Y. Li et al. / Tetrahedron Letters 49 (2008) 3632–3633
3633
O
O
H
N
R2COOH/HOBt/DIC
1. Boc-AA-OH/HOBt/DIC
NH2
R2
N
H
N
H
NH2
n
n
Si
Si
Si
n
R1
R1
O
O
2. 55% TFA/DCM
1
2
3
O
H
COIm2
1. 35% HF/H2O
2. H2O2/DMF
N
R2
1. BH3-THF
2. piperidine
HO
N
N
R2
N
N
R2
N
H
n
Si
n
Si
n
R1
R1
R1
5
4
6
Scheme 1. Synthesis 3,4-disubstituted 1-(x-hydroxyalkyl) imidazolin-2-one on aminoalkyl silica gel.
Table 1
Individual 3,4-disubstituted 1-(x-hydroxyalkyl) imidazolin-2-one
thesis of the 3,4-disubstituted 1-(x-hydroxyalkyl) imidazo-
lin-2-ones.
Entry
R1
R2
n
Yielda
Purityb
6a
6b
6c
6d
6e
6f
6g
6h
6i
–CH3
–CH2CH2Ph
–CH2Ph
–CH(C2H5)C6H5
–C3H7
–C6H13
–CH2Ph
–CH2CH2Ph
–CH(C2H5)C6H5
–CH2Ph
–CH2Ph(3-F)
–C3H4(1-C6H5)
–CH2C10H7
1
1
1
1
1
1
1
1
2
2
2
2
79
75
73
86
76
90
88
72
74
80
79
81
73
75
72
85
74
87
82
80
80
83
85
75
Acknowledgements
–CH2CH(CH3)2
–CH2CH(CH3)2
–CH2Ph
–CH2Ph
–H
This work was supported by the National Science
Foundation (R.A.H. NSF4501), the National Science
Foundation of China(Y.Y. NSFC20572098), and Zhejiang
Science and Technology Programme (Y.Y. 2005c3401).
–H
–CH(CH3)2
–CH(CH3)2
–CH(CH3)2
–CH3
References and notes
6j
6k
6l
1. (a) Geysen, H. M.; Meloen, R. H.; Barteling, S. J. Proc. Natl. Acad.
Sci. U.S.A. 1984, 81, 3998; (b) Houghten, R. A. Proc. Natl. Acad. Sci.
U.S.A. 1985, 82, 5131; (c) Houghten, R. A.; Pinilla, C.; Blondelle, S.
E.; Appiei, J. R.; Dooley, C. T.; Cuervo, J. H. Nature 1991, 345, 8486.
2. Houghten, R. A. Proc. Natl. Acad. Sci. U.S.A. 1985, 82, 5131.
3. (a) Nefzi, A.; Ostresh, J. M.; Yu, Y.; Houghten, R. A. J. Org. Chem.
2004, 69, 3603; (b) Yu, Y.; Ostresh, J. M.; Houghten, R. A. J. Org.
Chem. 2002, 67, 3138.
–CH3
a
Yields (in %) are based on the weight of silica gel before cleavage, the
weight of crude product, and are relative to the substitution10 of the resin.
b
Purity (in %) is determinated by the peak area of HPLC at 214 nm.
water at room temperature for 30 min to decompose the
silica forming tetrafluorosilane and water. After removing
the solvent and tetrafluorosilane by lyophilization, 1:1 (v/
v) hydrogen peroxide in DMF was added to further cleave
the Si–C bond and release the final product 6. After remov-
ing the solvent under vacuum and dissolving the product in
1:3 (v/v) acetonitrile in water, mixed bed ion-exchange
resin (AG 501-X8(D) from Bio-Rad Laboratories, Inc.)
was added to remove the byproduct produced by the par-
tially unreacted linker. The desired products 6 were
obtained in good purity9 and yield. The results are summa-
rized in Table 1.
In conclusion, we report here a new approach for the
parallel synthesis of 3,4-disubstituted 1-(x-hydroxyalkyl)
imidazolin-2-ones on ‘volatilizable’ aminoalkyl silica
gel. Both aminopropyl and aminobutyl silica gels were
demonstrated to be good supports for the solid-phase syn-
4. Houghten, R. A.; Yu, Y. J. Am. Chem. Soc. 2005, 127, 8582.
5. Pascal, J. H.; Moran, M. J.; Houghten, R. A. U.S. Patent 6,476,191,
2002.
6. Khatib, I. S.; Parish, R. V. J. Organomet. Chem. 1989, 369, 9.
7. Houghten, R. A.; Yu, Y. J. Am. Chem. Soc. 2005, 127, 8582–8583.
8. Ostresh, J. M.; Schoner, C. C.; Hamashin, V. T.; Nefzi, A.; Meyer,
J.-P.; Houghten, R. A. J. Org. Chem. 1998, 63, 8622.
9. The products were characterized by electrospray LC–MS under ESI
conditions and 1H and 13C NMR. 1H NMR of compound 6f: (500
MHz, DMSO-d6): d 1.52–1.58 (2H, q), 2.71–2.74 (2H, t), 3.06–3.09
(2H, t), 3.19–3.22 (4H, m), 3.23–3.24 (2H, d), 3.36–3.39 (2H, m), 4.42
(1H, s), 7.18–7.23 (3H, m), 7.27–7.30 (2H, m). 13C NMR (125 MHz,
DMSO-d6): d 30.5, 33.4, 40.9, 42.3, 42.4, 45.2, 58.4, 126.1, 128.3,
128.6, 139.4, 160.5.
10. The substitution level of the amino-functional silica gel was deter-
mined by coupling Boc–Ala–OH and phenylacetic acid. The methods
of coupling and cleavage are the same as described in the text. After
removing the ionic products with mixed bed ion-exchange resin for
1 h and lyophilization, 42 mg was obtained from the original 800 mg
resin. The substitution level is thus 0.2 mmol/g.