A facile and selective synthesis of 2-alkylamino-4H-imidazolin-4-ones

Article abstract of DOI:10.1081/SCC-100103536

The carbodiimides 2, obtained from aza-Wittig reactions of vinylimino-phosphorane 1 with aromatic isocyanates, reacted with aliphatic primary amines to give mainly 2-alkylamino-4H-imidazolin-4-ones 4 with unusual selectivity.

Full text of DOI:10.1081/SCC-100103536

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A FACILE AND SELECTIVE
SYNTHESIS OF 2-
ALKYLAMINO-4H-
IMIDAZOLIN-4-ONES
Ming-Wu Ding a , Zhi-Feng Xu a , Zhao-Jie Liu a &
Tian-Jie Wu a
a Institute of Organic Synthesis, Central China
Normal University , Wuhan, 430079, P.R. China
Published online: 09 Nov 2006.
To cite this article: Ming-Wu Ding , Zhi-Feng Xu , Zhao-Jie Liu & Tian-Jie Wu (2001)
A FACILE AND SELECTIVE SYNTHESIS OF 2-ALKYLAMINO-4H-IMIDAZOLIN-4-ONES,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 31:7, 1053-1057, DOI: 10.1081/SCC-100103536
To link to this article: http://dx.doi.org/10.1081/SCC-100103536
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SYNTHETIC COMMUNICATIONS, 31(7), 1053–1057 (2001)
A FACILE AND SELECTIVE SYNTHESIS OF
2-ALKYLAMINO-4H-IMIDAZOLIN-4-ONES
Ming-Wu Ding,* Zhi-Feng Xu, Zhao-Jie Liu, and
Tian-Jie Wu
Institute of Organic Synthesis, Central China Normal
University, Wuhan, 430079, P.R. China
ABSTRACT
The carbodiimides 2, obtained from aza-Wittig reac-
tions of vinylimino-phosphorane 1 with aromatic isocyanates,
reacted with aliphatic primary amines to give mainly 2-alkyl-
amino-4H-imidazolin-4-ones 4 with unusual selectivity.
4H-Imidazolin-4-ones are important heterocycles having bactericidal,
antiinflammatory, and angiotensin II antagonistical activities.1–4 Some of
them appear in a variety of biologically active molecules, particularly in
some alkaloids in which a common structural unit is a derivatized 2-(alkyl)-
amino-4H-imidazolin-4-one moiety.5–7 Although there are many known
methods for the synthesis of 4H-imidazolin-4-one,8–12 the 2-alkylamino
derivatives are not easily accessible by general routes. Here we report a
facile and selective synthesis of 2-alkylamino-4H-imidazolin-4-ones via the
reaction of aliphatic primary amines with functionalized carbodiimides
under mild conditions.
The easily accessible vinyliminophosphorane 113 reacted with
aromatic isocyanates to give carbodiimides 2, which were allowed to react
* Corresponding author.
1053
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

1054
DING ET AL.
with aliphatic primary amines to provide mainly imidazolinones 4, one of
the possible regioisomers. We obtained pure 4 from the reaction mixture by
recrystallization but not 5; however, 5 was found to exist in minor amount
by GC-MS detection. The structure of imidazolinones 4 is mainly deduced
from their 1H NMR data. Whenever the primary amine used is small
(R ¼ n-Pr) or bulky (R ¼ t-Bu), the cyclization was achieved all in moderate
to good yields with the same selectivity. The results are listed in Table 1.
The formation of 4 can be rationalized in terms of an initial nucleo-
philic addition to give the guanidine intermediate 3, which cyclized to give 4
across the arylamine group rather than the alkylamine one. This is probably
due to the geometry of the intermediate 3.
Table 1. Preparation of 2-Alkylamino-4H-imidazolin-4-ones 4
Compound
Ar
Ph
Ph
Ph
R
Condition
Yield (%)*
4a
4b
4c
4d
4e
4f
4g
4h
4i
n-C3H7
n-C4H9
n-C5H11
i-C3H7
t-C4H9
n-C3H7
n-C4H9
n-C5H11
i-C3H7
t-C4H9
r.t./2 h
r.t./2 h
r.t./2 h
r.t./4 h
r.t./6 h
r.t./2 h
r.t./2 h
r.t./2 h
r.t./6 h
r.t./8 h
67
66
63
81
86
63
67
69
83
80
Ph
Ph
4-Cl-Ph
4-Cl-Ph
4-Cl-Ph
4-Cl-Ph
4-Cl-Ph
4j
*Isolated yields based on iminophosphorane 1.

2-ALKYLAMINO-4H-IMIDAZOLIN-4-ONES
EXPERIMENTAL
1055
Melting points were uncorrected. MS were measured on a HP5988A
spectrometer. IR were recorded on a Shimadzu IR-408 infrared spectro-
meter. NMR were taken on a Varian XL-200 spectrometer. Vinylimino-
phosphorane 1 was prepared by the literature report (13).
General Preparation of 2-Alkylamino-4H-imidazolin-4-ones 4
To a solution of vinyliminophosphorane 1 (2.26 g, 5 mmol) in dry
methylene dichloride (15 mL) was added the aromatic isocyanate (5 mmol)
under nitrogen at room temperature. After the reaction mixture was stirred
for 2ꢀ4 h, the solvent was removed under reduced pressure and ether/
petroleum ether (1:2, 20 mL) was added to precipitate the triphenylpho-
sphine oxide. Filtered, the solvent was removed to give carbodiimide 2,
which was used directly without further purification.
To a solution of 2 prepared above in methylene dichloride (15 mL) was
added the primary amine (5 mmol). After the reaction mixture was stirred
for 2 h, the solvent was removed under reduced pressure and the residue was
recrystallized from methylene dichloride/ether to give 2-alkylamino-
4H-imidazolin-4-ones 4.
4a: yellow crystals, m.p. 183ꢁꢀ184ꢁC, 1H NMR(CDCl3,200 MHz)
ꢀ
8.16ꢀ7.10(m,10H,Ar-H), 6.70(s,1H, ¼ CH), 4.58(t,1H,J ¼ 5.4Hz,NH),
3.60ꢀ3.38(m,2H,NCH2),
1.85ꢀ1.45(m,2H,CH2),
0.94(t,3H,J ¼ 7.2 Hz,
cra=lCH3); MS(m/z), 305(Mþ,95%), 276(64%), 263(96%), 119(100%).
4b: yellow crystals, m.p. 174ꢁꢀ175ꢁC, H NMR(CDCl3,200 MHz) ꢀ
1
8.16ꢀ7.26(m,10H,Ar-H), 6.80(s,1H, ¼ CH), 4.58(s,1H,NH), 3.59ꢀ3.53
(m,2H,NCH2), 1.68ꢀ1.34(m,4H,CH2CH2), 0.97(t,3H,J ¼ 7.2 Hz,CH3);
MS(m/z), 319(Mþ,95%), 290(30%), 276(88%), 263(95%), 131(39%),
119(100%).
4c: yellow crystals, m.p. 172ꢁꢀ173ꢁC, 1H NMR(CDCl3,200 MHz)
ꢀ 8.16ꢀ7.26(m,10H,Ar-H), 6.80(s,1H, ¼ CH), 4.56(s,1H,NH), 3.62ꢀ3.52
(m,2H,NCH2), 1.69ꢀ1.32(m,6H,CH2CH2CH2 ), 0.92(t,3H,J ¼ 6.7 Hz,
CH3); MS(m/z), 333(Mþ,94%), 318(48%), 304(58%), 290(60%),
277(81%), 263(97%), 187(44%), 119(100%).
4d: yellow crystals, m.p. 122ꢁꢀ123ꢁC, 1H NMR(CDCl3,200 MHz)
ꢀ 8.20ꢀ7.29(m,10H,Ar-H), 6.84(s,1H, ¼ CH), 4.54ꢀ4.38(m,2H,NH and
NCH), 1.34(d,6H,J ¼ 6.2 Hz,2CH3); MS(m/z),305(Mþ,93%),290(36%),263
(90%),187(51%),119(100%).
4e: yellow crystals, m.p. 175ꢁ–176ꢁC, H NMR(CDCl3,200 MHz) ꢀ
1
8.18ꢀ7.26(m,10H,Ar-H), 6.79(s,1H, ¼ CH), 4.36(s,1H,NH), 1.54(s,9H,
3CH3); MS(m/z), 319 (Mþ,52%), 263(100%), 119(45%).

1056
DING ET AL.
4f: yellow crystals, m.p. 156ꢁꢀ157ꢁC, 1H NMR(CDCl3,200 MHz)
ꢀ 8.15ꢀ7.23(m,9H,Ar-H), 6.79(s,1H, ¼ CH), 4.55(s,1H,NH), 3.60ꢀ3.50
(m,2H,NCH2), 1.74ꢀ1.63(m,2H,CH2), 0.99(t,3H,J ¼ 7.3 Hz,CH3);MS(m/z),
339(Mþ,92%),310(49%),297(97%),153(100%),116(91%).
4g: light yellow crystals, m.p. 152ꢁꢀ153ꢁC, 1H NMR(CDCl3,
200 MHz) ꢀ 8.15ꢀ7.22(m,9H,Ar-H), 6.78(s,1H, ¼ CH), 4.54(s,1H,NH),
3.62ꢀ3.52(m,2H,NCH2), 1.68ꢀ1.34(m,4H,CH2CH2),0.97(t,3H,J ¼ 7.3 Hz,
CH3); MS(m/z),353(Mþ,99%), 310(64%),297(100%),153(89%),116(95%).
4h: yellow crystals, m.p. 107ꢁꢀ108ꢁC, 1H NMR(CDCl3,200 MHz)
ꢀ 8.15ꢀ7.22(m,9H,Ar-H), 6.80(s,1H, ¼ CH),4.48(s,1H,NH),3.62ꢀ3.52 (m,
2H,NCH2), 1.70ꢀ1.32(m,6H,CH2CH2CH2), 0.92(t,3H,J ¼ 7.0 Hz,CH3);
MS(m/z), 367(Mþ,98%),310(38%), 297(100%)153(56%), 116(71%).
4i: yellow crystals, m.p. 60ꢁꢀ61ꢁC, 1H NMR(CDCl3,200 MHz)
ꢀ
8.20ꢀ7.25(m,9H,Ar-H), 6.82(s,1H, ¼ CH), 452ꢀ4.36(m,2H,NH and
NCH), 1.32(d,6H,J ¼ 6.6 Hz,2CH3); MS(m/z), 339(Mþ,93%), 324(24%),
297(91%), 187(66%), 153(100%), 116(71%).
4j: light yellow crystals, m.p. 177ꢁꢀ178ꢁC 1H NMR(CDCl3,200 MHz)
ꢀ 8.21ꢀ7.26(m,9H,Ar-H), 6.81(s,1H, ¼ CH), 4.34(s,1H,NH), 1.58(s,9H,
3CH3); MS(m/z), 353(Mþ,38%), 297(100%), 153(34%), 116(18%).
ACKNOWLEDGMENTS
We gratefully acknowledge financial support of this work by the Dawn
Plan of Science and Technology for Young Scientists of Wuhan City and
Natural Science Foundation of Hubei Province.
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