Novel supramolecular organocatalysts of hydroxyprolinamide based on calix[4]arene scaffold for the enantioselective Biginelli reaction

Article abstract of DOI:10.1007/s11426-011-4374-z

A series of novel supramolecular organocatalysts of hydroxyprolinamide based on the upper rim of calix[4]arene scaffold have been developed to catalyze enantioselective multi-component Biginelli reaction. Under the optimal conditions, the reactions occurred with moderate-to-excellent enantioselectivities (up to 98% ee). A plausible transition state constructed by the supramolecular interaction of hydrogen bond and cation-π between catalysts and substrates has been proposed.

Full text of DOI:10.1007/s11426-011-4374-z

SCIENCE CHINA
Chemistry
November 2011 Vol.54 No.11: 1726–1734
doi: 10.1007/s11426-011-4374-z
• ARTICLES •
Novel supramolecular organocatalysts of hydroxyprolinamide
based on calix[4]arene scaffold for the enantioselective
Biginelli reaction
LI ZhengYi1, XING HuaiJie1, HUANG GuoLi2, SUN XiaoQiang1*,
JIANG JuLi2* & WANG LeYong2
1Key Laboratory of Fine Petrochemical Engineering, School of Petrochemical Engineering, Changzhou University,
Changzhou 213164, China
2Institute of Chemical Biology and Drug Innovation, School of Chemistry and Chemical Engineering,
Nanjing University, Nanjing 210093, China
Received April 26, 2011; accepted May 15, 2011; published online September 5, 2011
A series of novel supramolecular organocatalysts of hydroxyprolinamide based on the upper rim of calix[4]arene scaffold have
been developed to catalyze enantioselective multi-component Biginelli reaction. Under the optimal conditions, the reactions
occurred with moderate-to-excellent enantioselectivities (up to 98% ee). A plausible transition state constructed by the supra-
molecular interaction of hydrogen bond and cation– between catalysts and substrates has been proposed.
supramolecular organocatalyst, calix[4]arene, hydroxyprolinamide, enantioselective Biginelli reaction
line based on calix[4]arene scaffold can catalyze the enan-
1 Introduction
tioselective direct aldol reactions with good-to-excellent
enantioselectivities [19, 20]. As a part of our ongoing stud-
ies, we would like to report our preliminary results on hy-
droxyprolinamide based on calix[4]arene scaffold catalyzed
the enantioselective Biginelli reactions of aromatic alde-
hydes, ethyl acetoacetate, and urea.
The multi-component Biginelli reaction [21] offers an ef-
ficient way to access 3,4-dihydropyrimidin-2-(1H)-ones and
related heterocyclic compounds which have important
pharmacological and biological properties [22–27] such as
antiviral, antitumor, antibacterial, antihypertensive, and
antiinflammatory properties. However, in the past decade,
only the limited examples of the enantioselective Biginelli
reaction have been reported [28–37]. Recently, Feng et al.
[28] used hydroxyprolinamide based on diamantane 1
(Scheme 1) as organocatalyst assisted by a Brønsted acid to
smoothly catalyze asymmetric Biginelli reaction with up to
98% ee. Herein, more bulky, rigid, and tunable hydroxypro-
linamide organocatalysts based on calix[4]arene scaffold 2
The supramolecular catalysis of organic reactions is now a
contemporary challenge that is just being taken up by
chemists [1–7]. Especially supramolecular organocatalysis
through the weak forces which offers attractive alternatives
to metal (ion)-catalyzed reactions by combining supramo-
lecular recognition with chemical transformations in an en-
vironmentally benign fashion has attracted considerable
interest in recent years [8, 9]. Calix[4]arenes, as one of the
most important supramolecular building blocks, can be
useful in ion and metal complex because of their suitable
scaffold for the development of new bulky and structurally
well-defined ligands [10–15]. Combination of calixarene
cavity with chiral catalytic centre or inherent chirality [16,
17] might lead to multifunctional supramolecular asymmet-
ric catalyst [18]. Recently, we have demonstrated that pro-
*Corresponding author (email: xqsun@cczu.edu.cn; jjl@nju.edu.cn)
© Science China Press and Springer-Verlag Berlin Heidelberg 2011
chem.scichina.com www.springerlink.com

Li ZY, et al. Sci China Chem November (2011) Vol.54 No.11
1727
Scheme 1 Hydroxyprolinamide organocatalysts for enantioselective Biginelli reaction.
(Scheme 1) were designed for the enantioselective Biginelli
reaction. Furthermore, cooperation of more hydroxypro-
linamide moieties and the cativies derivated from calix[4]
arenes might improve the enantioselectivity of the process.
(0.65 g) which was dissolved in CHCl3 (30 mL). After addi-
tion of TFA (1 mL), the reaction mixture was stirred at
50 °C for 3 h. The solvent was removed, CHCl3 (30 mL)
and H2O (30 mL) were added. The pH of the mixture was
adjusted to 8–9 by the addition of aqueous NaOH (2 M),
and the water layer was extracted with additional CHCl3 (30
mL). The combined organic layer was washed with brine
(30 mL) and dried over anhydrous Na2SO4. The solvent was
removed to give pure yellow solid 2a (0.58 g, 74%).
2 Experimental
2.1 Materials and measurements
All reactions were performed in open atmosphere unless
noted. The commercially available reagents and solvents
were used without further purification unless otherwise
noted. Column chromatography was performed with silica
gel (200–300 mesh). All yields were given as isolated ones.
NMR spectra were recorded on a Bruker DPX 300 MHz
spectrometer. Chemical shifts () are reported in ppm
downfield from tetramethylsilane. Coupling constants (J
values) are reported in Hertz. IR and ESI-MS data were
measured on a Bruker Vector 22 as KBr pellets and a Fin-
nigan Mat TSQ 7000 instruments, respectively. Microa-
nalyses were obtained on a Perkin-Elmer 240 instrument,
and melting points (mp) were determined with a digital
electrothermal apparatus without further correction. HPLC
was performed on Perkin Elmer LC equipped with a chiral-
cel OD-H or AD-H column. Aminocalix[4]arenes 5 [38]
and racemic-4 [39] were prepared according to literature
procedures.
Compound 2a
Yellow solid, 74%, mp: 107–109 °C. []D26–5.5 (c = 1.0, in
THF). IR (KBr): 3413, 2959, 2929, 2868, 1677, 1605, 1533,
1460, 1382, 1290, 1245, 1205, 1134, 1085, 1029, 962, 763
1
cm1. H NMR (300 MHz, DMSO-d6):  = 0.97 (t, J = 7.5
Hz, 12H, CH3), 1.37–1.52 (m, 8H, CH2), 1.67–2.03 (m, 10H,
CH2), 2.72–2.91 (m, 2H, NCH2), 3.10 (d, J = 13.2 Hz, 2H,
ArCH2Ar), 3.16 (d, J = 13.2 Hz, 2H, ArCH2Ar), 3.75–3.89
(m, 9H, NCHCO + ArOCH2), 4.20 (m, 1H, HCOH), 4.31 (d,
J = 13.2 Hz, 2H, ArCH2Ar), 4.34 (d, J = 13.2 Hz, 2H,
ArCH2Ar), 4.76 (br s, 1H, OH), 6.45–6.62 (m, 7H, ArH),
6.68 (d, J = 7.5 Hz, 2H, ArH), 6.95 (d, J = 2.4 Hz, 1H, ArH),
6.97 (d, J = 2.4 Hz, 1H, ArH), 9.55 (s, 1H, CONH); 13C
NMR (75 MHz, CDCl3):  = 14.0, 19.3, 19.4, 22.6, 29.6,
30.9, 31.3, 31.4, 31.9, 32.1, 32.2, 32.3, 39.6, 54.8, 59.7,
72.2, 74.8, 120.1, 121.6, 122.0, 128.0, 128.2, 131.3, 134.3,
134.5, 134.7, 135.5, 136.0, 153.9, 156.2, 156.9, 170.3. Anal.
calcd for C49H64N2O6: C, 75.74; H, 8.30; N, 3.61. Found: C,
75.47; H, 8.59; N, 3.87. ESI-MS: m/z = 778 ([M + 1]+, 9%),
800 ([M + Na]+, 100%), 816 ([M + K]+, 38%).
2.2 Representative synthetic procedure for catalyst 2a
To a solution of trans-4-hydroxy-L-N-Boc-proline (0.25 g,
1.1 mmol) in CH2Cl2 (30 mL) was added TEA (0.11 mL,
1.1 mmol) and ethyl chloroformate (0.14 mL, 1.1 mmol) at
0 °C under stirring. After 15 min, 5-amino-25,26,27,28-
tetrabutoxycalix[4]arene 5a (0.66 g, 1.0 mmol) was added.
The reaction was allowed to warm to ambient temperature
and stirred for 7 h. After reaction, the mixture was washed
with KHSO4 (1 M), saturated NaHCO3, and brine. The or-
ganic phase was dried over anhydrous Na2SO4. The solvent
was evaporated under vacuum, and the residue was purified
by column chromatography with petroleum ether/ethyl ace-
tate (2:1, v/v) as an eluent to give Boc-protected product
Compound 2b
Yellow solid, 55%, mp: 153–155 °C. []D27–13.1 (c = 1.0,
in THF). IR (KBr): 3426, 2957, 2928, 2869, 1661, 1604,
1533, 1465, 1210, 1073, 1028, 966, 869, 764 cm1. 1H NMR
(300 MHz, DMSO-d6):  = 0.96 (t, J = 7.5 Hz, 12H, CH3),
1.42 (m, 8H, CH2), 1.62–2.00 (m, 12H, CH2), 2.74–2.90 (m,
4H, NCH2), 3.05 (d, J = 13.2 Hz, 1H, ArCH2Ar), 3.11 (d, J =
13.2 Hz, 2H, ArCH2Ar), 3.17 (d, J = 13.2 Hz, 1H, ArCH2Ar),
3.76–3.82 (m, 10H, NCHCO + ArOCH2), 4.19 (m, 2H,
HCOH), 4.28 (d, J = 13.2 Hz, 1H, ArCH2Ar), 4.31 (d, J =

1728
Li ZY, et al. Sci China Chem November (2011) Vol.54 No.11
1H NMR (300 MHz, DMSO-d6):  = 0.97 (t, J = 7.2 Hz,
12H, CH3), 1.35–1.48 (m, 8H, CH2), 1.66–1.98 (m, 16H,
CH2), 2.73–2.92 (m, 8H, NCH2), 3.10 (d, J = 13.2 Hz, 4H,
ArCH2Ar), 3.61–3.65 (m, 4H, NCHCO), 3.77–3.84 (m, 8H,
ArOCH2), 4.19 (m, 4H, HCOH), 4.32 (d, J = 13.2 Hz, 4H,
ArCH2Ar), 4.73 (br s, 4H, OH), 6.99 (s, 4H, ArH), 7.04 (s,
4H, ArH), 9.55 (s, 4H, CONH). 13C NMR (75 MHz,
DMSO-d6):  = 14.3, 19.3, 29.5, 30.9, 31.2, 31.3, 31.8, 32.1,
32.5, 55.4, 60.2, 71.8, 75.0, 119.9, 133.0, 134.7, 152.5,
172.4. Anal. calcd for C64H88N8O12: C, 66.18; H, 7.64; N,
9.65. Found: C, 66.42; H, 7.38; N, 9.45. ESI-MS: m/z =
1162 ([M + 1]+, 86%), 1184 ([M + Na]+, 100%).
13.2 Hz, 2H, ArCH2Ar), 4.34 (d, J = 13.2 Hz, 1H,
ArCH2Ar), 4.75 (br s, 2H, OH), 6.49–6.62 (m, 6H, ArH),
6.80–6.90 (m, 3H, ArH), 6.99 (d, J = 2.1 Hz, 1H, ArH),
9.49 (s, 1H, CONH), 9.51 (s, 1H, CONH); 13C NMR (75
MHz, CDCl3):  = 14.0, 19.3, 30.9, 31.3, 31.4, 32.2, 39.8,
55.2, 60.0, 72.8, 74.7, 120.0, 121.7, 128.1, 131.4, 131.5,
134.7, 134.9, 135.1, 135.2, 135.4, 135.6, 135.8, 135.9,
153.4, 156.5, 156.6, 172.8, 173.0. Anal. calcd for
C54H72N4O8: C, 71.65; H, 8.02; N, 6.19. Found: C, 71.84; H,
7.86; N, 6.35. ESI-MS: m/z = 906 ([M + 1]+, 7%), 928 ([M
+ Na]+, 100%), 944 ([M + K]+, 20%).
Compound 2c
Yellow solid, 79%, mp: 171–173 °C. []D27–6.5 (c = 1.0, in
THF). IR (KBr): 3423, 2958, 2927, 2869, 1660, 1608, 1535,
1465, 1212, 1129, 1073, 1028, 965, 868, 765 cm1. 1H NMR
(300 MHz, DMSO-d6):  = 0.96 (t, J = 7.2 Hz, 6H, CH3),
0.98 (t, J = 7.2 Hz, 6H, CH3), 1.28–1.36 (m, 4H, CH2),
1.49–1.61 (m, 4H, CH2), 1.85–2.06 (m, 12H, CH2), 2.72–
2.96 (m, 4H, NCH2), 3.10 (d, J = 12.9 Hz, 4H, ArCH2Ar),
3.69 (t, J = 6.6 Hz, 4H, ArOCH2), 3.85–3.95 (m, 6H,
NCHCO + ArOCH2), 4.22 (m, 2H, HCOH), 4.31 (d, J =
12.9 Hz, 4H, ArCH2Ar), 4.78 (br s, 2H, OH), 6.33 (s, 6H,
ArH), 7.29 (s, 4H, ArH), 9.76 (s, 2H, CONH); 13C NMR
(75 MHz, CDCl3):  = 13.9, 14.0, 19.1, 19.4, 19.5, 22.6,
29.6, 31.0, 31.8, 32.0, 32.2, 32.4, 40.1, 55.0, 59.7, 72.7, 74.7,
74.9, 119.8, 122.0, 128.4, 128.7, 128.8, 131.4, 134.8, 135.3,
153.0, 156.8, 172.3. Anal. calcd for C54H72N4O8: C, 71.65; H,
8.02; N, 6.19. Found: C, 71.86; H, 8.24; N, 5.98. ESI-MS:
m/z = 928 ([M + Na]+, 100%), 944 ([M + K]+, 30%).
2.3 The procedure for the synthesis of model catalyst 3
Synthesis of 7
4-Nitrophenol 6 (1.39 g, 10 mmol), K2CO3 (1.52 g, 11
mmol) and n-bromobutane (1.44 g, 10.5 mmol) were re-
fluxed in MeCN (50 mL) for 24 h under nitrogen gas. The
solvent was evaporated and the residue was taken up in
CH2Cl2 (50 mL), and then washed with HCl (1 N, 2 × 50 mL),
H2O (2 × 50 mL), and brine (50 mL). The organic phase
was dried over anhydrous MgSO4. The CH2Cl2 was re-
moved to give 1.81 g 7 without further purification. Yellow
solid, 93%, 1H NMR (300 MHz, CDCl3):  = 0.99 (t, J = 7.5
Hz, 3H, CH3), 1.45–1.57 (m, 2H, CH2), 1.76–1.86 (m, 2H,
CH2), 4.06 (t, J = 6.3 Hz, 2H, ArOCH2), 6.94 (d, J = 9.0 Hz,
2H, ArH), 8.20 (d, J = 9.0 Hz, 2H, ArH).
Synthesis of 8
Hydrazine hydrate (30 mL) was added to a suspension of 7
(1.81 g, 9.27 mmol) and a catalytic amount of Raney nickel
in methanol (50 mL). The mixture was refluxed for 4 h.
After cooling to room temperature, the mixture was filtered.
The filtrate was evaporated and the residue was taken up in
CH2Cl2 (50 mL), washed with water twice, and dried over
anhydrous MgSO4. The CH2Cl2 was removed to afford 8
(1.53 g). Brown oil, > 99%, 1H NMR (300 MHz, CDCl3):  =
0.97 (t, J = 7.5 Hz, 3H, CH3), 1.42–1.52 (m, 2H, CH2),
1.71–1.81 (m, 2H, CH2), 3.95 (t, J = 6.3 Hz, 2H, ArOCH2),
6.91 (d, J = 8.7 Hz, 2H, ArH), 7.45 (d, J = 8.7 Hz, 2H, ArH),
10.42 (br s, 2H, ArNH2).
Compound 2d
Yellow solid, 21%, mp > 280 °C. []D26–27.7 (c = 1.0, in
THF). IR (KBr): 3431, 2958, 2928, 2869, 1663, 1606, 1536,
1468, 1424, 1215, 1136, 1071, 1028, 966, 869, 765 cm–1. 1H
NMR (300 MHz, DMSO-d6):  = 0.93–0.99 (m, 12H, CH3),
1.19–1.57 (m, 10H, CH2), 1.75–2.00 (m, 12H, CH2), 2.61–
2.95 (m, 6H, NCH2), 3.06 (d, J = 13.5 Hz, 2H, ArCH2Ar),
3.14 (d, J = 13.5 Hz, 2H, ArCH2Ar), 3.64–4.00 (m, 11H,
NCHCO + ArOCH2), 4.22 (m, 3H, HCOH), 4.29 (d, J =
13.5 Hz, 2H, ArCH2Ar), 4.32 (d, J = 13.5 Hz, 2H, ArCH2Ar),
4.79 (br s, 3H, OH), 6.08–7.38 (m, 9H, ArH), 9.39 (s, 1H,
CONH), 9.75 (s, 2H, CONH). 13C NMR (75 MHz, DMSO-
d6):  = 14.3, 14.4, 19.2, 19.5, 30.9, 31.0, 32.0, 32.4, 55.5,
60.3, 71.9, 74.8, 74.9, 119.3, 119.9, 122.2, 128.0, 129.0,
129.6, 130.3, 132.9, 133.9, 135.6, 135.9, 152.0, 153.1, 155.8,
172.0, 172.7. Anal. calcd for C59H80N6O10: C, 68.58; H, 7.80;
N, 8.13. Found: C, 68.81; H, 7.55; N, 8.34. ESI-MS: m/z =
1034 ([M + 1]+, 37%), 1056 ([M + Na]+, 100%).
Synthesis of 3 from 8
The procedure was similar to the synthesis of 2a. White
solid, 92%, mp 195–197 °C. IR (KBr): 3366, 3288, 2954,
2871, 1667, 1658, 1600, 1549, 1514, 1466, 1415, 1299,
1
1250, 1173, 1123, 1084, 1031, 970, 833 cm1. H NMR
(300 MHz, DMSO-d6):  = 0.93 (t, J = 7.5 Hz, 3H, CH3),
1.36–1.49 (m, 2H, CH2), 1.63–1.73 (m, 2H, CH2), 1.93–
2.02 (m, 1H, CH2), 2.36–2.43 (m, 1H, CH2), 3.13 (d, J =
12.0 Hz, 1H, NCH2), 3.39 (d, J = 12.0 Hz, 1H, NCH2), 3.93
(t, J = 6.6 Hz, 2H, ArOCH2), 4.47–4.53 (m, 2H, OCH +
COCH), 5.62 (s, 1H, OH), 6.91 (d, J = 9.0 Hz, 2H, ArH),
Compound 2e
Yellow solid, 42%, mp > 280 °C. []D26–189.8 (c = 0.5, in
THF). IR (KBr): 3433, 2957, 2928, 2867, 1659, 1605, 1535,
1469, 1422, 1328, 1216, 1141, 1068, 1027, 966, 869 cm1.

Li ZY, et al. Sci China Chem November (2011) Vol.54 No.11
1729
7.53 (d, J = 9.0 Hz, 2H, ArH), 10.74 (s, 1H, CONH). 13C
NMR (75 MHz, DMSO-d6):  = 14.1, 19.1, 31.1, 53.6, 58.8,
67.5, 69.4, 114.8, 121.2, 131.6, 155.5, 166.4. Anal. calcd for
C15H22N2O3: C, 64.73; H, 7.97; N, 10.06. Found: C, 64.96;
H, 8.24; N, 9.83. ESI-MS: m/z = 279 ([M + 1]+, 100%), 301
([M + Na]+, 8%).
CDCl3):  = 8.19 (s, 1H), 8.16 (d, J = 9.0 Hz, 1H), 7.69 (d, J =
7.8 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 7.10 (s, 1H), 5.58 (s,
1H), 5.54 (d, J = 2.7 Hz, 1H), 4.13–4.09 (m, 2H), 2.39 (s,
3H), 1.20 (t, J = 7.2 Hz, 3H); HPLC (AD-H, hexane/2-
propanol 85/15, v/v, 1.0 mL, 254 nm), tR (major) = 13.11
min, tR (minor) = 17.49 min.
Product 4f [28]
2.4 General procedure for the asymmetric Biginelli
reaction
1
White solid; 90% ee, 22% yield; H NMR (300 MHz,
CDCl3):  = 8.12 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.4 Hz,
1H), 7.81–7.77 (m, 2H), 7.61–7.49 (m, 2H), 7.46–7.41 (m,
2H), 6.30 (s, 1H), 5.52 (s, 1H), 3.97–3.88 (m, 2H), 2.45 (s,
3H), 0.88 (t, J = 7.2 Hz, 3H); HPLC (AD-H, hexane/2-
propanol 85/15, v/v, 1.0 mL, 254 nm), tR (major) = 11.69
min, tR (minor) = 17.48 min.
A solution of catalyst 2a (5 mol%), p-toluic acid (5 mol%),
and piperidine·TFA (5 mol%) in THF (0.5 mL) was stirred
at room temperature for 30 min, then urea (0.6 mmol), al-
dehyde (0.5 mmol), ethyl acetoacetate (1.0 mmol), and THF
(0.5 mL) were added sequentially. The reaction mixture was
stirred at room temperature for 3–4.5 d. Then, the crude
product was purified by prepared TLC (petroleum ether/ethyl
acetate, 2/3) to afford the corresponding products. The enan-
tiomeric excesses were determined by HPLC (Daicel Chi-
ralpak AD-H or OD-H column).
Product 4g
1
White solid; 39% ee, 44% yield; H NMR (300 MHz,
CDCl3):  = 7.22 (d, J = 1.8 Hz, 1H), 7.04 (dd, J1 = 7.8 Hz,
J2 = 1.8 Hz, 2H), 6.89 (d, J = 7.8 Hz, 2H), 5.73 (s, 2H),
4.10–4.03 (m, 2H), 3.88 (s, 3H), 2.43 (s, 3H), 1.10 (t, J =
7.2 Hz, 3H); HPLC (OD-H, hexane/2-propanol 85/15, v/v,
1.0 mL, 254 nm), tR (major) = 9.49 min, tR (minor) = 13.29
min.
Product 4a [28]
1
White solid; 69% ee, 41% yield; H NMR (300 MHz,
CDCl3):  = 7.41 (s, 1H), 7.33–7.29 (m, 5H), 5.48 (s, 1H),
5.40 (d, J = 2.4 Hz, 1H), 4.11–4.04 (m, 2H), 2.36 (s, 3H),
1.17 (t, J = 7.2 Hz, 3H); HPLC (OD-H, hexane/2-propanol
85/15, v/v, 1.0 mL, 254 nm), tR (minor) = 8.42 min, tR (ma-
jor) = 10.78 min.
Product 4h
1
White solid; 67% ee, 32% yield; H NMR (300 MHz,
CDCl3):  = 7.38 (s, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.24 (d, J =
8.4 Hz, 2H), 5.42 (s, 1H), 5.38 (d, J = 2.4 Hz, 1H), 4.13–
4.06 (m, 2H), 2.35 (s, 3H), 1.18 (t, J = 7.2 Hz, 3H); HPLC
(OD-H, hexane/2-propanol 95/5, v/v, 1.0 mL, 254 nm), tR
(minor) = 14.85 min, tR (major) = 17.07 min.
Product 4b [28]
1
White solid; 91% ee, 32% yield; H NMR (300 MHz,
CDCl3):  = 7.99 (s, 1H), 7.23–7.06 (m, 4H), 5.61 (s, 1H),
5.37 (d, J = 2.7 Hz, 1H), 4.13–4.02 (m, 2H), 2.35 (s, 3H),
2.33 (s, 3H), 1.17 (t, J = 7.2 Hz, 3H); HPLC (OD-H,
hexane/2-propanol 85/15, v/v, 1.0 mL, 254 nm), tR (minor) =
7.83 min, tR (major) = 10.26 min.
Product 4i [35]
1
White solid; 34% ee, 36% yield; H NMR (300 MHz,
CDCl3):  = 7.98 (s, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.20 (d, J =
8.4 Hz, 2H), 5.78 (s, 1H); 5.36 (d, J = 2.7 Hz, 1H), 4.12–
4.05 (m, 2H), 2.34 (s, 3H), 1.18 (t, J = 7.2 Hz, 3H); HPLC
(AD-H, hexane/2-propanol 80/20, v/v, 0.8 mL, 254 nm), tR
(major) = 8.45 min, tR (minor) = 10.99 min.
Product 4c [28]
1
White solid; 98% ee, 32% yield; H NMR (300 MHz,
CDCl3):  = 7.25 (s, 1H), 6.93–6.80 (m, 4H), 5.38 (d, J =
2.7 Hz, 1H), 5.35 (s, 1H), 4.13–4.06 (m, 2H), 3.79 (s, 3H),
2.36 (s, 3H), 1.18 (t, J = 7.2 Hz, 3H); HPLC (OD-H,
hexane/2-propanol 85/15, v/v, 1.0 mL, 254 nm), tR (minor) =
11.87 min, tR (major) = 13.88 min.
Product 4j
1
White solid; 20% ee, 26% yield; H NMR (300 MHz,
CDCl3):  = 8.19 (d, J = 8.7 Hz, 2H), 7.51 (d, J = 8.7 Hz,
2H), 7.32 (s, 1H), 5.63 (s, 1H), 5.53 (d, J = 2.7 Hz, 1H),
4.15–4.08 (m, 2H), 2.38 (s, 3H), 1.20 (t, J = 7.2 Hz, 3H);
HPLC (AD-H, hexane/2-propanol 85/15, v/v, 1.0 mL, 254
nm), tR (major) = 15.78 min, tR (minor) = 18.98 min.
Product 4d [28]
1
White solid; 90% ee, 38% yield; H NMR (300 MHz,
CDCl3):  = 7.98 (s, 1H), 7.30–7.21 (m, 4H), 5.76 (s, 1H),
5.38 (d, J = 2.7 Hz, 1H), 4.11–4.07 (m, 2H), 2.36 (s, 3H),
1.18 (t, J = 7.2 Hz, 3H); HPLC (OD-H, hexane/2-propanol
85/15, v/v, 1.0 mL, 254 nm), tR (minor) = 8.14 min, tR
(major) = 9.12 min.
3 Results and discussion
3.1 Synthesis of catalysts 2 and 3
Product 4e
1
White solid; 80% ee, 48% yield; H NMR (300 MHz,
A series of novel organocatalysts of trans-4-hydroxy-

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Li ZY, et al. Sci China Chem November (2011) Vol.54 No.11
prolinamides based on calix[4]arenes 2 have been prepared
conveniently within two steps which are depicted in Scheme
2. Starting from various aminocalix[4]arenes 5 [38], con-
densation with Boc-L-hydroxyproline by ClCOOEt in dried
CH2Cl2 in the presence of a mild base triethylamine (TEA)
gave Boc-protected products, and then hydrolysis in dried
CHCl3 in the presence of F3CCO2H (TFA) at 50 °C afforded
target compounds 2, respectively. As comparison, pro-
linamide derivate 3 as model catalyst was prepared by the
similar procedure from p-butoxybenzenamine (Scheme 3).
lix[4]arene scaffold 2 were evaluated for their catalytic effi-
ciencies in the enantioselective Biginelli reaction of ben-
zaldehyde, ethyl acetoacetate, and urea. As shown in Table
1, compared to the results obtained from the reactions cata-
lyzed by di-, tri- and tetra-hydroxyprolin-calix[4]arene-
amides 2b–2e with 10%–45% ee, mono-hydroxyprolina-
mide based on calix[4]arene 2a with 54% ee was evidently
the best choice for the present reaction system in terms of
enantioselectivity. It might be ascribed to the effect of steric
hindrance on the upper rim of calix[4]arene. More groups of
hydroxyprolinamide conducted the cavity of calixarene
binding toward the guest molecules difficultly.
3.3 Optimization of reaction conditions
The new optimization of reaction conditions including acid,
solvent, and additive for catalyst 2a was then carried out,
respectively, and the results are summarized in Table 2.
Firstly, various substituted benzoic acids combined with 2a
were employed to catalyze the reaction in THF (entries 1–3).
It is interesting that catalyst 1 assisted by aromatic acid
bearing electron-donating groups such as 4-methoxybenzoic
acid could not catalyze the Biginelli reaction [28], while 2a
with p-toluic acid was the best assembly than benzoic acid
and 4-nitrobenzic acid. Secondly, in the presence of p-toluic
acid, the solvent effects were then studied (Table 2, entries
3–6). It is obvious that THF is the best solvent compared
with DMF, 1,4-dioxane, and CHCl3. Finally, we surveyed
the effects of the organic amine salts as additive in the
Scheme 2 Synthesis of hydroxyprolin-calix[4]arene-amides 2.
3.2 Screening of catalysts for the Biginelli reaction
As a preliminary test, using the optimal conditions of cata-
lyst 1 in Feng’s work [28], organocatalysts based on ca-
Scheme 3 Synthesis of model catalyst 3.
Table 1 Evaluation of the catalysts 2 in the asymmetric Biginelli reaction of benzaldehyde, ethyl acetoacetate, and ureaa)
Entry
Catalyst
2a
Loading (mol%)
Yield (%)b)
ee (%)c)
54
1
2
3
4
5
5
5
44
38
46
35
65
2b
10
2c
3
45
2d
2
26
2e
1.5
22
a) A solution of 2-chloro-4-nitrobenzoic acid (5 mol%), t-BuNH2·TFA (5 mol%), benzaldehyde (0.5 mmol), and urea (0.6 mmol) in 1,4-dioxane/THF
(2:8, v/v, 1.0 mL) was stirred at 25 °C for 30 min, then catalyst (1.5–5 mol%) and ethyl acetoacetate (1.0 mmol) were added sequentially. The reactions were
performed at 25 °C for 2.5 d; b) isolated yield; c) determined by HPLC analysis (Chiralcel OD-H).

Li ZY, et al. Sci China Chem November (2011) Vol.54 No.11
1731
Table 2 Screening of acids, solvents and additives for the Biginelli reaction catalyzed by 2aa)
Entry
1
Acid
Solvent
THF
Additive
Yield (%)b)
ee (%)c)
55
Benzoic acid
p-Nitrobenzoic acid
p-Toluic acid
p-Toluic acid
p-Toluic acid
p-Toluic acid
p-Toluic acid
p-Toluic acid
p-Toluic acid
p-Toluic acid
p-Toluic acid
p-Toluic acid
p-Toluic acid
p-Toluic acid
15
29
36
16
8





2
THF
58
3
THF
61
4
DMF
1,4-Dioxane
CHCl3
THF
46
5
56
6
7
60

7
tBuNH2·p-TSA
Piperidine·p-TSA
Pyridine·p-TSA
Piperidine·HCl
Piperidine·TFA
Piperidine·TFA
Piperidine·TFA
Piperidine·TFA
trace
10
42
24
30
41
42
38
n.d.
69
8
THF
9
THF
26
10
11
12d)
13e)
14f)
THF
69
THF
69
THF
69
THF
68
THF
9
a) A solution of catalyst 2a (5 mol%), acid (5 mol%) and additive (5 mol%) in solvent (1.0 mL) was stirred at room temperature for 30 min, then urea
(0.5 mmol), benzaldehyde (0.5 mmol), and ethyl acetoacetate (0.5 mmol) were added sequentially. The reactions were performed at room temperature for 2 d;
b) isolated yield; c) determined by HPLC analysis (Chiralcel OD-H); d) the ratio of benzaldehyde/urea/ethyl acetoacetate was 1:1.2:2, and the reaction time
was prolonged to 3 d; e) 10 mol% of catalyst 2a was used; f) model catalyst 3 (5 mol%) was used.
presence of p-toluic acid in THF, and the results are listed in
Table 2, entries 7–11. Although the yield decreased from
36% to 30%, the enantioselectivity could be increased from
61% ee to 69% ee when piperidine·TFA was employed
(Table 2, entry 11 vs. entry 3). Further elevation of yield
without loss of enantioselectivity could be achieved by
changing the ratio of benzaldehyde/urea/ethyl acetoacetate
from 1:1:1 to 1:1.2:2 and prolonging the reaction time from
2 to 3 d (Table 2, entry 12). But more loading of catalyst 2a
(10 mol%) could not obviously influence the reaction (Ta-
ble 2, entry 13). Accordingly, extensive screening has
shown that the optimized reaction conditions are 1:1.2:2 of
benzaldehyde/urea/ethyl acetoacetate, 5 mol% 2a, 5 mol%
p-toluic acid, and 5 mol% piperidine·TFA in THF at room
temperature.
react with urea and ethyl acetoacetate, and the results were
listed in Table 3. The location and electronic effect of sub-
stituent on the aromatic ring have a significant influence on
the enantioselectivity of the process. The reactions of meta-
substituted aromatic aldehydes afforded good-to-excellent
enantioselectivities (80%–98% ee, Table 3, entries 2–5),
while none- and para-substituted ones given lower ee val-
ues (20%–69% ee, Table 3, entries 1 and 7–10). Under the
same location of substituents, aromatic aldehydes with elec-
tron-donating groups conducted higher enantioselectivities
than electron-withdrawing ones. Furthermore, good enanti-
oselectivity (90% ee, Table 3, entry 6) was also observed
when fused-ring 1-naphthaldehyde was employed.
3.5 Mechanism studies
In order to display the importance of calix[4]arene skel-
eton in 2a, L-prolinamide derivative 3 as model catalyst was
further investigated in the Biginelli reaction of benzalde-
hyde, urea, and ethyl acetoacetate under the optimal reac-
tion conditions described above. Without calix[4]arene
scaffold, only 9% ee was obtained (Table 2, entry 14). It
demonstrated that the calix[4]arene skeleton in 2a played an
important role in helping to enantiocontrol the Biginelli
reaction.
Based on the experimental results above, combining the
structural characteristics of calix[4]arene [10–15] and hy-
droxyprolinamide [28], a possible transition state (TS) was
proposed. As depicted in Figure 1, one face of the enamine
was efficiently shielded by the steric hindrance of the bulky
calix[4]arene skeleton, whereas the other face was available
to attack the imine. Hence, a stable six-membered-ring TS
afforded the products with R configuration in the favorable
TS-1, while the unfavorable TS-2 underwent an unstable
eight-membered-ring and unactivated N-acylimine TS
which conducted S products. Herein the piperidine·TFA, as
a bridge between carbonyl of the enamine and the elec-
tron-rich cavity of calix[4]arene built by the supramolecular
interaction of double hydrogen bond and cation- [40, 41]
3.4 Scope of the enantioselective Biginelli reaction
With the optimized conditions in hand, the scope and limi-
tations for the Biginelli reaction catalyzed by 2a were ex-
amined. A range of aromatic aldehydes were employed to

1732
Li ZY, et al. Sci China Chem November (2011) Vol.54 No.11
Table 3 Scope of the enantioselective Biginelli reaction catalyzed by 2aa)
Entry
Ar
Product
4a
Time (d)
Yield (%)b)
ee (%)c) (Configuration)d)
1
2
C6H5
3
3
41
32
32
38
48
22
44
32
36
26
69 (R)
91 (R)
98 (R)
90 (R)
80
3-MeC6H4
3-MeOC6H4
3-ClC6H4
3-NO2C6H4
1-Naphthyl
4-MeOC6H4
4-tBuC6H4
4-BrC6H4
4-NO2C6H4
4b
4c
3
3
4
4d
4e
3.5
4.5
3
5
6
4f
90
7
4g
4
39
8
4h
4i
4
67
9
4
34 (R)
20
10
4j
4.5
a) Reagents and conditions: catalyst 2a (5 mol%), p-toluic acid (5 mol%), piperidine·TFA (5 mol%), urea (0.6 mmol), aldehyde (0.5 mmol), ethyl aceto-
acetate (1.0 mmol), THF (1.0 mL), room temperature; b) isolated yield; c) determined by HPLC analysis (Chiralcel OD-H or AD-H); d) the absolute config-
uration was determined by comparison of the retention time with the ref. [28, 35].
Figure 1 Plausible transition states in the asymmetric Biginelli reaction.
respectively, could further constrain the rotation of enamine,
which leaded to the higher enantioselectivity of the process.
The cation- supramolecular interaction between piperi-
toward higher field ( = 0.053, 0.069 and 0.090 ppm, re-
spectively) because of the shield effect induced by ca-
lix[4]arene cavity. The degrees of the chemical shift chang-
es of methylene protons (: H < H < H) demonstrated
the orientation of piperidine ring in the cavity (Distance
between methylene and cavity: D < D < D) which was in
agreement with the model in transition states (Figure 1).
Furthermore, the achiral Brønsted acid (p-toluic acid) as the
1
dine·TFA and calix[4]arene cavity can be confirmed by H
NMR chemical shift change of the piperidine moiety in
CDCl3 induced by the ring current effect of calix[4]arene
[40]. As shown in Figure 2, all the chemical shift of meth-
ylene protons (H, H and H) on piperidine ring moved

Li ZY, et al. Sci China Chem November (2011) Vol.54 No.11
1733
Figure 2 1H NMR chemical shift change of the piperidine moiety in CDCl3 induced by the ring current effect of calix[4]arene. (a) Calix[4]arene (I) at 5
mM; (b) piperidine·TFA (II) at 5 mM; (c) complex (I + II) at 100 mM.
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3
4
ponents of six-membered-ring in TS-1. Therefore, the in-
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5
6
4 Conclusions
In conclusion, we have developed a series of novel supra-
molecular organocatalysts of hydroxyprolinamide based on
the upper rim of calix[4]arene scaffold for the enantioselec-
tive Biginelli reaction. Under the optimal conditions, the
reactions occurred with moderate-to-excellent ee values,
especially the reactions of meta-substituted aromatic alde-
hydes with electron-donating groups and the fused-ring al-
dehyde afforded excellent enantioselectivities (90%–98%
ee). A plausible transition state constructed by the supramo-
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have been proposed to demonstrate the importance of ca-
lix[4]arene scaffold, p-toluic acid, and piperidine·TFA. This
work has further extended the application of calixarene in
asymmetric catalysis and presented an new way to prepare
valuably optically active 3,4-dihydropyrimidin-2-(1H)-
ones from enantioselective Biginelli reaction.
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We gratefully acknowledge financial support from the National Natural
Science Foundation of China (21002009, 21072093 & 20872051), the
Doctoral Fund of Ministry of Education of China (20090091110017), and
Priority Academic Program Development of Jiangsu Higher Education
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