A recyclable fluorous organocatalyst for Diels-Alder reactions

Article abstract of DOI:10.1016/j.tetlet.2006.10.101

Chiral fluorous imidazolidinone catalyst 2 provides consistently high enantioselectivities in Diels-Alder reactions of dienes and α,β-unsaturated aldehydes. The catalyst can be readily separated from the reaction products by fluorous solid-phase extractio

Full text of DOI:10.1016/j.tetlet.2006.10.101

Tetrahedron Letters 47 (2006) 9287–9290
A recyclable fluorous organocatalyst for Diels–Alder reactions
Qianli Chu,a Wei Zhanga,* and Dennis P. Curranb
aFluorous Technologies, Inc., University of Pittsburgh Applied Research Center, 970 William Pitt Way,
Pittsburgh, PA 15238, United States
bDepartment of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, United States
Received 25 September 2006; revised 17 October 2006; accepted 20 October 2006
Available online 13 November 2006
Abstract—Chiral fluorous imidazolidinone catalyst 2 provides consistently high enantioselectivities in Diels–Alder reactions of
dienes and a,b-unsaturated aldehydes. The catalyst can be readily separated from the reaction products by fluorous solid-phase
extraction, and recovered in excellent purity for direct reuse.
Ó 2006 Elsevier Ltd. All rights reserved.
Over the past decade, much interest has been devoted to
the development of highly efficient organocatalysts for a
variety of reactions, and the pace of growth in this field
of chemistry has been breathtaking.1–3 However, the
need for high loading and separation of the organo-
catalyst from the product are still the issues that need
to be addressed in this area.4,5
Described in this paper is a recyclable fluorous imidazo-
lidinone organocatalyst which has comparable yields
and enantioselectivities to the standard organocatalyst.
It can be recovered by fluorous solid-phase extraction
(F-SPE)6e and has significantly better recovery yield
and purity than that of the standard catalyst recovered
by acid–base extraction.
Fluorous organocatalysts are of high interest because
they are soluble in common reaction solvents, yet they
can be easily separated from the reaction mixture for
subsequent reuse.6,7 Recently, enantioselective Michael
additions have been achieved with fluorous pyrrolidine
derivatives as recyclable catalysts.8
The only structural difference between the fluorous
catalyst 2 and the original imidazolidinone 1 is that
the fluorous tag13 (p-C8F17CH2CH2–C6H4–) is attached
to the N-methyl group. Since the single fluorous tag is
away from the functional group for catalysis,9 it
was hypothesized that this design would not affect the
activity of the catalyst.
Chiral imidazolidinone 1 (Scheme 1) is a well-known
enantioselective catalyst for many different chemical
transformations2c such as Diels–Alder,9a,b Michael
addition,10a 1,3-dipolar addition,10b and Friedel–Crafts
alkylation reactions.10c Although polymer-supported
chiral imidazolidinones have been known for several
years,11,12 there is no reported fluorous variant to date.
A simple three-step synthesis for the fluorous chiral imid-
azolidinone 2 is shown in Scheme 2.14 N-Fmoc-amide 3
was obtained by an amide coupling reaction of Fmoc-
Phe-OH with a fluorous amine. Subsequent de-protec-
tion with piperidine gave aminoamide 4. Treatment of
4 with excess amount of acetone in DMF with micro-
wave irradiation gave the fluorous organocatalyst 2.
The overall yield of the three-step synthesis was 66%.
Fluorous compound 2 is a stable white solid, and it
was kept on bench for weeks without any sign of
decomposition.
O
1. R = -CH3
R
N
Ph
NH
2. R = -CH2C6H4-p-CH2CH2C8F17
A typical Diels–Alder reaction of acrolein and cyclohex-
adiene was conducted using either standard imidazolid-
inone 1 or its fluorous variant 2 as the catalyst (Table 1).
We first carried out the Diels–Alder reaction with
the normal imidazolidinone catalyst following the
Scheme 1. The chiral imidazolidinone 1 and its fluorous variant 2.
*
Corresponding author. Tel.: +1 412 826 3062; fax: +1 412 826
3053; e-mail: w.zhang@fluorous.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.101

9288
Q. Chu et al. / Tetrahedron Letters 47 (2006) 9287–9290
O
O
NH2
N
H
Ph
HOBt, DIC
CH2Cl2, 25 oC, 1 h
HO
Ph
+
HN
HN
C8F17
Fmoc
Fmoc
C8F17
3
Fmoc-phe-oh
O
O
piperidine-DMF
25 oC, 1 h
Me2CO, DMF
Ph
N
N
Ph
H
NH
microwave, 150 oC, 30 min
NH2
C8F17
C8F17
4
2
Scheme 2. Synthesis of the fluorous chiral imidazolidinone 2.
Table 1. The Diels–Alder reaction of acrolein and cyclohexadiene catalyzed by either the organic imidazolidinone 1 or its fluorous variant 2
H
Catalyst 1 or 2, (10 mol%)
+
+
CHO
CH3CN-H2O, 25 oC, 40 h
O
CHO
5-Endo
5-Exo
Entry
Catalyst yield
(%)
5 endo:exo
ee% of 5-endoa
Recovery of catalyst (%)
Purity of recovered catalystb (%)
1
2
1
2
82
86
90.3:9.7
93.4:6.6
88.4
93.4
65c
84d
74
99
a Determined by GC with Bodman Chiraldex C-TA column.
b Determined by GC.
c Recovered by acid–base extraction.
d Recovered by F-SPE.
literature procedures.9 Acrolein (100 lL, 1.5 mmol) and
cyclohexadiene (48 lL, 0.5 mmol) were added into a
solution of 1ÆHCl salt (14 mg, 0.05 mmol) with 2 mL
CH3CN–H2O (95:5, v:v). The mixture was stirred for
40 h at 25 °C. An acid–base extraction was utilized to
separate the product and recover the organocatalyst.15
Thus, a 0.05 M HCl aqueous solution was added to
the reaction mixture. The solution was extracted with
diethyl ether three times. The organic phases were com-
bined, washed with aqueous NaHCO3, dried and con-
centrated to give the product 5. The acidic phase was
neutralized and extracted with diethyl ether to provide
7.8 mg (65%) of recovered 1. Although the product yield
(82%) and ee (88.4%) were comparable to the reported
data,9 the recovery of the organocatalyst 1 under the
procedures described above was moderate and its purity
was only 74% (Table1, Entry 1). This purity is not suffi-
cient for direct reuse of the recovered catalyst. More-
over, for some reactants (e.g., substance with –OH),
the acid–base extraction approach might disturb the
functional group in the final product.
1% Et3N for fluorous catalyst 2. Concentration of the
THF fraction gave the fluorous catalyst 2 in good recov-
ery (84%) and excellent purity (99%). The purity was as-
sessed by GC and 1H NMR analyses (Fig. 1). The chiral
GC of the major endo products from both organic cata-
lyst 1 and fluorous catalyst 2 are shown in Figure 2.
While the yields, endo:exo ratios and high enantioselec-
tivities of the product were comparable to those of the
control experiment showing the similar catalytic activity
of the two catalysts, the recovery of the fluorous catalyst
2 is much more efficient and its purity was good enough
for direct reuse (Table 1, entries 1 and 2).
To probe the scope of both diene and dienophile (a,b-
unsaturated aldehydes) as the reaction components for
The fluorous imidazolidinone 2 catalyzed reactions were
then performed with wet solvents and under aerobic
atmosphere, similar to the reaction conditions described
above without much effort of modification.16 After the
reaction mixture was stirred for 40 h at room tempera-
ture, 0.1 g of MP-carbonate was added and the mixture
was shaken for 30 min to free the amine 2. After filtra-
tion, the solution was concentrated and then loaded onto
a 0.5 g endcapped FluoroFlashÒ silica gel cartridge for
F-SPE.14 The cartridge was first eluted with CH3CN–
H2O (65:35) for product 5, then with THF containing
Figure 1. 1H NMR spectrum of the fluorous chiral imidazolidinone 2
after recovery by F-SPE.

Q. Chu et al. / Tetrahedron Letters 47 (2006) 9287–9290
9289
Figure 2. Chiral GC (Bodman Chiraldex C-TA column, 90 °C, 23 psi) chromatograms of the Diels–Alder products. Left: from organic
imidazolidinone 1; Right: from fluorous imidazolidinone 2.
the fluorous reactions and separations, four other Diels–
Alder reactions were conducted (Table 2).16 We found
that variation on olefin substituents did not decrease
in yield, endo:exo ratios and enantioselectivity (Table
2, entry 1, Me; entry 4, Pr) compared to the control
experiments using standard imidazolidinone 1 (Table
2, entry 2, M; entry 5, Pr). Meanwhile, similar stereose-
lectivity and yield were achieved using the recovered flu-
orous organocatalyst 2 (Table 2, entry 1 and entry 3
with recovered 2). The result confirms the quality of
recovered fluorous imidazolidinone catalyst. Further-
more, the [4+2] cycloaddition between acrolein and
two acyclic dienes also gave high yields and enantiose-
lectivities (Table 2, entries 6 and 7). Thus, the generality
of the fluorous imidazolidinone 2 as an efficient recycla-
ble organo-catalyst for Diels–Alder reactions has been
clearly demonstrated.
In addition, a Diels–Alder reaction between acrolein
and cyclohexadiene with fluorous organocatalyst 2 was
also carried out at gram scale (Table 2, entry 8).16 The
consistent results between the small scale reactions
shown in Table 1 and the gram scale reaction is a good
indicator that fluorous catalyst has good potential for
scale up reactions.
In summary, a simple procedure for preparation of a
chiral fluorous imidazolidinone catalyst 2 was devel-
oped. The fluorous organocatalyst 2 provides consis-
tently high enantioselectivities in Diels–Alder reactions
of dienes and a,b-unsaturated aldehydes, and it can
readily be recovered from the reaction mixture by
F-SPE with excellent purity. The recovered fluorous
organocatalyst is ready for reuse.
Table 2. Diels–Alder reactions of different dienophiles and dienes catalyzed by the chiral fluorous imidazolidinone 2 as well as two control
experiments catalyzed by the standard organocatalyst 1
Entry Diene Dienophile
Catalyst
Product (s)
Yield endo:
ee% of
Recovery
Purity of
(%)
exo
endo (exo)a of catalyst recovered
endo
exo
2b (%)
catalystc
(%)
O
1
2
80
46:54
91.6 (81.6) 81
97
CHO
CHO
CHO
2
3
1
80d
78e
46:54
46:54
92.6 (80.0) NA
91.2 (81.4) 80
NA
97
Recovered 2
4
2
1
89
47:53
47:53
93.0 (79.1) 81
93.0 (75.4) NA
98
O
Pr
Pr
CHO
Pr
5
86d
NA
6
2
2
78
85
NA
NA
92.6
88.5
80
82
98
98
O
CHO
CHO
7
O
8
2
83f
92.1:7.8 92.2
86
97
O
CHO
CHO
a Determined by GC with Bodman Chiraldex C-TA column.
b Recovered by F-SPE.
c Determined by GC.
d Control reaction catalyzed by standard catalyst 1.
e Reaction catalyzed by recovered fluorous catalyst 2.
f Gram scale reaction.

9290
Q. Chu et al. / Tetrahedron Letters 47 (2006) 9287–9290
extracted with AcOEt. The organic layer was washed with
Acknowledgement
aqueous NaHCO3 and concentrated to give 4.5 g (98%
yield) of 3. This product was analyzed by LCMS:
m/z = 923 [M+H]+. (2) Fmoc deprotection: Compound
3 (2.3 g, 2.5 mmol) in 20 mL of 1:4 piperidine/DMF was
stirred at 25 °C for 1 h. The concentrated reaction mixture
was mixed with 50 mL of H2O, extracted with ether.
Concentrated organic residue was triturated with hexanes
to give desired product 4 as a white solid (1.4 g, 80%).
This product was analyzed by GC; LCMS: m/z = 701
This work was supported by the National Institute
of General Medical Sciences SBIR Grants
(2R44GM062717-02 and 2R44GM067326-02).
References and notes
1
[M+H]+; H NMR (270 MHz, CDCl3): d = 7.63 (m, 1H),
1. Berkessel, A.; Gro¨ger, H. Asymmetric Organocatalysis—
From Biomimetic Concepts to Applications in Asymmetric
Synthesis; Wiley-VCH: Weinheim, 2005.
2. Selected reviews on organocatalysis: (a) Dalko, P.;
Moisoan, L. Angew. Chem., Int. Ed. 2004, 43, 5138; (b)
Houk, K. N.; List, B. Acc. Chem. Res. 2004, 37, 487; (c)
Lelais, G.; MacMillan, D. W. C. Aldrichim. Acta 2006, 39,
79; (d) Kocˇvsky´, P.; Malkov, A. Tetrahedron 2006, 62,
255.
7.25 (m, 8H), 4.45 (d, 2H), 3.67 (dd, 1H), 3.32 (dd, 1H),
2.91 (m, 2H), 2.75 (m, 1H), 2.32 (m, 2H) and 1.50 (br, 3H);
13C NMR: (270 MHz, CDCl3): d = 26.13, 32.99, 41.58,
42.81, 56.51, 102–125 (m, CF2, CF3) 126.91, 128.27,
128.65, 128.80, 129.41, 136.98, 137.91, 138.35, 174.20. (3)
Cycloaddition: Compound 4 (0.5 g, 0.7 mmol) and 1.0 mL
of acetone in 1.5 mL of DMF was irradiated under a
single-mode microwave reactor at 250 w, 150 °C for
30 min. The reaction mixture was concentrated under
vacuum. The residue was purified by flash column
chromatography with hex:EtOAc (1:1) and then 100%
EtOAc to give 0.44 g (85% yield) of 2 as a white solid. The
product 2 was analyzed by GC; LCMS and HRMS: m/z =
741.1710 [M+H]+ (100%, calcd mass 741.1774), 594.1
[C8F17CH2CH2C6H5CH2N@C(CH3)2]+ (24%); 1H NMR
(270 MHz, CDCl3): d = 7.30 (m, 5H), 7.12 (m, 4H), 4.65
(d, 1H), 4.08 (d, 1H), 3.89 (t, 1H), 3.17 (m, 2H), 2.88 (m,
2H), 2.34 (m, 2H) 1.71 (br, 1H) 1.22 (s, 3H) and 1.00 (s,
3H); 13C NMR (270 MHz, CDCl3): d = 26.09, 27.91,
32.85, 36.48, 43.24, 58.82, 104–125 (m, CF2, CF3) 126.91,
127.80, 128.29, 128.59, 129.90, 136.46, 136.64, 138.05,
174.16.
3. Selected papers in this field: (a) Enders, D.; Huttl, M. R.
¨
M.; Grondal, C.; Raabe, G. Nature 2006, 441, 861; (b)
Mitsumori, S.; Zhang, H.; Cheong, P. H.-Y.; Houk, K. N.;
Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006,
128, 1040.
4. Baker, R. T.; Kobayshi, S.; Leitner, W. Adv. Synth. Catal.
2006, 348, 1337.
5. Rousseau, R. W. Handbook of Separation Process Tech-
nology; Wiley: New York, 1987.
6. General reviews on fluorous chemistry: (a) Handbook of
Fluorous Chemistry; Gladysz, J. A., Curran, D. P.,
´
Horvath, I. T., Eds.; Wiley-VCH: Weinheim, 2004; (b)
Gladysz, J. A.; Curran, D. P. Tetrahedron 2002, 58, 3823;
(c) Curran, D. P. Angew. Chem., Int. Ed. 1998, 7, 1175; (d)
Zhang, W. Tetrahedron 2003, 59, 4475; (e) Zhang, W.;
Curran, D. P. Tetrahedron, in press.
15. General procedure for the control experiments and the
acid–base extraction: To a solution of 1ÆHCl salt (14 mg,
0.05 mmol) with 2 mL CH3CN–H2O (95:5, v:v), acrolein
(100 lL, 1.5 mmol) and cyclohexadiene (48 lL, 0.5 mmol)
were added. The solution was stirred for 40 h at 25 °C.
Then, 5 mL 0.05 M HCl aqueous solution was added to
the reaction mixture. The solution was extracted with
4 mL diethyl ether three times. The organic phases were
combined, washed with aqueous NaHCO3, dried over
Na2SO4 and concentrated to give the product. The acidic
phase was neutralized with aqueous NaHCO3 and
extracted with 4 mL diethyl ether three times. The
combined ethyl ester layer was dried over Na2SO4. Free
catalyst 1 (7.8 mg, 65%) was obtained from concentration
of the ester layer with a purity of 74%.
´
7. Selected papers on fluorous synthesis: (a) Horvath, I. T.;
´
Rabai, J. Science 1994, 266, 72–76; (b) Luo, Z. Y.; Zhang,
Q. S.; Oderaotoshi, Y.; Curran, D. P. Science 2001, 291,
1766; (c) Villard, A.-L.; Warrington, B. H.; Ladlow, M. J.
Comb. Chem. 2004, 6, 611; (d) Hein, J. E.; Geary, L. M.;
Jaworski, A. A.; Hultin, P. G. J. Org. Chem. 2005, 70,
9940–9946; (e) Kaleta, Z.; Makowski, B. T.; Soos, T.;
Dembinski, R. Org. Lett. 2006, 8, 1625–1628; (f) Zhang,
W.; Lu, Y.; Chen, C. H.-T.; Curran, D. P.; Geib, S. Eur. J.
Org. Chem. 2006, 2055.
8. (a) Zu, L.; Li, H.; Wang, J.; Yu, X.; Wang, W.
Tetrahedron Lett. 2006, 47, 5131; (b) Zu, L.; Wang, J.;
Li, Hao; Wang, W. Org. Lett. 2006, 8, 3077.
16. General procedure for imidazolidinone-catalyzed Diels–
Alder reaction: To a solution of 2 (37 mg, 0.05 mmol) and
HCl (0.05 mmol) in 2 mL CH3CN–H2O (95:5, v:v),
acrolein (100 lL, 1.5 mmol) and cyclohexadiene (48 lL,
0.5 mmol) were added. The solution was stirred for 40 h at
25 °C. Then, 0.1 g of MP-carbonate was added and the
mixture was shaken for 0.5 h to free the amine 2. After
filtration, the solution was concentrated and then loaded
onto a 0.5 g FluoroFlashÒ silica gel cartridge for F-SPE.
It was first eluted with 4 mL CH3CN–H2O (65:35, v:v) to
get the product 5. After that, 4 mL THF with 1% Et3N
was used to elute the fluorous catalyst 2 out of the
cartridge. The concentrated THF fraction gave the fluor-
ous catalyst 2 (31 mg) as a white solid in good recovery
(84%) and excellent purity (99%). In case of the reactions
with cyclopentdiene, 1.5 mmol diene and 0.5 mmol acro-
lein derivative were used. For the gram scale reaction,
555 mg (0.75 mmol) 1, 1.5 mL acrolein (22 mmol) and
0.75 mL cyclohexadiene (7.5 mmol) were used, and the
F-SPE was conducted on a 10 g endcapped FluoroFlashÒ
silica gel cartridge.
9. (a) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2000, 122, 4243; (b) Wilson, R. M.; Jen,
W. S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127,
11616.
10. (a) Brown, S. P.; Goodwin, N. C.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2003, 125, 1192; (b) Jen, W. S.; Wiener, J.
J. M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122,
9874; (c) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2001, 123, 4370.
11. Benaglia, M.; Celentano, G.; Cinquini, M.; Puglisi, A.;
Cozzi, F. Adv. Synth. Catal. 2002, 344, 149.
12. Selka¨la¨, S. A.; Tois, J.; Pihko, P. M.; Koskinen, A. M. P.
Adv. Synth. Catal. 2002, 344, 941.
13. www.fluorous.com. Professor Dennis P. Curran owns an
equity interest in Fluorous Technologies, Inc.
14. General procedure for the synthesis of fluorous chiral
imidazolidinone 2: (1) Amide coupling: A mixture of F-
benzylamine (2.9 g, 5 mmol), Fmoc-amino acid (2.1 g, 5.5
mmol), HOBT (0.7 g, 5.5 mmol), DIC (0.65 g, 5.5 mmol)
in 15 mL of CH2Cl2 was stirred at 25 °C for 1 h. The
reaction mixture was concentrated, mixed with H2O, and