ACS Combinatorial Science
Research Article
5 and 8 is shown in Scheme 1. In path a, a coupling reaction of
α-amino acid methyl ester 1 and isothiocyanate 2 generates
thiourea 3 first. In the next step, nucleophilic attack of the
sulfur atom (soft nucleophile) at the soft electrophilic carbon
of the bromomethyl group affords isothiourea A.16 Intra-
molecular nucleophilic attack of the NH2 group at carbonyl
carbon and the subsequent loss of H2O from B furnishes 2-
iminothioazole 5. In path b, a base-promoted intramolecular
attack of the N1H group at the methyl ester moiety generates
thiohydantoin 7 with the liberation of methanol. Thiohydntoin
intermediate 7 tautomerizes into 7A, and intermolecular attack
of the sulfur atom at the carbon of bromomethyl group
subsequently eliminates HBr to yield 2-thioxoimidazolin-4-one
8.17
afford methyl (S,Z)-3-phenyl-2-(4-phenyl-2-(phenylimino)-
thiazol-3(2H)-yl)propanoate 5{1,1,1} (150 mg, 88%).
Methyl (Z)-3-Phenyl-2-(4-phenyl-2-(phenylimino)-
thiazol-3(2H)-yl)propanoate (5{1,1,1}). 1H NMR (400
MHz, CDCl3): δ 7.41−7.28 (m, 3H), 7.25−7.16 (m, 5H),
7.15−7.10 (m, 2H), 7.08−7.03 (m, 1H), 6.94−6.90 (m, 2H),
6.70 (d, J = 7.3 Hz, 2H), 5.52 (s, 1H), 4.53 (dd, J = 11.1, 4.0
Hz, 1H), 3.95 (dd, J = 14.0, 11.1 Hz, 1H), 3.84 (s, 3H), 3.23
(dd, J = 14.0, 4.0 Hz, 1H). 13C NMR (101 MHz, CDCl3): δ
170.4, 156.4, 150.5, 140.2, 137.6, 130.9, 129.4, 129.3, 129.1,
129.0, 128.4, 128.3, 126.6, 123.0, 121.3, 95.1, 60.1, 52.6, 32.9.
HRMS calcd for C25H23N2O2S: m/z 415.1483. Found:
415.1483 (M+H)+. [α]D = −269.20 (c = 0.005, CH2Cl2).
27
HPLC analysis (2% i-PrOH/hexane, 0.3 mL min−1, 254 nm):
92% ee, tR = 19.1
Representative Procedure for the Synthesis of 5-
Benzyl-2-((2-oxo-2-phenylethyl)thio)-3-phenyl-3,5-di-
hydro-4H-imidazol-4-one (8{1,1,1}). To the stirred solution
of phenyl isothiocyanate 2{1} (113 mg, 1.5 mmol) in
acetonitrile (10 mL) was added K2CO3 (77 mg, 1 mmol)
and L-phenylalanine methyl ester 1{1} (100 mg, 1 mmol), and
the reaction mixture was stirred at 25 °C for 2 h. To the above
reaction mixture, 2-bromoacetophenone 4{1} (166 mg, 1.5
mmol) was added, and the reaction was stirred at the same
temperature for 14 h. After completion of the reaction, the
solvent was evaporated. The residue was diluted with water
(15 mL) and extracted with dichloromethane (3 × 10 mL).
The combined organic layers were washed with brine (30 mL),
dried over MgSO4, and concentrated under reduced pressure.
The residue was purified by flash column chromatography (8−
15% ethyl acetate in hexanes) to afford 5-benzyl-2-((2-oxo-2-
phenylethyl)thio)-3-phenyl-3,5-dihydro-4H-imidazol-4-one
8{1,1,1} (205 mg, 92%).
CONCLUSION
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In conclusion, we have developed a novel protocol for the
rapid synthesis of 2-imino thiazolines and 2-thioxoimidazolin-
4-ones by a base controlled multicomponent reaction employ-
ing chiral amino esters, isothiocyanates, and α-bromoketones/
alkyl halides. In this reaction, the absence of a base afforded 2-
imino thiazolines, whereas basic conditions delivered 2-
thioxoimidazolin-4-ones. Employment of aliphatic isothiocya-
nates under neutral conditions gave a mixture of 2-imino
thiazolines and 2-thioxoimidazolin-4-ones. The isolation of
intermediates indicated the formation of 2-imino thiazoline
through an isothiourea intermediate. However, the formation
of a hydantoin intermediate proceeds through intramolecular
cyclization of isothiourea in the presence of a base to deliver 2-
thioxoimidazolin-4-one. This methodology comprises the
amalgamation of a single reactant replacement and con-
dition-based divergence approach in a multicomponent
reaction to achieve skeletal diversity.
1H NMR (400 MHz, CDCl3): δ 8.05 (d, J = 7.1 Hz, 2H),
7.64 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.6 Hz, 2H), 7.35−7.42
(m, 3H), 7.15−7.25 (m, 5H), 6.93−6.84 (m, 2H), 4.70 (d, J =
16.7 Hz, 1H), 4.62 (d, J = 16.7 Hz, 1H), 4.50 (dd, J = 6.1, 4.4
Hz, 1H), 3.31 (dd, J = 13.5, 4.4 Hz, 1H), 3.14 (dd, J = 13.5,
6.1 Hz, 1H). 13C NMR (101 MHz, CDCl3): δ 192.8, 180.1,
161.0, 135.6, 135.6, 133.9, 131.8, 129.8, 129.4, 129.2, 128.8,
128.5, 128.0, 127.3, 126.9, 69.7, 38.5, 37.4. HRMS calcd for
C24H21N2O2S: m/z 401.1318. Found: 401.1323 (M+H)+.
EXPERIMENTAL SECTION
General Methods. H NMR (400 MHz) and 13C NMR
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1
(101 MHz) spectra were recorded on 400-MR automated
spectrometer. Chemical shifts are reported in parts per million
(ppm) on the δ scale from an internal standard (TMS).
Analytical thin-layer chromatography (TLC) was performed
using 0.25 mm silica-gel-coated Kiselgel 60 F254 plates. Flash
chromatography was performed using the indicated solvent
and silica gel 60 (Merck, 230−400 mesh). High-resolution
mass spectra (HRMS) were recorded in ESI mode using a
TOF mass spectrometer. All materials were purchased from
commercial sources and used without further purification.
Representative Procedure for the Synthesis of
Methyl (S,Z)-3-Phenyl-2-(4-phenyl-2-(phenylimino)-
thiazol-3(2H)-yl)propanoate (5{1,1,1}). To the stirred
solution of phenyl isothiocyanate 2{1} (113 mg, 1.5 mmol)
in acetonitrile (10 mL) was added L-phenylalanine methyl
ester 1{1} (100 mg, 1 mmol) dropwise, and the reaction
mixture was stirred at 25 °C for 2 h. 2-Bromoacetophenone
4{1} (166 mg, 1.5 mmol) was added to the above reaction
mixture, and the reaction was stirred for 4 h. 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
washed with brine (30 mL), dried over MgSO4, and
concentrated in vacuo. The residue was purified by flash
column chromatography (2−5% ethyl acetate in hexanes) to
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
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S
Full spectroscopic data (1H, 13C NMR, HRMS and
HPLC) of compounds 5{1,1,1}−5n and 8{1,1,1}−
X-ray crystallographic data of compound 5{1,1,3} (CIF)
X-ray crystallographic data of compound 8{3,1,8}(CIF)
X-ray crystallographic data of compound 7{1,1} (CIF)
AUTHOR INFORMATION
Corresponding Author
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ORCID
Notes
The authors declare no competing financial interest.
F
ACS Comb. Sci. XXXX, XXX, XXX−XXX