Reactions with ActiVe Methylene Compounds
solution was filtered, the filtrate was added dropwise to a cold 2 N
HCl solution (50 mL), and the white precipitate formed was filtered,
washed with cold water (100 mL), and dried at rt, giving 1.46 g
(4.3 mmol, 87%) of pure 5b, mp 118 °C. Crystals for X-ray
diffraction of 5f and 5h were obtained from chloroform. The
acetylacetone derivative 5i, mp 134 °C, was crystallized in 79%
yield during filtration of the Et3NHCl from the DMF solution.
The dimedone derivative 5j was prepared similarly except that
the precipitate obtained after the addition of 2 contained both 5j
and Et3NHCl. Shaking with cold water (50 mL) gave pure 5j, mp
206-7 °C, in 82% yield after filtration and drying.
Reaction of â-Chloroethyl Isocyanate 2 with N,N-Dimethyl-
cyanoacetamide 1k, N-Methylcyanoacetamide 1l, and Cyanoac-
etamide 1m. On addition of 1k (0.56 g, 5 mmol) to a suspension
of Na (0.12 g, 5.2 mmol) in dry THF (20 mL) under nitrogen
hydrogen was evolved. After the mixture was stirred overnight at
rt, a white precipitate was formed. A solution of 2 (0.43 mL, 5
mmol) in dry THF (10 mL) was added dropwise to the solution
during 30 min, and the precipitate was dissolved. The reaction
mixture was refluxed for 4 h, and the formed NaCl was filtered.
The solvent was evaporated, giving crude 5k. Crystallization from
EtOAc-petroleum ether (40-60 °C) followed by cooling for 48 h
gave 0.67 g (3.70 mmol, 74%) of 5k, mp 160 °C.
Reaction of â-Chloroethyl Isothiocyanate 3 with 1a,b and 1d-
g. The reactions of 1a,b and 1d-g with 3 were conducted as
described for the reaction with 2. Only with 1g (1.77 g, 10 mmol)
was the precipitate obtained immediately after addition of 3 (0.96
mL, 10 mmol) a mixture of 6g and Et3NHCl. Cold water (50 mL)
was added with stirring for 20 min. The insoluble solid was filtered,
washed with cold water (100 mL), and dried at 60 °C, giving 2.39
g (9.1 mmol, 91%) of pure 6g, mp 204 °C dec. In the preparation
of 6f, after the Et3NHCl was filtered and the solution was poured
into a 2 N HCl solution, no precipitate was obtained. The mixture
was extracted (3 × 50 mL EtOAc), washed with water (2 × 100
mL), and dried, most of the solvent was evaporated, and the
remainder gave after standing overnight 88% yield of yellow
crystals of 6f, mp 80-2 °C.
for which protonation of the intermediate anion to the open-
chain thioenol 15a or the enol-thioamide 15c is preferred over
cyclization.
Internal Rotation in Compounds 5 and 6. The unsym-
metrical compounds 5 display signals for an apparent single
isomer at rt, whereas the unsymmetrical compounds 6 show
two isomers at rt. By lowering the temperature of solutions of
several compounds 5, the rate of internal rotation around the
C(1)-C(2) formal double bond is reduced and two isomers are
observed. Consequently, the rotational barrier around the C(1)-
C(2) bond is lower for 5 than for 6.
Precedents for lower barriers in O- vs S-derivatives are known
for push-pull alkenes, Me2NCHdCH(CdX)R,14 for amides vs
thioamides,15 and for substituted oxa- vs thiadiazoles.16 The
N-methylthiazolidine analogue of 5o displays a low barrier of
<9.4 kcal/mol in toluene.17
The closer compounds to ours are 5p and 6h. The oxygen
derivative 5p showed only signals for one isomer, and the
rotational barrier could not be measured, whereas 6h displayed
two isomers with ∆Gq (kJ/mol) of 67.2 (Tc 330 K) in DMF,
68.2 (Tc 335 K) in DMSO, and g76.9 (Tc > 380 K) in CD2Cl2.
The HF/6-311G** calculated barriers for 5p and 6h are 85.2
and 112.7, respectively.
Consequently, ∆Gq(6h) . ∆Gq(5p) and two isomers of 6h
were observed. It was concluded that the length of the central
double bond is the parameter to quantify the push-pull effect
and that the difference between the high occupation of the π
and the low occupation of the π* orbital of the O and S
derivatives accounts for the difference in the barriers of the N,S-
and N,O-heterocycles.10b
Reaction of γ-Chloropropyl Isocyanate 4 and o-2-Chlorom-
ethyl Phenyl Isocyanate 8 with Compounds 1a-c and 1a,b,
Respectively. The procedure is identical with that described for
the reaction with 2, except for a slower reaction when Et3NHCl
started to precipitate only 2 h after the addition of the isocyanates
4 and 8.
Experimental Section
Reaction of Barbituric Acid 1c with â-Chloroethyl Isocyanate
2 and Isothiocyanate 3, γ-Chloropropyl Isocyanate 4, and Ethyl
o-Isothiocyanatobenzoate 10. A similar procedure used with all
of these compounds is demonstrated for the reaction with 2: To a
CaCl2-protected solution of barbituric acid (1.28 g, 10 mmol) in
dry DMF (10 mL) was added dry Et3N (6 mL, 20 mmol). The
solution became warm, and a precipitate was formed. After being
stirred for 15 min at rt, 2 (0.85 mL, 10 mmol) was added, and the
mixture was stirred overnight at rt. After 4 h reflux the yellow color
turned brown. The precipitate is a mixture of Et3NHCl and 5c. After
being shaken with cold water (100 mL), the remaining solid was
filtered, washed with cold water (200 mL) and then with acetone
(100 mL), and dried at rt, giving 1.88 g (95%) of pure 5c, mp 217
°C dec.
Materials. Compounds 1 were either commercial or prepared
by standard procedures. Compounds 2-4, 8, 10, 12, and 14 were
purchased from a commercial supplier.
NMR and Analytical Data. The NMR data for compounds 5-7,
9, 10, and 11c are given in Tables S1 and S2, for 14 and 15c in
Tables S3 and S4 and for 16a-d in Tables S5 and S6. Analytical
data, mp’s, and yields for all compounds are given in Table S8
(Supporting Information).
Reaction of â-Chloroethyl Isocyanate 2 with 1a,b, 1d-j, and
1n,o. The procedure used with minor modifications in the reaction
rates, the solvent, and the yields is demonstrated for bis(2,2,2-
trifluoroethyl) malonate 1b: A solution of 1b (1.35 g, 5 mmol) in
dry DMF (10 mL) under nitrogen turned warm when dry Et3N (1.5
mL,10 mmol) was added. After being stirred for 10 min, 2 (0.43
mL, 5 mmol) was added, the solution became warm, and Et3NHCl
was formed immediately. After being stirred overnight at rt, the
A similar procedure, using barbituric acid (0.128 g, 1 mmol)
and 10 (0.173 g, 1 mmol) gave the product 11c (89%), mp 385 °C
dec. EtOH was also identified.
Reactions of Barbituric Acid 1c with Ethyl o-Isocyanatoben-
zoate 12 and Ethoxycarbonyl Isothiocyanate 14. The procedure
for barbituric acid (0.15 g, 1.2 mmol) with 12 (0.23 mL, 1.2 mmol)
resembles that for the reaction with 10, except that after the addition
of 12 and stirring for 30 min, the precipitate had dissolved, and
after additional stirring overnight and acidification with cold 2 N
HCl solution (20 mL), 0.32 g (1 mmol, 84%) of the enol 13c, mp
220 °C, was obtained.
(14) Dabrowski, J; Kozerski, L. Org. Magn. Reson. 1972, 4, 137.
Dabrowski, J.; Kamienska-Trela, K. Org. Magn. Reson., 1972, 4, 421.
Filleux-Blanchard, M. L.; Mabon, F.; Martin, G. J. Tetrahedron. Lett 1974,
3907. Filleux-Blanchard, M. L.; Clesse, F.; Bignebat, J.; Martin, G. J.
Tetrahedron Lett. 1969, 981.
(15) Piccinni-Leopardi, C.; Fabre, O.; Zimmerman, D.; Reisse, J.; Cornea,
F.; Fulea, C. Can. J. Chem. 1977, 55, 2649.
(16) Liljefors, T. Org. Magn. Reson. 1974, 6, 144.
(17) Shvo, Y.; Belsky, I. Tetrahedron 1969, 25, 4649.
J. Org. Chem, Vol. 71, No. 26, 2006 9749