152

Poly(ethylene glycol)-Supported Chiral Imidazolidin-4-one
COMMUNICATIONS
The relevant issue of recovery and recycling of the Experimental Section
catalyst was then addressed. The catalyst was recovered
from the reaction mixture by evaporation of the solvent
under reducedpressure, precipitation with diethyl ether,
Compound 2
Mp 99 101 8C; [a]D23: À 78.2 (c 0.72, CH2Cl2); IR: n ˆ 3270,
1675, 1620 cmÀ1; 1H NMR (300 MHz, CDCl3/D2O): d ˆ 7.04 (B
part of AB system, 2H, J ˆ 8.5 Hz, aromatic protons), 6.74 (A
part of AB system, 2H, J ˆ 8.5 Hz, aromatic protons), 3.73 (t,
1H, J ˆ 5.8 Hz, CHN), 3.29 (ddd, 1H, J ˆ 12.0, 6.7, 3.2 Hz, one
H of NCH2), 3.04 (ddd, 2H, J ˆ 15.0, 5.8, 5.4 Hz, ArCH2), 2.89
(ddd, 1H, J ˆ 12.0, 6.2, 3.1 Hz, one H of NCH2), 1.43 1.49 (m,
2H, NCH2CH2), 1.21 1.31 (m, 2H, CH3CH2), 1.27 (s, 3H,
CMe), 1.17 (s, 3H, CMe), 0.90 (t, 3H, J ˆ 7.3 Hz, CH2CH3);
Anal.: found: C 69.71, H 8.64, N 10.23; C16H24N2O2 (276.4)
requires: C 69.53, H 8.75, N 10.14.
and filtration. The recovered material was then dried at
90 8C under high vacuum to eliminate traces of water
that the hygroscopic PEG could have absorbed from the
solvent. The recovery yields ranged between 70 and
80%. NMR analysis showed that the recovered material
was a mixture of protonated and unprotonated 3. As
such, this material was found to promote a sluggish
cycloaddition reaction. However, addition of TFA
regenerated an active catalyst that was successfully
employed in a second cycle affording the product in 61%
yield, 94/6 endo/exo ratio, and 87% ee (Table 1, en-
try 13). Iteration of the recovery/recycling protocol was
possible for other two cycles, both occurring in almost
unchanged stereoselectivities but in decreasing yields
(entries 14 and 15). When the catalyst was used in a fifth
cycle, the yield was very low (10 15% after 60 h).
The decrease in chemical efficiency of the recovered
catalyst was confirmed by repeating the recycling
experiments and using an internal-standard calibrated
GC analysis to asses the reaction yield without being
hampered by the problems associated with the isolation
of the relatively volatile adduct 4.[12]1H NMR analysis of
the recovered samples of 3 indicated extensive degra-
dation after three cycles, showing broadening of the
signals of the imidazolidinone moiety and a decreased
intensity of its peaks with respect to those of the
aromatic protons of the linker, which remained virtually
unchanged.[13] Thus, it seems possible that prolonged
exposure of 3 to the acidic reaction medium led to
catalyst degradation resulting in the observed decreased
yields upon recycling. The fact that the ee of the product
did not change as dramatically as the chemical yield (1st
cycle, 92% ee; 4th cycle, 85% ee) suggests that the
catalyst degradation product(s) did not affect the steric
course of the reaction. Catalyst stability and recycling
are undergoing further studies.
Synthesis of Catalyst Precursor 3
To a solution of 2 (3.0 g, 0.575 mmol, loading 0.192 meq/g),
previously dried under vacuum at 90 8C for 1 h, in dry DMF
(7 mL), compound (S)-1 (0.200 g, 0.72 mmol) dissolved in
DMF (3 mL) and Cs2CO3 (0.562 g, 1.725 mmol) were added.
After 24 h stirring at 60 8C, the mixture was cooled at room
temperature, the solvent was evaporated under vacuum, and
the residue was dissolved in CH2Cl2 (3 mL). The resulting
solution was poured dropwise in Et2O(150 mL). The precipi-
tated white solid was filtered, washed with Et2O(2 Â 25 mL),
and dried under vacuum to give 3; yield: 2.69 g (0.50 mmol,
1
loading 0.186 meq/g). H NMR (300 MHz, CDCl3, with pre-
saturation of the PEG methylene signals at d ˆ 3.63; relaxation
delay: 6 s; acquisition time: 4 s): d ˆ 7.05 7.11 (m, 4H,
aromatic protons), 6.77 6.81 (m, 4H, aromatic protons), 4.07
(t, 2H, J ˆ 4.7 Hz, PEGCH2OAr), 3.84 3.88 (m, 4H, PE-
GOCH2CH2Ar and CH2CH2CH2OAr), 3.37 (t, 1H, J ˆ 5.2 Hz,
CHN), 3.33 (s, 3H, MeOPEG), 3.21 3.30 (m, 1H, one H of
NCH2), 3.04 (ddd, 2H, J ˆ 15.0, 5.2, 4.7 Hz, ArCH2), 2.80 2.91
(m, 1H, one H of NCH2), 2.70 (t, 2H, J ˆ 7.8 Hz, PEGOArCH2
), 1.95 2.08 (m, 2H, CH2CH2CH2), 1.40 1.50 (m, 2H, NCH2
CH2), 1.20 1.30 (m, 2H, CH3CH2), 1.23 (s, 3H, CMe), 1.13 (s,
3H, CMe), 0.88 (t, 3H, J ˆ 7.2 Hz, CH2CH3).
In conclusion, these results showed that a modified
PEG is a convenient support of an organic catalyst for
the enantioselective Diels Alder cycloaddition. The
supported catalyst secured stereoselectivity very similar
to that observed with a related, non-immobilized
catalyst. Simple catalyst recovery and recycling was
General Procedure for the Diels Alder Cycloaddition
To a stirred solution of compound 3 (0.500 g, 0.093 mmol) in a
95/5 CH3CN/H2Omixture (10 mL), trifluoroacetic acid
(7.2 mL, 0.095 mmol) was added and the mixture stirred for
5 min at 24 8C. Freshly distilledacrolein (0.186 mL, 2.79 mmol)
and 1,3-cyclohexadiene (0.086 mL, 0.93 mmol) were added in
also demonstrated, although only for a limited number this order. The mixture was stirred at 24 8C for 40 h. Na2SO4
was then added, the mixture was filtered, and the organic
solvent evaporated under vacuum. The residue was dissolved
in the minimum amount of CH2Cl2 and then poured in Et2O
(30 mL). The precipitate was filtered off, and the solid was
washed with Et2O(5 mL). Average recovery of catalyst ranged
from 70 to 80% (0.360 to 0.400 g) after drying under high
vacuum. The filtrate was concentrated under vacuum and the
residue was purified by flash chromatography with an 80:20
hexanes: Et2Omixture as eluent to give the product; yield:
of cycles. These findings can be useful in designing
practical enantioselective catalytic reactions with con-
tinuous catalyst recycle, and widen the scope of PEGs as
convenient supports for chiral organic catalysts.
1
0.085 g (67%). The H NMR data were in agreement with
those reported.[14] Conversion of the product to the corre-
Adv. Synth. Catal. 2002, 344, 149 152
151

Maurizio Benaglia, et al
COMMUNICATIONS
sponding N,N-diphenylhydrazone (N,N-diphenylhydrazine,
EtOH, MgSO4, 24 8C, 15 h, > 95% yield) was necessary for
ee determination by HPLC [Chiralcel OD, flow rate 0.8 mL/
min, l ˆ 230; for the endo isomer: hexane/i-PrOH ˆ 99:1; tR:
5.40 min (minor) and 5.80 min (major); for the exo isomer:
hexane/i-PrOH ˆ 95:5; tR: 12.60 min (minor) and 13.30 min
(major)].
addition of metal was necessary to fully restore the
catalytic activity of the immobilized species.
[7] M. Benaglia, G. Celentano, F. Cozzi, Adv. Synth. Catal.
2001, 343, 171 173.
[8] a) K. A. Ahrendt, C. J. Borths, D. W. C. MacMillan, J.
Am. Chem. Soc. 2000, 122, 4243 4244; for other
applications of ammonium salts derived from imidazo-
lidin-4-ones as chiral organic catalysts see: b) W. S. Jen,
J. J. M. Wiener, D. W. C. MacMillan, J. Am. Chem. Soc.
2000, 122, 9874 9875; c) N. A. Paras, D. W. C. MacMil-
lan, J. Am. Chem. Soc. 2001, 123, 4370 4371.
[9] R. Annunziata, M. Benaglia, M. Cinquini, F. Cozzi,
Chem. Eur. J. 2000, 6, 133 138.
[10] For a detailed description of the isolation, purification,
and yield determination of PEG-supported compounds,
see Ref.[9].
[11] a) O. Cervinka, O. Kriz,Collect. Czech. Chem. Commun.
1968, 33, 2342 2345; b) M. Nakazaki, K. Naemura, S.
Harita, Bull. Chem. Soc. Jpn. 1975, 48, 1907 1913. The
assignments of the absolute configuration to exo-4 and 5
are tentative and based on a mode of addition of the
diene to the aldehyde similar to that leading to endo-(S)-
4 (Ref.[8a]).
Acknowledgements
This work was supported by CNR (Agenzia 2000) and MURST
(Progetto Nazionale Stereoselezione in Sintesi Organica. Me-
todologie ed Applicazioni).
References and Notes
[1] Chiral Catalyst Immobilization and Recycling, (Eds.:
D. E. De Vos, I. F. J. Vankelecom, P. A. Jacobs), Wiley-
VCH, Weinheim, 2000.
[2] D. J. Gravert, K. D. Janda, Chem. Rev. 1997, 97, 489
509.
[3] For recent reports comparing the efficiency of soluble
and insoluble polymer-supported catalysts see: a) T. S.
Reger, K. D. Janda, J. Am. Chem. Soc. 2000, 122, 6929
6934; b) R. Annunziata, M. Benaglia, M. Cinquini, F.
Cozzi, G. Tocco, Org. Lett. 2000, 2, 1737 1739.
[4] a) C. Bolm, A. Gerlach, Angew. Chem. Int. Ed. Engl.
1997, 36, 741 743; b) H. Han, K. D. Janda, Angew.
Chem. Int. Ed. Engl. 1997, 36, 1731 1733; c) M. Glos, O.
Reiser, Org. Lett. 2000, 2, 2045 2048; d) R. Annunziata,
M. Benaglia, M. Cinquini, F. Cozzi, M. Pitillo, J. Org.
Chem. 2001, 66, 3160 3166.
[12] The GC yields (cycle, at 24 h, at 40 h, isolated) were the
following: 1, 64%, 77.5%, 67%; 2, 60%, 73%, 60%; 3,
26%, 51%, 48%; 4, undetermined, 35%, 33%. The GC
analysis did not show the presence of any degradation
products. Endo/exo ratios were identical to those re-
ported in entries 8, 13 15. In the reactions carried out
with recycled catalysts the amounts of reagents and
solvents for a new cycle were adjusted to the amount of
recovered 3.
[13] Interestingly, an analogue of (S)-1 having a benzyl
instead of the 4-hydroxybenzyl group at C-5, did not
show any degradation when exposed to excess TFA in
95/5 CD3CN/D2Oat room temperature for 120 h either
in the absence or in the presence of the bismethyl ether
[5] Review on asymmetric organic catalysis: P. I. Dalko, L.
Moisan Angew. Chem. Int. Ed. Engl. 2001, 40, 3726
3748.
[6] For instance, both soluble, PEG-supported- (Ref.[4d]) and
insoluble, polystyrene-supported bisoxazolines/Cu(II)
of PEG2000
.
[14] K. Ishiara, H. Kurihara, M. Matsumoto, H. Yamamoto, J.
Am. Chem. Soc. 1998, 120, 6920 6930. The reported
1H NMR spectrum of endo-4 lists 13 rather than 12 pro-
tons.
complexes
see: S. Orlandi, A. Mandoli, D. Pini, P.
Salvadori, Angew. Chem. Int. Ed. Engl. 2001, 40, 2519
2521 showed considerable decrease of catalytic effi-
ciency upon recovery and recycling. In both cases
152
Adv. Synth. Catal. 2002, 344, 149 152