A rapid parallel synthesis of 2-dialkylamino-4H-imidazolin-4-ones

Article abstract of DOI:10.1081/SCC-120018926

2-Dialkylamino-4H-imidazolin-4-ones 6 were rapidly synthesized by a solution-phase parallel synthetic method, which includes Aza-Wittig reaction of iminophosphorane 3 with aromatic isocynate to give carbodiimide 4 and subsequent reaction of 4 with various

Full text of DOI:10.1081/SCC-120018926

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A Rapid Parallel Synthesis of 2-Dialkylamino-4H-
imidazolin-4-ones
Ming-Wu Ding a , Yong Sun a , Shang-Jun Yang a , Xiao-Peng Liu a & Zhao-Jie Liu a
a Institute of Organic Synthesis , Central China Normal University , Wuhan, P.R. China
Published online: 17 Aug 2006.
To cite this article: Ming-Wu Ding , Yong Sun , Shang-Jun Yang , Xiao-Peng Liu & Zhao-Jie Liu (2003) A Rapid Parallel Synthesis
of 2-Dialkylamino-4H-imidazolin-4-ones, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 33:10, 1651-1658, DOI: 10.1081/SCC-120018926
To link to this article: http://dx.doi.org/10.1081/SCC-120018926
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 10, pp. 1651–1658, 2003
A Rapid Parallel Synthesis of
2-Dialkylamino-4H-imidazolin-4-ones
*
Ming-Wu Ding, Yong Sun, Shang-Jun Yang,
Xiao-Peng Liu, and Zhao-Jie Liu
Institute of Organic Synthesis, Central China Normal
University, Wuhan, P.R. China
ABSTRACT
2-Dialkylamino-4H-imidazolin-4-ones 6 were rapidly synthesized by
a solution-phase parallel synthetic method, which includes Aza-
Wittig reaction of iminophosphorane 3 with aromatic isocynate to
give carbodiimide 4 and subsequent reaction of 4 with various
aliphatic secondary amine in a parallel fashion.
Key Words: 4H-Imidazolin-4-ones; Aza-Wittig reaction; Parallel
synthesis.
*Correspondence: Ming-WuDing, Institute of Organic Synthesis, Central
China Normal University, Wuhan, 430079, P.R. China; E-mail: ding5229@
yahoo.com.cn.
1651
DOI: 10.1081/SCC-120018926
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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1652
Ding et al.
Many 4H-imidazolin-4-ones have shown biological and pharmaceu-
tical activities.[1–3] Some of them exhibited good antibacterial and angio-
tensin II antagonistical activities,[4–6] whereas others appear in a variety
of biologically active molecules, particularly in some alkloids in which a
common structural unit is a derivatized 2-amino-4H-imidazolin-4-one
moiety.[7,8]
Recently, combinatorial synthesis of libraries containing small
organic molecules has become a rapid evolving area of research.[9,10] It
includes solid-phase and solution-phase synthetic techniques. Although
some solid phase synthetic methods for 4H-imidazolin-4-one have been
reported,[11,12] there is no solution phase synthetic route to 2-dialkyl-
amino-4H-imidazolin-4-ones. In our work on synthesis of biologically
active imidazolinones, we developed a facile synthesis of 2-dialkyl-
amino-4H-imidazolin-4-ones.[13,14] Here we wish to report further an
efficient solution-phase parallel synthesis of some unreported derivatives
of 2-dialkylamino-4H-imidazolin-4-ones 6. By using this parallel
synthetic method, 6 was rapidly obtained and the separation of 6 from
the reaction mixture was easily carried out by simple recrystallization.
The vinyliminophosphorane 3 can be easily prepared according to
the following procedure: azide 1 was condensed with benzaldehyde in
presence of sodium ethoxide to give vinyl azide 2 in 58% yield.
Staudinger reaction of 2 with Ph3P gave vinyliminophosphorane 3 in
82% yield.
The vinyliminophosphorane 3 reacted with aromatic isocyanates to
give carbodiimide 4. After removing the byproduct Ph3PO by recrystalli-
zation, the solution 4 was divided equivalently into several parts to which
were added various aliphatic secondary amines separately. The resulted
solution was stood at room temperature for 2–30 h and then recrystal-
lized to give imidazolinones 6 in satisfactory yields. The formation of 6
can be rationalized in terms of an initial nucleophilic addition to give the
guanidine intermediate 5, which cyclized to give 6. It is noteworthy that
the isolated yield of 6 was good even when NR1R2 is bulky di-iso-
propylamine (Sch. 1). The results are listed in Table 1.
In summary, the above solution-phase parallel synthetic method
provides a high-speed synthesis of 2-dialkylamino-4H-imidazolin-4-ones.

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2-Dialkylamino-4H-imidazolin-4-ones Synthesis
1653
Scheme 1.
Due to easily accessible and versatile starting material, this method has the
potential in synthesis of many biologically and pharmaceutically active
imidazolinone derivatives.
EXPERIMENTAL
Melting points were uncorrected. MS were measured on a HP5988A
spectrometer. IR were recorded on a PE-983 infrared spectrometer.
NMR were taken on a Varian Mercury 400 spectrometer. Elementary
analysis were taken on a CHN 2400 elementary analysis instrument.
Preparation of Vinyliminophosphorane 3
To a well-stirred solution containing sodium (6.0 g, 260 mmol) in dry
ethanol (160 mL), a solution of ethyl azidoacetate 1 (33.5 g, 260 mmol)
and benzaldehyde (13.8 g, 130 mmol) in dry ethanol (30 mL) was added
dropwise at ꢀ10ꢁC under nitrogen. The reaction mixture was stirred
at 0ꢁC for 4 h. After this, it was poured into aqueous 30% ammonium
chloride (240 mL) and the formed solid was separated by filtra-
tion, washed with water (30 mL) and dried to give vinyl azide 2,
yield 16.4 g (58%).
To a solution of Ph3P (19.6 g, 75 mmol) in dry CH2Cl2 (60 mL), a
solution of the azide 2 (16.3 g, 75 mmol) in dry CH2Cl2 (40 mL) was
added dropwise at room temperature and stirred for 4 h. The solvent
was removed under reduced pressure and the residual was recrystallized
from methylene dichloride/petroleum ether (1:2) to give vinylimino-
phosphorane 3, yield 27.7 g (82%), m.p. 148–150ꢁC (lit.[15] 149ꢁC).

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1654
Ding et al.
Table 1. Preparation of 2-dialkylamino-4H-imidazolin-4-ones 6.
Compound
Ar
NR1R2
Condition
Yielda (%)
6a
6b
6c
6d
6e
6f
4-Me-Ph
4-Me-Ph
4-Me-Ph
4-Me-Ph
4-Me-Ph
4-Me-Ph
NEt2
N(n-Pr)2
r.t./2 h
r.t./2 h
r.t./2 h
r.t./2 h
r.t./2 h
r.t./24 h
93
86
82
83
83
78
N(n-Bu)2
N(n-C5H11)2
N(n-C6H13)2
N(i-Pr)2
6g
4-Me-Ph
r.t./8 h
80
6h
6i
4-Me-Ph
4-Me-Ph
r.t./2 h
r.t./2 h
91
92
6j
3-Cl-Ph
3-Cl-Ph
3-Cl-Ph
3-Cl-Ph
3-Cl-Ph
3-Cl-Ph
NEt2
N(n-Pr)2
r.t./12 h
r.t./12 h
r.t./12 h
r.t./12 h
r.t./12 h
r.t./30 h
87
82
81
79
85
73
6k
6l
N(n-Bu)2
N(n-C5H11)2
N(n-C6H13)2
N(i-Pr)2
6m
6n
6o
6p
3-Cl-Ph
r.t./16 h
76
6q
6r
3-Cl-Ph
3-Cl-Ph
r.t./12 h
r.t./12 h
88
89
aIsolated yields based on iminophosphorane 3.
General Procedure for Parallel Synthesis of
2-Dialkylamino-4H-imidazolin-4-ones 6
To a solution of vinyliminophosphorane 3 (12.2 g, 27 mmol) in dry
methylene dichloride (90 mL) was added 4-methylphenyl isocyanate
(3.59 g, 27 mmol) or 3-chlorophenyl isocyanate (4.14 g, 27 mmol) under

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2-Dialkylamino-4H-imidazolin-4-ones Synthesis
1655
nitrogen at room temperature. After the reaction mixture was stood for
4–8 h, the solvent was removed off under reduced pressure and ether/
petroleum ether (1:2, 180 mL) was added to precipitate triphenylpho-
sphine oxide. Filtered, the filtrate was condensed and methylene
dichloride was added to make a solution of carbodiimide 4 (90 mL),
which was divided into nine parts (10 mL every part). To each part
of 4 prepared above (10 mL) was added separately diethylamine
(0.31 mL, 3 mmol), or di-n-propylamine (0.42 mL, 3 mmol), or di-n-
butylamine (0.51 mL, 3 mmol), or di-n-pentylamine (0.61 mL, 3 mmol),
or di-n-hexylamine (0.71 mL, 3 mmol), or di-iso-propylamine (0.43 mL,
3 mmol), or di-iso-butylamine (0.52 mL, 3 mmol), or piperidine
(0.30 mL, 3 mmol), or morpholine (0.26 mL, 3 mmol). After the reaction
mixture was stood for 2–30 h, the solvent was removed off under
reduced pressure and the residual was recrystallized from methylene
dichloride/petroleum ether to give 2-dialkylamino-4H-imidazolin-4-ones
6a–6r separately.
1H NMR, 13C NMR, IR, MS, and Elementary Analysis
for Some Compounds 6
6a: yellow crystals, m. p. 117–118ꢁC, H NMR (CDCl3, 400 MHz) ꢀ
1
8.12–7.14 (m, 9H, Ar-H), 6.72 (s, 1H, ¼CH), 3.25 (q, 4H, J ¼ 7.2 Hz,
2NCH2), 2.41 (s, 3H, CH3Ph), 1.05 (t, 6H, J ¼ 7.2 Hz, 2CH3); 13C NMR
(CDCl3, 400 MHz) ꢀ 171.3 (C¼O), 158.5 (C2), 138.6, 138.4, 135.8, 133.0,
130.6, 130.2, 128.3, 127.8, 126.9 (Ar-C), 116.2 (¼CH), 43.7 (NCH2), 21.7
(PhCH3), 13.6 (CH3); IR (cmꢀ1), 1719, 1642, 1556; MS (m/z), 333 (Mþ,
31%), 304 (27%), 215 (26%), 200 (30%), 133 (37%), 116 (94%), 100
(100%); Anal. calcd. for C21H23N3O: C, 75.65; H, 6.95; N, 12.60.
Found: C, 75.54; H, 6.80; N, 12.85.
6b: yellow crystals, m. p. 94–95ꢁC, H NMR (CDCl3, 400 MHz) ꢀ
1
8.13–7.15 (m, 9H, Ar-H), 6.73 (s, 1H, ¼CH), 3.19 (t, 4H, J ¼ 7.3 Hz,
2NCH2), 2.41 (s, 3H, CH3Ph), 1.60–1.54 (m, 4H, 2CH2), 0.76 (t, 6H,
J ¼ 7.3 Hz, 2CH3); 13C NMR (CDCl3, 400 MHz) ꢀ 171.5 (C¼O), 158.7
(C2), 138.8, 138.7, 136.1, 133.2, 130.9, 130.4, 128.5, 128.0, 127.2 (Ar-C),
116.3 (¼CH), 51.6 (NCH2), 22.0, 21.9, 12.0 (CH2CH3 and PhCH3); IR
(cmꢀ1), 1720, 1640, 1556; MS (m/z), 361 (Mþ, 26%), 318 (13%), 290
(50%), 200 (37%), 116 (100%); Anal. calcd. for C23H27N3O: C, 76.42;
H, 7.53; N, 11.62. Found: C, 76.33; H, 7.61; N, 11.78.
6c: yellow crystals, m. p. 130–131ꢁC, H NMR (CDCl3, 400 MHz) ꢀ
1
8.15–7.14 (m, 9H, Ar-H), 6.73 (s, 1H, ¼CH), 3.23 (t, 4H, J ¼ 7.3 Hz,
2NCH2), 2.41 (s, 3H, CH3Ph), 1.57–0.84 (m, 14H, 2CH2CH2CH3);

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1656
Ding et al.
13C NMR (CDCl3, 400 MHz) ꢀ 171.1 (C¼O), 158.3 (C2), 138.5, 138.2,
135.8, 132.9, 130.5, 130.0, 128.1, 127.5, 126.9 (Ar-C), 115.7 (¼CH), 49.4
(NCH2), 30.3, 21.5, 20.4, 14.2 (CH2CH2CH3 and PhCH3); IR (cmꢀ1),
1722, 1638, 1555; MS (m/z), 389 (Mþ, 15%), 333 (10%), 290 (38%),
200 (16%), 116 (100%); Anal. calcd. for C25H31N3O: C, 77.08; H, 8.02;
N, 10.79. Found: C, 77.17; H, 7.94; N, 10.93.
6f: yellow crystals, m. p. 163–165ꢁC, H NMR (CDCl3, 400 MHz) ꢀ
1
8.16–7.14 (m, 9H, Ar-H), 6.70 (s, 1H, ¼CH), 3.70–3.52 (m, 2H, 2NCH),
2.41 (s, 3H, CH3Ph), 1.26 (d, 12H, J ¼ 7.0 Hz, 4CH3); 13C NMR (CDCl3,
400 MHz) ꢀ 171.4 (C¼O), 157.5 (C2), 138.7, 138.3, 136.1, 133.9, 130.7,
130.3, 128.4, 127.9, 127.2 (Ar-C), 116.3 (¼CH), 49.3 (NCH), 21.9, 21.7
(CH3 and PhCH3); IR (cmꢀ1), 1721, 1638, 1550; MS (m/z), 361 (Mþ,
18%), 318 (60%), 304 (23%), 214 (18%), 116 (100%); Anal. calcd. for
C23H27N3O: C, 76.42; H, 7.53; N, 11.62. Found: C, 76.21; H, 7.44;
N, 11.81.
6g: yellow crystals, m. p. 164–166ꢁC, H NMR (CDCl3, 400 MHz) ꢀ
1
8.15–7.14 (m, 9H, Ar-H), 6.73 (s, 1H, ¼CH), 3.08 (d, 4H, J ¼ 6.6 Hz,
2NCH2), 2.42 (s, 3H, CH3Ph), 2.08–1.96 (m, 2H, 2CH), 0.84 (d, 12H,
J ¼ 6.8 Hz, 4CH3); 13C NMR (CDCl3, 400 MHz) ꢀ 170.8 (C¼O), 158.5
(C2), 138.2, 137.8, 135.4, 132.6, 130.2, 129.7, 127.8, 127.3, 126.3 (Ar-C),
115.7 (¼CH), 57.5 (NCH2), 27.8, 21.3, 20.2 (CH(CH3)2 and PhCH3);
IR (cmꢀ1), 1720, 1636, 1555; MS (m/z), 389 (Mþ, 9%), 290 (100%),
145 (32%), 116 (83%); Anal. calcd. for C25H31N3O: C, 77.08; H, 8.02;
N, 10.79. Found: C, 77.23; H, 8.15; N, 10.58.
6k: yellow crystals, m. p. 124–125ꢁC, H NMR (CDCl3, 400 MHz) ꢀ
1
8.13–7.20 (m, 9H, Ar-H), 6.75 (s, 1H, ¼CH), 3.19 (t, 4H, J ¼ 7.3 Hz,
2NCH2), 1.62–1.54 (m, 4H, 2CH2), 0.79 (t, 6H, J ¼ 6.5 Hz, 2CH3);
13C NMR (CDCl3, 400 MHz) ꢀ 170.7 (C¼O), 158.1 (C2), 138.2, 136.9,
136.8, 135.7, 135.1, 130.9, 130.6, 128.7, 128.4, 128.3, 128.2, 127.4, 125.5
(Ar-C), 117.3 (¼CH), 51.5 (NCH2), 21.8, 11.9 (CH2CH3); IR (cmꢀ1),
1723, 1640, 1558; MS (m/z), 381 (Mþ, 11%), 383 (4%), 310 (29%), 200
(30%), 116 (100%); Anal. calcd. for C22H24ClN3O: C, 69.19; H, 6.33;
N, 11.00. Found: C, 69.43; H, 6.24; N, 11.16.
6l: yellow crystals, m. p. 118–120ꢁC, H NMR (CDCl3, 400 MHz) ꢀ
1
8.15–7.20 (m, 9H, Ar-H), 6.76 (s, 1H, ¼CH), 3.22 (t, 4H, J ¼ 7.3 Hz,
2NCH2), 1.58–0.86 (m, 14H, 2CH2CH2CH3);13C NMR (CDCl3,
400 MHz) ꢀ 170.9 (C¼O), 158.2 (C2), 138.4, 137.1, 135.9, 135.3, 131.1,
130.8, 128.9, 128.6, 128.5, 128.4, 127.6, 125.7 (Ar-C), 117.5 (¼CH), 49.9
(NCH2), 30.7, 20.9, 14.6 (CH2CH2CH3); IR (cmꢀ1), 1724, 1635, 1556;
MS (m/z), 409 (Mþ, 7%), 411 (3%), 310 (24%), 200 (18%), 116 (100%);
Anal. calcd. for C24H28ClN3O: C, 70.32; H, 6.88; N, 10.25. Found:
C, 70.14; H, 6.95; N, 10.44.

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2-Dialkylamino-4H-imidazolin-4-ones Synthesis
1657
6o: yellow crystals, m. p. 148–150ꢁC, HNMR (CDCl3, 400 MHz) ꢀ
8.18–7.16 (m, 9H, Ar-H), 6.73 (s, 1H, ¼CH), 3.72–3.55 (m, 2H, 2NCH),
1.28 (d, 12H, J ¼ 7.0 Hz, 4CH3); 13C NMR (CDCl3, 400 MHz) ꢀ 170.5
(C¼O), 156.7 (C2), 138.4, 137.6, 135.8, 134.9, 130.9, 130.6, 128.5, 128.2,
127.4, 126.9, 126.3, 125.5 (Ar-C), 117.3 (¼CH), 49.5 (NCH), 21.8 (CH3);
IR (cmꢀ1), 1722, 1638, 1552; MS (m/z), 381 (Mþ, 10%), 383 (3%),
338 (37%), 214 (18%), 153 (38%), 116 (100%); Anal. calcd. for
C22H24ClN3O: C, 69.19; H, 6.33; N, 11.00. Found: C, 69.03; H, 6.42;
N, 11.17.
1
ACKNOWLEDGMENT
We gratefully acknowledge financial support of this work by the
National Natural Science Foundation of China (Project No. 20102001).
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Received in Japan May 6, 2002