Synthesis of a library of imidazolin-4-ones using poly(ethylene glycol) as soluble support

Article abstract of DOI:10.1055/s-2007-984912

A library of imidazolin-4-ones has been synthesized using poly(ethylene glycol) (PEG) as soluble polymer support. The imidazolin-4-ones 6 or 7 were synthesized effectively by reaction of primary amine with PEG-supported carbodiimides 4, which were obtaine

Full text of DOI:10.1055/s-2007-984912

2280
LETTER
Synthesis of a Library of Imidazolin-4-ones Using Poly(ethylene glycol) as
Soluble Support
Synthesis of
a
Libr
o
ar
y
of Imida
n
zolin-4-ones
g
using Poly(
e
-
thylene
Xglycol) ia Li, Chang Xie, Ming-Wu Ding,* Zu-Ming Liu, Guang-Fu Yang*
Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, Central China Normal University, Wuhan 430079,
P. R. of China
Fax +86(27)67862041; E-mail: mwding@mail.ccnu.edu.cn
Received 10 February 2007
philes under mild conditions.7 Herein we wish to report an
Abstract: A library of imidazolin-4-ones has been synthesized
efficient synthesis of imidazolin-4-ones from PEG-sup-
ported iminophosphorane in parallel fashion. Commer-
cially available, inexpensive difunctional PEG-4000 was
using poly(ethylene glycol) (PEG) as soluble polymer support. The
imidazolin-4-ones 6 or 7 were synthesized effectively by reaction of
primary amine with PEG-supported carbodiimides 4, which were
obtained from aza-Wittig reaction of PEG-supported iminophos- chosen as a soluble polymer support in this study.
phoranes 3 with isocyanates.
As shown in Scheme 1, chloroacetyl chloride was added
dropwise to the soluble support PEG 4000 in the presence
of Et3N in anhydrous MeCN at 0 °C. The mixture was
Key words: poly(ethylene glycol), polymer-supported, aza-Wittig
reaction, imidazolin-4-one, ylides
then heated to refluxing temperature for 24 hours. The re-
sulting PEG-supported alkyl chloride 1 was obtained by
Imidazolin-4-ones have received considerable attention
over the last few years due to their interesting biological
activities. Some of them have exhibited promising
pharmacological activities,1 others have been shown to
possess good herbicidal activities, such as imazametha-
benz and imazethapyr.2 They are also a key structural
skeleton in some alkaloids.3 Hence these heterocycles, in
particular 2,3,5-trisubstituted imidazolin-4-ones, have be-
come attractive combinatorial chemistry libraries in drug
discovery and crop protection.
precipitation in diethyl ether in 95% yield. A solution of 1
in anhydrous MeCN was then treated with sodium azide
under nitrogen atmosphere and the mixture was heated for
20 hours at reflux. Similarly, the PEG-supported azide 2
was obtained by precipitation in diethyl ether.8 Further
reaction of 2 with triphenylphosphine furnished the PEG-
supported iminophosphorane 3, which was allowed to re-
act with aromatic isocyanates to produce PEG-supported
carbodiimides 4 via intermolecular aza-Wittig reaction.9
Table 1 Liquid-Phase Synthesis of Imidazolin-4-ones by aza-
Wittig Reaction
There are many known methods for the synthesis of
imidazolin-4-ones, including the aza-Wittig reaction.4
Recently several approaches to access this class of
compounds based on solid-phase synthesis have been
reported.5 However, there is still no report on the use of
soluble polymer support to prepare these molecules.
Entry
Product Ar
R
Conditions Yielda
(%)
6a
7a
Ph
Ph
i-Pr
i-Pr
r.t./5 h
r.t./5 h
45
40
1
2
Currently, liquid-phase synthesis using soluble polymers
technique has attracted widespread interest in the field of
combinatorial chemistry.6 It possesses both the advantag-
es of conventional liquid-phase synthesis and solid-phase
synthesis. Moreover, the soluble polymer-bound species
allow using routine analytical methods (1H NMR, TLC or
IR) the monitoring of the reaction progress and determin-
ing the structures of products attached to polymer support
directly. Poly(ethylene glycol) (PEG) is an ideal support
and the most widely used polymer for liquid-phase
combinatorial synthesis in terms of its controllable solu-
bility in different solvents. Recently we have been inter-
ested in the synthesis of imidazolinones, quinazolinones
and thienopyrimidinones via aza-Wittig reaction of a- or
b-ethoxycarbonyl iminophosphorane with aromatic iso-
cyanate and subsequent reaction with various nucleo-
6b
7b
Ph
Ph
c-Hex
c-Hex
r.t./5 h
r.t./5 h
44
38
3
4
6c
6d
6e
6f
Ph
n-Pr
n-Bu
i-Bu
PhCH2
Hb
r.t./2 h
r.t./2 h
r.t./3 h
r.t./2 h
r.t./1 h
r.t./1 h
r.t./1 h
r.t./1 h
r.t./1 h
r.t./1 h
91
88
84
78
85
92
87
82
86
80
Ph
5
Ph
6
Ph
7
6g
6h
6i
Ph
8
Ph
Me
9
Ph
Et
10
11
12
6j
3-MeC6H4
3-MeC6H4
3-MeC6H4
Hb
6k
6l
Me
Et
SYNLETT 2007, No. 14, pp 2280–2282
Advanced online publication: 20.07.2007
DOI: 10.1055/s-2007-984912; Art ID: W03807ST
© Georg Thieme Verlag Stuttgart · New York
0
3
.0
9
.2
0
0
7
a Isolated yields based on PEG-supported carbodiimide 4.
b Concentrated ammonia solution was used.

LETTER
Synthesis of a Library of Imidazolin-4-ones using Poly(ethylene glycol)
2281
O
O
O
O
ClCH2COCl
NaN3, MeCN
reflux, 20 h
OH
N3
Cl
Et3N, MeCN
reflux, 24 h
2
1
O
O
O
O
Ph3P, CH2Cl2
r.t., 1 h
ArNCO, CH2Cl2
r.t., 2 h
N=C=NAr
O
N=PPh3
4
3
O
O
O
(a)
N
RNH2, CH2Cl2
r.t., 1–5 h
NHR
N
Ar
N
R
+
N
N
_
OH
NHAr
(b)
NHR
NHAr
5
6
7
Scheme 1 Synthesis of imidazolin-4-ones 6 or 7 using poly(ethylene glycol) as soluble support
However, when alkyl isocyanates were reacted with product. However, when steric hindrance was present in
iminophosphorane 3, the corresponding carbodiimides the intermediate 5, a mixture of 6 and 7 was obtained.
were not obtained probably due to dimerization or poly-
merization.10
Acknowledgment
With the PEG-supported carbodiimides 4 in hand, we
switched our attention to its application in liquid-phase
combinatorial synthesis. After the PEG-supported carbo-
We greatly acknowledge financial support of this work from the
National NSFC (No. 20572030, 20672041 and 20432010), the
Cultivation Fund of the Key Scientific and Technical Innovation
diimides 4 reacted with primary amine at room tempera-
ture, the cleaved PEG support was precipitated by
addition of diethyl ether and separated by simple filtra-
tion. The imidazolin-4-ones 6 or 7 were obtained by re-
crystallization from a solvent mixture of hexane and
dichloromethane (1:1–1:3) or by column chromatography
on silica gel [EtOAc–petroleum ether (1:2) as the elu-
Project of Ministry of Education of China (No. 705039), Key
Project of Science and Technology of Ministry of Education of
China (No. 107082 and 106116), Program for Excellent Research
Group of Hubei Province (No. 2004ABC002), Natural Science
Foundation of Hubei Province (2006ABB016), and Science Leader
Plan of Wuhan City (No. 200750730312).
ent].11 In some cases, a trace amount of the PEG residue References and Notes
and Ph3PO was present together with the final products 6
(1) (a) Gadwood, R. C.; Kamdar, B. V.; Dubray, L. A. C.;
or 7. This problem could be easily solved by passing the
crude product through a pad of silica gel using EtOAc–pe-
troleum ether (1:3–1:1) as the eluent. A variety of primary
amines and isocyanates could be used for this synthetic
strategy and the products were obtained in good yields
(Table 1).
Wolfe, M. L.; Smith, M. P.; Watt, W.; Mizsak, S. A.; Groppi,
V. E. J. Med. Chem. 1993, 36, 1480. (b) Cafieri, F.;
Fattorusso, E.; Mangoni, A.; Taglialatela-Scafati, O.
Tetrahedron Lett. 1996, 37, 3587. (c) Chan, G. W.; Mong,
S.; Hemling, M. E.; Freyer, A. J.; Offen, P. H.; DeBrosse, C.
W.; Sarau, H. M.; Westley, J. W. J. Nat. Prod. 1993, 56, 116.
(2) The Imidazolinone Herbicides; Shaner, D. L.; O’Connor, S.
L., Eds.; CRC Press: Boca Raton, 1991.
As can be seen in Scheme 1, reaction between the PEG-
supported carbodiimides 4 with primary amine should af-
ford the PEG-supported guanidine intermediates 5. From
these intermediates 5, the formation of two regioisomeric
imidazolin-4-ones 6 (pathway a) or 7 (pathway b) could
take place. When primary amines with functional groups
such as n-propyl, n-butyl, benzyl, methylamine, etc.
(Table 1, entries 3–12) were used, regioselective cycliza-
tion with the formation of 2-arylaminoimidazolin-4-one 6
took place. However, for primary amines having function-
al groups like isopropyl and cyclohexylamine (Table 1,
entries 1 and 2), both of the products 6 and 7 were formed.
The results indicated that for this type of transformation,
regioselectivity toward the formation of 6 seemed to be
influenced not only by the difference in the nucleophilic
character of the two nitrogen atoms of the guanidine inter-
mediate 5, but also by steric factor. Thus, when nucleo-
philic, sterically non-hindered primary amines were used,
2-arylamino-imidazolin-4-ones 6 were formed as the sole
(3) (a) Sato, H.; Tsuda, M.; Watanabe, K.; Kobayashi, J.
Tetrahedron 1998, 54, 8687. (b) Loukaci, A.; Guyot, M.;
Chiaroni, A.; Riche, C. J. Nat. Prod. 1998, 61, 519.
(c) Gulla, G.; Mancini, I.; Zibrowius, H.; Pietra, F. Helv.
Chim. Acta 1989, 72, 1444.
(4) (a) Cole, J. O.; Ronzio, A. R. J. Am. Chem. Soc. 1994, 66,
1584. (b) Kumar, P.; Makerjee, A. K. Indian J. Chem., Sect.
B 1979, 18, 240. (c) Ashare, R.; Mukerjee, A. K. Indian J.
Chem. Soc., Sect. B 1986, 25, 762. (d) Takeuchi, H.;
Hagiwara, S.; Eguchi, S. Tetrahedron 1989, 45, 6375.
(e) Ding, M. W.; Tu, H. Y.; Liu, Z. J. Synth. Commun. 1997,
27, 3657.
(5) (a) Li, J.; Zhang, Z.; Fan, E. Tetrahedron Lett. 2004, 45,
1267. (b) Fu, M. M.; Fernandez, M.; Smith, M. L.; Flygare,
J. A. Org. Lett. 1999, 1, 1351. (c) Drewry, D. H.; Ghiron, C.
Tetrahedron Lett. 2000, 41, 6989. (d) Li, M.; Wilson, L. J.
Tetrahedron Lett. 2001, 42, 1455. (e) Yu, Y. P.; Ostresh, J.
M.; Houghten, R. A. J. Comb. Chem. 2001, 3, 521.
(f) Lange, U. E. W. Tetrahedron Lett. 2002, 43, 6857.
(g) Yang, K. X.; Lou, B. L.; Saneii, H. Tetrahedron Lett.
2002, 43, 4463. (h) Yu, Y. P.; Ostresh, J. M.; Houghten, R.
Synlett 2007, No. 14, 2280–2282 © Thieme Stuttgart · New York

2282
H.-X. Li et al.
LETTER
A. J. Org. Chem. 2002, 67, 3138. (i) Yu, Y. P.; Ostresh, J.
M.; Houghten, R. A. Tetrahedron 2002, 58, 3349.
(j) Evindar, G.; Batey, R. A. Org. Lett. 2003, 5, 1201.
NH), 6.94–7.33 (m, 5 H, ArH). MS: m/z (%) = 257 (6) [M+],
176 (88), 131 (10), 118 (100). Anal. Calcd for C15H19N3O:
C, 70.01; H, 7.44; N, 16.33. Found: C, 70.25; H, 7.41; N,
16.24. 7b: white crystals; mp 92–93 °C. 1H NMR (400 MHz,
CDCl3): d = 1.07–2.04 (m, 10 H, 5 × CH2), 3.73 (s, 1 H, NH),
3.80–3.90 (m, 1 H, CH), 4.22 (s, 2 H, CH2), 7.25–7.55 (m, 5
H, ArH). MS: m/z (%) = 257 (5) [M+], 202 (3), 174 (100),
146 (15), 119 (70). Anal. Calcd for C15H19N3O: C, 70.01; H,
7.44; N, 16.33. Found: C, 70.17; H, 7.57; N, 16.18. 6c: white
crystals; mp 76–77 °C. 1H NMR (400 MHz, CDCl3): d =
0.98 (t, J = 7.2 Hz, 3 H, Me), 1.73–1.82 (m, 2 H, CH2), 3.66
(t, J = 7.2 Hz, 2 H, NCH2), 3.91 (s, 2 H, CH2), 4.58 (s, 1 H,
NH), 6.98–7.34 (m, 5 H, ArH). MS: m/z (%) = 217 (54)
[M+], 174 (100), 118 (85). Anal. Calcd for C12H15N3O: C,
66.34; H, 6.96; N, 19.34. Found: C, 66.45; H, 6.78; N, 19.38.
6d: white crystals; mp 46–47 °C. 1H NMR (400 MHz,
CDCl3): d = 0.97 (t, J = 7.2 Hz, 3 H, Me), 1.37–1.73 (m, 4 H,
CH2CH2), 3.69 (t, J = 7.2 Hz, 2 H, NCH2), 3.89 (s, 2 H, CH2),
4.60 (s, 1 H, NH), 6.96–7.33 (m, 5 H, ArH). MS: m/z (%) =
231 (58) [M+], 202 (18), 188 (58), 176 (64), 146 (33), 100
(100). Anal. Calcd for C13H17N3O: C, 67.51; H, 7.41; N,
18.17. Found: C, 67.42; H, 7.36; N, 18.22. 6e: white crystals;
mp 82–84 °C. 1H NMR (400 MHz, CDCl3): d = 0.97 (d, J =
6.8 Hz, 6 H, 2 × Me), 2.20–2.30 (m, 1 H, CH), 3.51 (d, J =
7.6 Hz, 2 H, NCH2), 3.90 (s, 2 H, CH2), 4.60 (s, 1 H, NH),
6.95–7.33 (m, 5 H, ArH). MS: m/z (%) = 231 (7) [M+], 176
(100), 119 (32), 106 (28). Anal. Calcd for C13H17N3O: C,
67.51; H, 7.41; N, 18.17. Found: C, 67.47; H, 7.53; N, 18.36.
6f: white crystals; mp 87–88 °C. 1H NMR (400 MHz,
CDCl3): d = 3.91 (s, 2 H, CH2), 4.65 (s, 1 H, NH), 4.87 (s, 2
H, NCH2), 6.96–7.54 (m, 10 H, ArH). MS: m/z (%) = 265 (7)
[M+], 236 (9), 207 (21), 160 (38), 91 (100). Anal. Calcd for
C16H15N3O: C, 72.43; H, 5.70; N, 15.84. Found: C, 72.28; H,
5.61; N, 15.98. 6g: white crystals; mp 264–266 °C. 1H NMR
(400 MHz, DMSO-d6): d = 3.74 (s, 2 H, CH2), 7.05–7.49 (m,
5 H, ArH), 7.55 (s, 1 H, NH), 9.92 (s, 1 H, NH). MS: m/z
(%) = 175 (83) [M+], 146 (112), 118 (100). Anal. Calcd for
C9H9N3O: C, 61.70; H, 5.18; N, 23.99. Found: C, 61.95; H,
5.17; N, 23.93. 6h: white crystals; mp 97–98 °C. 1H NMR
(400 MHz, DMSO-d6): d = 2.98 (s, 3 H, NMe), 3.84 (s, 2 H,
CH2), 7.02 (s, 1 H, NH), 6.95–7.29 (m, 5 H, ArH). MS: m/z
(%) = 189 (92) [M+], 160 (62), 132 (100). Anal. Calcd for
C10H11N3O: C, 63.48; H, 5.86; N, 22.21. Found: C, 63.41; H,
5.71; N, 22.36. 6i: white crystals; mp 113–114 °C. 1H NMR
(400 MHz, CDCl3): d = 1.31 (t, J = 7.2 Hz, 3 H, Me), 3.77
(q, J = 7.2 Hz, 2 H, NCH2), 3.91 (s, 2 H, CH2), 4.60 (s, 1 H,
NH), 7.01–7.34 (m, 5 H, ArH). MS: m/z (%) = 203 (51)
[M+], 174 (36), 160 (63), 146 (21), 104 (100). Anal. Calcd
for C11H13N3O: C, 65.01; H, 6.45; N, 20.67. Found: C,
65.25; H, 6.57; N, 20.60. 6j: white crystals; mp 253–255 °C.
1H NMR (400 MHz, DMSO-d6): d = 2.29 (s, 3 H, Me), 3.86
(s, 2 H, CH2), 6.75–7.24 (m, 4 H, ArH), 7.53 (s, 1 H, NH),
9.86 (s, 1 H, NH). MS: m/z (%) = 203 (46) [M+], 174 (45),
160 (9), 146 (100), 91 (60). Anal. Calcd for C10H11N3O: C,
63.48; H, 5.86; N, 22.21. Found: C, 63.31; H, 5.94; N, 22.02.
6k: white crystals; mp 108–109 °C. 1H NMR (400 MHz,
CDCl3): d = 2.33 (s, 3 H, Me), 3.17 (s, 3 H, Me), 3.91 (s, 2
H, CH2), 4.60 (s, 1 H, NH), 6.78–7.22 (m, 4 H, ArH). MS:
m/z (%) = 203 (45) [M+], 174 (45), 146 (100), 118 (41).
Anal. Calcd for C11H13N3O: C, 65.01; H, 6.45; N, 20.67.
Found: C, 65.13; H, 6.59; N, 20.53. 6l: white crystals; mp
101–102 °C. 1H NMR (400 MHz, CDCl3): d = 1.30 (t, J = 7.2
Hz, 3 H, Me), 2.33 (s, 3 H, Me), 3.75 (q, J = 7.2 Hz, 2 H,
NCH2), 3.90 (s, 2 H, CH2), 4.64 (s, 1 H, NH), 6.79–7.20 (m,
4 H, ArH). MS: m/z (%) = 217 (100) [M+], 188 (48), 174
(94), 160 (21), 118 (82). Anal. Calcd for C12H15N3O: C,
66.34; H, 6.96; N, 19.34. Found: C, 66.31; H, 6.82; N, 19.46.
(6) (a) Sheng, S. R.; Wang, Q.; Wang, Q. Y.; Guo, L.; Liu, X.
L.; Huang, X. Synlett 2006, 1887. (b) Kreidler, B.; Baro, A.;
Christoffers, J. Synlett 2005, 465. (c) Lin, X. F.; Zhang, J.;
Cui, S. L.; Wang, Y. G. Synthesis 2003, 1569. (d) Kumar,
H. M. S.; Qazi, N. A.; Shafi, S.; Kumar, V. N.; Krishna, A.
D.; Yadav, J. S. Tetrahedron Lett. 2005, 46, 7205. (e)Reed,
N. N.; Dickerson, T. J.; Boldt, G. E.; Janda, K. D. J. Org.
Chem. 2005, 70, 1728. (f) Attanasi, O. A.; De Crescentini,
L.; Favi, G.; Filippone, P.; Lillini, S.; Mantellini, F.;
Santeusanio, S. Org. Lett. 2005, 7, 2469.
(7) (a) Xu, S. Z.; Hu, Y. G.; Ding, M. W. Synthesis 2006, 4180.
(b) Yuan, J. Z.; Fu, B. Q.; Ding, M. W.; Yang, G. F. Eur. J.
Org. Chem. 2006, 4170. (c) Ding, M. W.; Xu, S. Z.; Zhao, J.
F. J. Org. Chem. 2004, 69, 8366. (d) Ding, M. W.; Chen, Y.
F.; Huang, N. Y. Eur. J. Org. Chem. 2004, 3872. (e) Ding,
M. W.; Zeng, G. P.; Wu, T. J. Synth. Commun. 2000, 30,
1599.
(8) PEG-Supported Azide 2. A mixture of PEG-supported
chloride 1 (10 mmol) and sodium azide (0.78 g, 12 mmol) in
anhyd MeCN (100 mL) was stirred for 20 h at reflux under
a nitrogen atmosphere. The mixture was filtered, the filtrate
was condensed and Et2O was added to precipitate the PEG-
1
supported azides 2. H NMR (400 MHz, CDCl3): d = 3.47–
3.82 (s, PEG-OCH2CH2O), 3.92 (s, 2 H, CH2N), 4.34 (t, J =
6.4 Hz, 2 H, PEG-OCH2CH2OCO). IR (KBr): 2108 (N3),
1744 (C=O), 1242 cm–1.
(9) PEG-Supported Carbodiimide 4a. A solution of
triphenylphosphine (2.62 g, 10 mmol) in anhyd CH2Cl2 (10
mL) was added dropwise under nitrogen at r.t. to a well-
stirred solution of the PEG-supported azide 2 (10 mmol) in
anhyd CH2Cl2 (100 mL). The reaction mixture was stirred at
r.t. for 1 h, then phenyl isocyanate (1.19 g, 10 mmol) was
added at 0 °C. After the reaction mixture was stirred at r.t.
for 2 h, the solvent was removed under reduced pressure.
The PEG-supported carbodiimide 4a (Ar = Ph) was
precipitated by addition of Et2O and was separated by simple
filtration. 1H NMR (400 MHz, CDCl3): d = 3.48–3.64 (m,
PEG-OCH2CH2O), 3.82 (s, 2 H, NCH2COO), 4.30 (t, J = 6.4
Hz, 2 H, PEG-CH2OCO). IR (KBr): 2144 (N=C=N), 1753
(C=O), 1242 cm–1.
(10) Molina, P.; Alajarin, M.; Lopez-Leonardo, C. J. Prakt.
Chem. 1993, 335, 305.
(11) Imidazolin-4-ones 6 and 7: A solution of primary amine (2
mmol) in CH2Cl2 (5 mL) was added to PEG-supported
carbodiimide 4 (2 mmol) in CH2Cl2 (10 mL), and the
mixture was stirred for the time shown in Table 1 at r.t. The
PEG was precipitated by addition of Et2O and was separated
by simple filtration. The imidazolin-4-ones were obtained by
recrystallization from a solvent mixture of hexane and
CH2Cl2 (1:1–1:3) or by column chromatography on silica gel
(EtOAc–PE, 1:3–1:1). Spectral data for imidazolin-4-ones 6
and 7: 6a: white crystals; mp 130–131 °C. 1H NMR (400
MHz, CDCl3): d = 1.52 (d, J = 7.2 Hz, 6 H, 2 × Me), 3.84 (s,
2 H, CH2), 4.57–4.61 (m, 2 H, NH, CH), 6.97–7.34 (m, 5 H,
ArH). MS: m/z (%) = 217 (32) [M+], 174 (100), 118 (77), 146
(30), 106 (48). Anal. Calcd for C12H15N3O: C, 66.34; H,
6.96; N, 19.34. Found: C, 66.03; H, 7.12; N, 19.38. 7a: white
crystals; mp 101–102 °C. 1H NMR (400 MHz, CDCl3): d =
1.17–1.22 (m, 6 H, 2 × Me), 3.79–4.02 (m, 2 H, NH, CH),
4.20–4.25 (m, 2 H, CH2), 7.24–7.57 (m, 5 H, ArH). MS:
m/z (%) = 217 (11) [M+], 174 (66), 118 (100). Anal. Calcd
for C12H15N3O: C, 66.34; H, 6.96; N, 19.34. Found: C, 66.41;
H, 7.05; N, 19.11. 6b: white crystals; mp 132–134 °C. 1H
NMR (400 MHz, CDCl3): d = 1.22–2.38 (m, 10 H, 5 × CH2),
3.81 (s, 2 H, CH2), 4.14–4.21 (m, 1 H, CH), 4.53 (s, 1 H,
Synlett 2007, No. 14, 2280–2282 © Thieme Stuttgart · New York

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