Volonterio et al.
NMR (235.4 MHz, CDCl3) δ -63.2 (d, J ) 8.6 Hz, 3F); EIMS
(m/z) 338 [M+ (100)], 323 (64), 223 (80), 83 (78).
binatorial chemistry. Resolution of this issue, as well as
the development of a stereoselective version of the domino
process, is currently in progress in our laboratory.
Synthesis of Hydantoins. Reactions in the Presence
of a Base. General Procedure. To a stirred solution of
carbodiimide 2 (1 equiv) in an organic solvent (0.1 M solution)
was added 1 equiv of TMP followed by a solution of
R,â-unsarurated carboxylic acid 1 (1 equiv) in a minimum
amount of the same organic solvent. The resulting solution
was stirred overnight. The organic solvent was evaporated
under reduced pressure, diluted with AcOEt, and extracted
with 1 M HCl aqueous solution. The combined organic layers
were dried over anhydrous NaSO4, filtered, and concentrated
under vacuum, and the crude was purified by flash chroma-
tography.
Experimental Section
General Methods. Commercially available reagent-grade
solvents were employed without purification. Melting points
(mp) are uncorrected and were obtained on a capillary ap-
1
paratus. H NMR spectra were run on 250, 400, or 500 MHz
spectrometers. Chemical shifts are expressed in parts per
million (δ), using tetramethylsilane (TMS) as an internal
standard for 1H and 13C nuclei (δH and δC ) 0.00), while C6F6
was used as an external standard (δF 162.90) for 19F.
Synthesis of Hydantoins Starting from N-Acylureas
6. General Procedure. To a stirred solution of N-acylurea 6
(1 equiv) in dry DMF (0.1 M solution) was added 1.1 equiv of
NaH (60% in weight oil dispersion) at 0 °C under a nitrogen
atmosphere. After total consumption of starting material (TLC
monitoring), water was added, the organic solvent evaporated
under reduced pressure, and the resulting mixture extracted
with AcOEt. The combined organic layers were dried over
anhydrous NaSO4, filtered, and concentrated under vacuum,
and the crude was purified by flash chromatography.
3-Benzyl-1-(4-methoxy-phenyl)-1-[4-(4-methoxy-phen-
yl)-4-oxo-but-2-enoyl]-urea (6b): Rf ) 0.73 (hexane/AcOEt
) 50:50); mp 145-147 °C; FTIR (microscope) ν 1724, 1663
cm-1; 1H NMR (400 MHz, CDCl3) δ 9.50 (br t, J ) 4.4 Hz, 1H),
7.89 (d, J ) 8.8 Hz, 2H), 7.86 (d, J ) 15.0 Hz, 1H), 7.40-7.25
(m, 5H), 7.15 (d, J ) 8.8 Hz, 2H), 6.96 (d, J ) 8.8 Hz, 2H),
6.93 (d, J ) 8.8 Hz, 2H), 6.75 (d, J ) 15.0 Hz, 1H), 4.56
(d, J ) 5.4 Hz, 2H), 3.87 (s, 3H), 3.84 (s, 3H); 13C NMR (100.6
MHz, CDCl3) δ 187.3, 168.2, 164.2, 160.0, 154.6, 138.1, 135.8,
133.0, 131.2, 130.4, 129.8, 129.7, 128.7, 127.8, 127.5, 115.0,
114.1, 55.5, 55.4, 44.8; EIMS (m/z) 444 [M+ (4)], 311 (58), 133
(45), 123 (57), 91 (100).
General Procedure for the Preparation of 1a. To a
stirred solution of ylide 9 (3.0 g, 8.0 mmol) in DCM (40 mL)
was added dropwise neat ethyl trifluoropyruvate (1.6 g,
9.5 mmol). The solution was stirred for 90 min, the solvent
evaporated in vacuo, and the crude purified through a short
silica gel column. The recovered compounds were dissolved in
a 20% TFA solution in DCM, and after 2 h the solvent was
removed by evaporation. 1a (7.6 mmol, 95% overall yield) was
recovered as a 1:1 mixture of diastereoisomers.
1
(E)-1a: H NMR (400 MHz, CDCl3) δ 9.36 (br s, 1H), 7.31
(s, 1H), 4.36 (q, J ) 7.0 Hz, 2H), 1.36 (t, J ) 7.0 Hz, 3H);
13C NMR (100.6 MHz, CDCl3) δ 168.4, 161.0, 135.0 (q, J ) 3.4
Hz), 128.5 (q, J ) 33.6 Hz), 120.4 (q, J ) 274.3 Hz), 63.0, 13.9;
19F NMR (235.4 MHz, CDCl3) δ -66.7 (s, 3F).
(Z)-1a: FTIR (neat) ν 1743, 1724 cm-1; 1H NMR (400 MHz,
CDCl3) δ 9.70 (br s, 1H), 6.67 (q, J ) 1.3 Hz, 1H), 4.33 (q, J )
7.0 Hz, 2H), 1.30 (t, J ) 7.0 Hz, 3H); 13C NMR (100.6 MHz,
CDCl3) δ 167.6, 161.2, 135.6 (q, J ) 3.1 Hz), 128.9, 120.7
(q, J ) 274.3 Hz), 63.1, 13.4; 19F NMR (235.4 MHz, CDCl3) δ
-62.9 (s, 3F); EIMS (m/z) 212 [M+ (100)].
Synthesis of Hydantoins. Reactions in the Absence of
a Base. General Procedure. To a stirred solution of R,â-
unsaturated carboxylic acid 1 (1 equiv) in DCM (0.1 M
solution) was added 1 equiv of carbodiimide 2. After total
consumption of starting material (TLC monitoring), the or-
ganic solvent was evaporated under reduced pressure and the
crude purified by flash chromatography.
1-Benzyl-3-(4-methoxy-phenyl)-5-[2-(4-methoxy-phen-
yl)-2-oxo-ethyl]-imidazolidine-2,4-dione (12b): Rf ) 0.59
(hexane/AcOEt ) 50:50); mp 107-108 °C; FTIR (microscope)
1
ν 1775, 1727, 1673 cm-1; H NMR (400 MHz, CDCl3) δ 7.75
(d, J ) 8.8 Hz, 2H), 7.44 (d, J ) 8.8 Hz, 2H), 7.30-7.12
(m, 5H), 6.99 (d, J ) 8.8 Hz, 2H), 6.88 (d, J ) 8.8 Hz, 2H),
4.70 (d, J ) 15.3 Hz, 1H), 4.48 (d, J ) 15.3 Hz, 1H), 4.46
(dd, J ) 5.2 and 3.4 Hz, 1H), 3.86 (s, 3H), 3.83 (s, 3H), 3.51
(dd, J ) 17.8 and 3.4 Hz, 1H), 3.33 (dd, J ) 17.8 and 5.2 Hz,
1H); 13C NMR (100.6 MHz, CDCl3) δ 193.5, 172.4, 164.0, 159.3,
156.5, 136.2, 130.3, 128.9, 128.8, 128.6, 128.2, 127.8, 127.7,
125.0, 114.4, 113.8, 55.8, 55.5, 45.8, 37.9; EIMS (m/z) 444
[M+ (23)], 309 (39), 135 (42), 123 (46), 108 (74), 91 (100).
(S,S)-(1,3-Diisopropyl-2,5-dioxo-imidazolidin-4-yl)-3,3,3-
trifluoro-propionic Acid Ethyl Ester (8a): Rf ) 0.30
(hexane/AcOEt ) 90:10); FTIR (microscope) ν 1778, 1748, 1703
1
cm-1; H NMR (400 MHz, CDCl3) δ 4.35-4.18 (m, 4H), 3.92
(dq, J ) 9.6 and 1.8 Hz, 1H), 3.65 (septet, J ) 7.0 Hz, 1H),
1.42 (d, J ) 2.6 Hz, 3H), 1.40 (d, J ) 2.6 Hz, 3H), 1.39
(d, J ) 6.7 Hz, 3H), 1.29 (d, J ) 6.7 Hz, 3H), 1.27 (t, J ) 7.0
Hz, 3H); 13C NMR (100.6 MHz, CDCl3) δ 170.0, 163.1, 156.3,
123.7 (q, J ) 279.3 Hz), 62.4, 57.1, 51.1 (q, J ) 27.7 Hz,), 48.4,
44.4, 20.6, 19.6, 19.0, 18.9, 14.1; 19F NMR (235.4 MHz, CDCl3)
δ -64.9 (d, J ) 9.5 Hz, 3F); EIMS (m/z) 338 [M+ (100)], 323
(58), 223 (79).
Acknowledgment. Politecnico di Milano and CNR
are gratefully acknowledged for economic support.
(S,R)-(1,3-Diisopropyl-2,5-dioxo-imidazolidin-4-yl)-3,3,3-
trifluoro-propionic Acid Ethyl Ester (8a): Rf ) 0.27
(hexane/AcOEt ) 90:10); FTIR (microscope) ν 1781, 1755, 1713
Supporting Information Available: Copies of 1H or 13
C
NMR spectra for compounds (Z)-1a, 6b-d, 6h-i, 8a-g, 8i-
u, 12a-m, 12o,p, and 13n,q-t; thermal ellipsoid plot of
compounds 8c and 12e; characterization data for compounds
6c,d, 6h-k, 8b-u, 12a,c-t, 13a,e,j,m,n, and 13p-t; and
complete data (excluding structure factor) of the crystal
structure in CIF format. This material is available free of
cm-1 1H NMR (400 MHz, CDCl3) δ 4.46 (s, 1H), 4.35-4.22
;
(m, 3H), 3.91 (dq, J ) 9.0 and 1.6 Hz, 1H), 3.64 (septet,
J ) 6.7 Hz, 1H), 1.44 (d, J ) 6.7 Hz, 3H), 1.39 (d, J ) 7.0 Hz,
3H), 1.36 (d, J ) 7.0 Hz, 3H), 1.32 (t, J ) 7.0 Hz, 3H), 1.26
(d, J ) 6.7 Hz, 3H); 13C NMR (100.6 MHz, CDCl3) δ 170.1,
165.1, 156.2, 123.2 (q, J ) 283.8 Hz), 63.0, 56.6, 50.4
(q, J ) 27.2 Hz), 47.9, 44.3, 20.2, 19.4, 19.1, 19.0, 13.9; 19F
JO0480848
2170 J. Org. Chem., Vol. 70, No. 6, 2005