Organic & Biomolecular Chemistry
Paper
form 6A, and its subsequent alkylation affords 2-thioxoimid- (1.74 mL, 3 mmol) and methyl (S)-2-amino-3-(3,4-dimethoxy-
azolin-4-one 7 through path b, or undergoes air oxidation to phenyl)propanoate 1a (100 mg, 0.41 mmol), and the reaction
afford 5-benzylidene 2-thioxoimidazolidin-4-one 8. 8 may con- mixture was sonicated at 50 °C for 3 h. To the above reaction
sequently undergo tautomerization to form 5-benzylidene- mixture, 2-bromoacetophenone 4a (125 mg, 0.62 mmol) was
2
-mercapto-4H-imidazol-4-one 8′, followed by alkylation with added and the reaction was further sonicated for 2 h. After
α-bromoketone 4 to provide substituted 4-arylidene imidazo- completion of the reaction, the solvent was evaporated. The
lin-5-one 9. In path a, nucleophilic addition of thiourea 3 to residue was diluted with water (15 mL) and extracted with di-
α-bromoketone 4 would yield isothiourea A. Then, intra- chloromethane (3 × 10 mL). The combined organic layers were
molecular addition followed by elimination of a water mole- washed with brine (30 mL), dried over MgSO
4
and concen-
cule would provide 2-iminothiazoline 5.
trated under reduced pressure. The resulting residue was puri-
fied using flash column chromatography (8–15% ethyl acetate
in hexanes) to afford (S)-4-(3,4-dimethoxybenzyl)-2-((2-oxo-2-
phenylethyl)thio)-1-phenyl-1H-imidazol-5(4H)-one 9a as a pale
yellow solid (160 mg, 84%).
Conclusions
We have developed a simple one-pot synthesis of 4-arylidene
imidazolin-5-ones via a multicomponent reaction of L-amino
acid methyl esters, iso-, isothio- or isoseleno-cyanates, and
α-bromoketones. The isolation of hydantoin and 2-thioxo-
imidazolidin-4-one intermediates indicated that the reaction
sequence proceeds through formation of a hydantoin first
followed by subsequent air oxidation. Use of the mild base
NaHCO3 afforded 2-thioxoimidazolin-4-ones, whereas using
1
Yellow solid, (82%, 157 mg); mp: 80–82 °C; H NMR
(
400 MHz, DMSO-d
6
) δ 8.06 (d, J = 7.2 Hz, 2H), 7.92 (s, 1H),
.74 (t, J = 7.4 Hz, 1H), 7.62–7.57 (m, 3H), 7.55–7.53 (m, 1H),
.47–7.42 (m, 3H), 6.89 (s, 1H), 6.65 (d, J = 8.5 Hz, 2H), 5.09 (s,
7
7
2
13
3
H), 3.74 (s, 3H), 3.50 (s, 3H); C NMR (101 MHz, CDCl )
δ 197.4, 168.5, 159.2, 151.2, 148.9, 136.5, 134.3, 133.8, 132.6,
1
1
29.6, 129.3, 128.9, 128.6, 127.4, 127.0, 126.9, 125.9, 113.6,
+
10.9, 55.9, 55.6, 42.4, 19.1; HRMS (ESI) m/z: [M + H] Calcd
3
equivalents of triethylamine provided 4-arylidene imidazo-
−1
for C H N O S: 459.1379, found: 459.1377; IR (cm , neat):
2
6
22 2 4
lin-5-ones. Extension of this methodology was demonstrated
through synthesizing 2-iminothiazolines and 2-thioxoimid-
3059, 2919, 2851, 1420.
azolin-4-ones, either under neutral or basic reaction Representative procedure for the synthesis of (S,Z)-methyl
conditions.
3-(3,4-dimethoxy-phenyl)-2-(4-phenyl-2-(phenylimino)thiazol-
(2H)-yl)propanoate (5a)
To a stirred solution of phenyl isothiocyanate 2a (85 mg,
.62 mmol) in acetonitrile (10 mL), methyl (S)-2-amino-
3
General methods
0
1
13
3-(3,4-dimethoxy-phenyl)propanoate 1a (100 mg, 0.41 mmol)
was added dropwise and the reaction mixture was sonicated
at 50 °C for 30 min. 2-Bromoacetophenone 4a (125 mg,
H NMR (400 MHz) and C NMR (101 MHz) spectra were
recorded using a 400-MR automated spectrometer. Chemical
shifts are reported in parts per million (ppm) on the δ scale
relative to an internal standard (TMS). Analytical thin-layer
chromatography (TLC) was performed using 0.25 mm silica
gel-coated Kiselgel 60 F254 plates. The ultrasound-assisted reac-
tions were carried out in a Elmasonic P ultrasonic cleaner with
a frequency of 37 kHz. Flash chromatography was performed
using the indicated solvent and silica gel 60 (Merck,
0
.62 mmol) was added to the above reaction mixture and the
reaction was further sonicated for 30 min. After completion
of the reaction, the solvent was removed. The residue was
diluted with water (15 mL) and extracted with dichloro-
methane (3 × 10 mL). The combined organic layers were
4
washed with brine (30 mL), dried over MgSO and concen-
trated in vacuo. The resulting residue was purified using flash
column chromatography (2–5% ethyl acetate in hexanes) to
afford (S,Z)-methyl 3-(3,4-dimethoxyphenyl)-2-(4-phenyl-2-
2
30–400 mesh). High-resolution mass spectrometry (HRMS)
spectra were recorded in ESI mode using a TOF mass spectro-
meter. Enantiomeric excess (ee) values were determined using
chiral HPLC with a Lux 5µm cellulose-1 (250 × 4.6 mm) analyti-
cal column. Melting points were recorded with Yanaco micro-
melting point apparatus and are uncorrected. All materials
were purchased from commercial sources and used without
further purification.
(
(
phenylimino)thiazol-3(2H)-yl)propanoate 5a as a yellow oil
186 mg, 94%).
1
Yellow oil; H NMR (400 MHz, CDCl
3
) δ 7.34 (m, 3H), 7.25
(
m, 2H), 7.11 (m, 2H), 7.06 (m, 1H), 6.76 (d, J = 8.3 Hz, 2H),
.69 (d, J = 8.1 Hz, 1H), 6.47 (dd, J = 8.1, 2.0 Hz, 1H), 6.36 (d,
J = 2.0 Hz, 1H), 5.53 (s, 1H), 4.54 (dd, J = 11.1, 4.0 Hz, 1H),
.94 (m, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.67 (s, 3H), 3.16 (dd,
6
3
1
3
J = 14.0, 4.0 Hz, 1H); C NMR (101 MHz, CDCl ) δ 170.4,
3
Experimental section
Representative procedure for the synthesis of
1
1
1
4
48.8, 147.7, 140.3, 131.0, 130.0, 129.3, 129.0, 128.3, 123.0,
21.3, 112.1, 111.2, 95.1, 60.2, 56.0, 55.5, 52.6, 32.4, 31.8,
(Z)-5-(3,4-dimethoxybenzylidene)-2-((2-oxo-2-phenylethyl)thio)-
+
4.1; HRMS (ESI) m/z: [M + H] Calcd for C H N O S:
2
7
27 2 4
3
-phenyl-3,5-dihydro-4H-imidazol-4-one (9a)
27
75.1692, found: 475.1692; [α]D = −115.08 (c = 0.0429,
−1
To a stirred solution of phenyl isothiocyanate 2a (85 mg, CH
2
Cl
2
); HPLC analysis: 10% i-PrOH/hexane, 0.3 mL min ,
0
.62 mmol) in acetonitrile (10 mL) was added triethylamine 254 nm; 99% ee; t = 8.9 min.
R
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