A novel synthesis of oxazolidine-2,4-diones via an efficient fixation of CO₂ with 3-aryl-2-alkynamides

Abstract

A very mild protocol for fixation of carbon dioxide with 2-alkynamides in DMSO at 30 °C using a CO₂ balloon in the presence of K₂CO₃ has been developed, which leads to an efficient assembly of oxazolidine-2,4-diones. It is observed that the regioselectivity was controlled by the aryl group.

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Introduction

Recently much attention has been paid to the chemistry of carbon dioxide as an attractive carbon resource in organic synthesis. More and more methods for transformations of CO₂ into useful organic compounds have been reported.¹ In this area, the reaction of propargyl alcohols and amines with CO₂ yielding cyclic carbonates and urethanes has already been well described in the literature.² However, due to the low nucleophilicity of amide, the fixation of CO₂ with amide has seldom been reported.³ On the other hand, we noticed that oxazolidine-2,4-diones are widely used in medicine and agriculture as antiepileptic agents,^4a anti-inflammatory agents,^4b–c herbicides,^4f–g and the synthesis of oxazolidine-2,4-diones is usually lengthy (Fig. 1).⁴ Besides transformations from heterocyclic intermediates, the most general methods are the cyclizations of α-hydroxy esters with urea or isocyanates and α-hydroxy amides with chloroformates or carbonates (Scheme 1).^4a,5 However, the most efficient route to oxazolidine-2,4-diones would be from the reactions of 2-alkenamide or 2-alkynamide with CO₂. Recently, we have reported the fixation of CO₂ with 2,3-allenamides under mild conditions to synthesize 1,3-oxazine-2,4-diones (eqn (1)).⁶ Herein, we wish to report a simple chemical fixation of CO₂ with 3-aryl-2-alkynamides for unexpected synthesis of oxazolidine-2,4-diones.

Fig. 1 Some biologically active oxazolidine-2,4-diones.

Scheme 1 Synthesis of oxazolidine-2,4-diones.

Results and discussion

We used N-benzyl-3-phenylpropiolamide 1a as the substrate to test the reaction under the CO₂ transformation conditions for the reaction of 2,3-allenamides with CO₂.⁶ Fortunately, we observed the formation of a new solid compound in 16% yield determined by ¹H NMR spectroscopy (entry 1, Table 1). With the X-ray diffraction study, we learned that the solid compound was oxazolidine-2,4-dione 2a with a single Z configuration but not 1,3-oxazine-2,4-dione 3a as we were expecting (Fig. 2).⁷ Encouraged by this result, we optimized the reaction conditions for the chemical fixation of CO₂ with 1a. Some typical reaction conditions are summarized in Table 1. Due to the possible instability of product 2a, we lowered the reaction temperature to 30 °C, and 2a was formed in 75% yield determined by ¹H NMR spectroscopy with 9% recovery of starting material 1a within 11 h (entry 2, Table 1). No reaction occurred with 100% recovery of starting material 1a when commercial DMSO was used, which shows that a trace amount of water in DMSO may stop this transformation in the deprotonation step (entry 3, Table 1). When 2.0 equiv of K₂CO₃ were used, 2a was obtained in 75% yield determined by ¹H NMR spectroscopy with complete conversion of the starting material 1a within 11 h (entry 6, Table 1). Increasing the concentration of K₂CO₃ to 3.0 equiv did not improve the yield of 2a very much (entry 7, Table 1). Without the CO₂ balloon, the yield of 2a dropped to 66% determined by ¹H NMR spectroscopy under the CO₂ atmosphere (entry 8, Table 1). When the reaction was carried out in the presence of K₂CO₃ under N₂ atmosphere, the formation of oxazolidine-2,4-dione 2a was not observed with 93% recovery of the starting material 1a, which indicated that the CO₂ unit in the product 2a was from the CO₂ gas, not the carbonate base K₂CO₃ (entry 9, Table 1).

Table 1 Optimization of reaction conditions for the reaction of N-benzyl-3-phenylpropiolamide 1a with carbon dioxide^a

entry	solvent	base (equiv)	temp. (°C)	time (h)	yield (%) of 2a	recovery of 1a
a The reaction was carried out using 0.2 mmol of 1a in dried solvent with a CO2 balloon, and the yields were determined by ^1H NMR analysis with CH2Br2 as the internal standard. b DMSO was commercially available and used without treatment. c The reaction was carried out under CO2 atmosphere. d The reaction was carried out under N2 atmosphere.
1	DMSO	1.0	70	3	16	0
2	DMSO	1.0	30	11	75	9
3^b	DMSO	1.0	30	11	0	100
4	DMF	2.0	30	11	65	22
5	DMA	2.0	30	11	40	30
6	DMSO	2.0	30	11	75	0
7	DMSO	3.0	30	11	77	0
8^c	DMSO	2.0	30	11	66	0
9^d	DMSO	2.0	30	11	0	93

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Fig. 2 ORTEP representation of 2a.

Some typical results of different 3-aryl-2-alkynamides under the optimized conditions are listed in Table 2. The substituent R² on the nitrogen atom of 2-alkynamides can be alkyl, benzyl and allyl groups (entries 1–4, Table 2). When the i-propyl group substituted 2-alkynamide 1e was applied, the product 2e was afforded in 68% yield with 16% recovery of 1e even using 3.0 equiv of K₂CO₃ due to the steric effect (entry 5, Table 2). Using a stronger base such as Cs₂CO₃, the yield of 2e was 46% though the starting material 1e was consumed completely (entry 6, Table 2). However, when 3-phenylpropiolamide 1f was applied, no reaction occurred with 64% recovery of the starting material (entry 7, Table 2). The substituent R¹ can be phenyl groups bearing both electron-donating and electron-withdrawing groups (entries 8–12, Table 2). Heterocyclic aryl groups such as 2- or 3-thienyl group substituted 2-alkynamides could also be applied to the reaction with slightly lower yields (entries 13 and 14, Table 2). It should be noted that the reaction of cyclohexenyl substituted propiolamides 1n and n-butyl substituted propiolamides 1o under the same reaction conditions did not occur with recovery of starting materials, which shows the importance of the aryl group moiety for this transformation (entries 15–16, Table 2).

Table 2 Reaction of different 2-alkynamides with carbon dioxide^a

entry	R^1	R^2	time (h)	isolated yield (%) of 2
a The reaction was carried out using 0.2 mmol of 1 and 2.0 equiv of K2CO3 in DMSO (distilled from CaH2) with a CO2 balloon at 30 °C unless otherwise stated. b K2CO3 (3.0 equiv) was used. c Compound 1e was recovered in 16% yield. d Cs2CO3 (2.0 equiv) was used. e Compound 1f was recovered in 64% yield. f Compound 1n was recovered in 92% yield. g Compound 1o was recovered in 100% yield.
1	Ph	Bn (1a)	11	62 (2a)
2	Ph	n-Bu (1b)	11	80 (2b)
3	Ph	Et (1c)	11	66 (2c)
4	Ph	allyl (1d)	11	72 (2d)
5^b^,^c	Ph	i-Pr (1e)	11	68 (2e)
6^d	Ph	i-Pr (1e)	11	46 (2e)
7^e	Ph	H (1f)	11	0
8	4-PrC6H4	n-Bu (1g)	12	69 (2g)
9	4-MeC6H4	n-Bu (1h)	16	69 (2h)
10	4-MeOC6H4	n-Bu (1i)	11	67 (2i)
11	4-MeOC6H4	Bn (1j)	11	68 (2j)
12	4-FC6H4	n-Bu (1k)	11	72 (2k)
13	3-thienyl	Bn (1l)	11	61 (2l)
14^b	2-thienyl	Bn (1m)	11	55 (2m)
15^f	cyclohexenyl	Bn (1n)	11	0
16^g	n-Bu	Bn (1o)	11	0

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Based on these facts, a rational mechanism for the formation of 2 is depicted in Scheme 2. The amide 1 would lose a proton under the basic conditions with K₂CO₃ to form anionic intermediate M1, which may attack the carbon atom in carbon dioxide to form the intermediate M2. There is an issue of regioselectivity (α vs. β). When the R′ is an allenyl group, the oxygen anion would attack the central carbon atom in the allene moiety (β carbon atom) to form six-membered product 4, which was controlled by the carbonyl group. However, when the amide was changed to 3-aryl-2-alkynamide, although both 5-exo-dig and 6-endo-dig are favored according to the Baldwin's rule, the oxygen anion in the intermediate M2 would attack α carbon atom in the C–C triple bond to form five-membered product 2, which was obviously directed by the aryl group. This also explains why the aryl group is so important in this reaction and why the alkyl substituted 2-alkynamides fail for this reaction.

Scheme 2 Reaction mechanism.

Conclusions

In conclusion, we have developed a very mild protocol for fixation of carbon dioxide with 2-alkynamides in DMSO at 30 °C using a CO₂ balloon in the presence of K₂CO₃, which leads to an efficient assembly of oxazolidine-2,4-diones. The regioselectivity of this reaction was controlled by the aryl group which is different from the reaction of 2,3-allenamides with carbon dioxide. As a result of the easy availability of starting materials, the usefulness of the products and the efficient fixation of carbon dioxide, this reaction may have potentials in organic synthesis. Further studies including expanding the substrate scope in this area are being pursued in our laboratory.

Experimental

Materials

DMSO was distilled from CaH₂. THF was distilled from Na/benzophenone. Et₃N was distilled from KOH. The other commercially available chemicals were purchased and used without additional purification unless noted otherwise.

Synthesis of starting materials

Known compounds 1a,^8a1b,^8b1c,^8c1d,^8d1e,^8c1f,^8a1j,^8e1o^8f and new compounds 1g–1i, 1k–1n were prepared following the known procedure.^8a

N-(n-Butyl)-3-(4-n-propylphenyl)propiolamide (1g). To the reaction vessel containing ethyl 3-(4-n-propylphenyl)propiolate (1.0808 g, 5.00 mmol) were added 2 mL of H₂O and 2 mL of n-BuNH₂ sequentially, Then the resulting solution was stirred at room temperature. After 15 h, the reaction was diluted with 25 mL of CH₂Cl₂, washed with water twice, and dried over anhydrous Na₂SO₄. After filtration and evaporation, chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 5/1) of the crude product afforded 1g (1.1213 g, 92%) as a solid, m.p.: 48.0–49.0 °C (n-hexane/CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃) δ 7.51–7.39 (m, 2H, Ar-H), 7.22–7.10 (m, 2H, Ar-H), [5.92 (bs), 5.76 (bs), 1H, NH], [3.49 (q, J = 6.8 Hz), 3.35 (q, J = 6.7 Hz), 2H, N-CH₂], 2.70–2.50 (m, 2H, Ar-CH₂), 1.71–1.47 (m, 4H, 2×MeCH₂), 1.46–1.30 (m, 2H, CH₂), 1.01–0.83 (m, 6H, 2×Me); MS (m/z): 244 (M⁺ + 1, 2.47), 243 (M⁺, 14.26), 171 (100); IR (KBr, cm⁻¹): 3285, 2959, 2931, 2866, 2226, 1629, 1537, 1464, 1433, 1410, 1375, 1307, 1223, 1179, 1151, 1112; Anal. Calcd. for C₁₆H₂₁NO: C 78.97, H 8.70, N 5.76; Found: C 79.16, H 8.72, N 6.08%.

N-(n-Butyl)-3-(p-tolyl)propiolamide (1h). Following the procedure for the preparation of 1g, the reaction of 1.0657 g (5.67 mmol) of ethyl 3-(p-tolyl)propiolate, 2 mL of H₂O and 2 mL of n-BuNH₂ afforded 1.0541 g (86%) of 1h (eluent: petroleum ether/ethyl acetate = 10/1–5/1) as a solid, m.p.: 56.9–57.4 °C (n-hexane/CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃) δ 7.47–7.37 (m, 2H, Ar-H), 7.22–7.10 (m, 2H, Ar-H), [5.95 (bs), 5.81 (bs), 1H, NH], [3.48 (q, J = 6.7 Hz), 3.35 (q, J = 6.7 Hz), 2H, N-CH₂], [2.38 (s), 2.36 (s), 3H, Ar-CH₃], 1.63–1.48 (m, 2H, CH₂), 1.48–1.30 (m, 2H, MeCH₂), 1.01–0.88 (m, 3H, Me); MS (m/z): 216 (M⁺ + 1, 1.61), 215 (M⁺, 10.30), 143 (100); IR (KBr, cm⁻¹): 3271, 2961, 2932, 2872, 2216, 1630, 1534, 1464, 1377, 1353, 1303, 1222, 1209, 1182, 1023; Anal. Calcd. for C₁₄H₁₇NO: C 78.10, H 7.96, N 6.51; Found: C 77.99, H 7.81, N 6.63%.

N-(n-Butyl)-3-(4-methoxyphenyl)propiolamide (1i). Following the procedure for the preparation of 1g, the reaction of 1.0130 g (4.97 mmol) of ethyl 3-(4-methoxyphenyl)propiolate, 2 mL of H₂O and 2 mL of n-BuNH₂ afforded 1.1276 g (98%) of 1ias a solid, m.p.: 66.2–67.0 °C (n-hexane/CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃) δ 7.53–7.42 (m, 2H, Ar-H), 6.92–6.80 (m, 2H, Ar-H), 6.02 (bs, 1H, NH), [3.82 (s), 3.81 (s), 3H, OMe], [3.47 (q, J = 7.0 Hz), 3.34 (q, J = 6.8 Hz), 2H, N-CH₂], 1.65–1.48 (m, 2H, CH₂), 1.48–1.27 (m, 2H, MeCH₂), 1.00–0.87 (m, 3H, Me); MS (m/z): 232 (M⁺ + 1, 2.02), 231 (M⁺, 13.76), 159 (100); IR (KBr, cm⁻¹): 3269, 3051, 2959, 2925, 2871, 2210, 1630, 1605, 1537, 1510, 1465, 1438, 1287, 1252, 1224, 1172, 1107, 1031; Anal. Calcd. for C₁₄H₁₇NO₂: C 72.70, H 7.41, N 6.06; Found: C 72.69, H 7.41, N 6.07%.

N-(n-Butyl)-3-(4-fluorophenyl)propiolamide (1k). Following the procedure for the preparation of 1g, the reaction of 0.9706 g (5.06 mmol) of ethyl 3-(4-fluorophenyl)propiolate, 2 mL of H₂O and 2 mL of n-BuNH₂ afforded 1k with some minor impurity after purification by chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 5/1). This product was further purified by recrystallization to afford 0.9623 g (87%) of 1k (n-hexane/CH₂Cl₂) as a solid, m.p.: 59.1–59.5 °C (n-hexane/CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃) δ 7.60–7.45 (m, 2H, Ar-H), 7.15–6.98 (m, 2H, Ar-H), [5.97 (bs), 5.85 (s), 1H, NH], [3.48 (q, J = 6.7 Hz), 3.35 (q, J = 6.6 Hz), 2H, N-CH₂], 1.65–1.46 (m, 2H, CH₂), 1.46–1.29 (m, 2H, MeCH₂), 1.00–0.81 (m, 3H, Me); ¹⁹F NMR (282 MHz, CDCl₃) δ −107.15, −107.61 (standard by frequency conversion of CDCl₃); MS (m/z): 220 (M⁺ + 1, 1.17), 219 (M⁺, 7.79), 147 (100); IR (KBr, cm⁻¹): 3304, 2964, 2935, 2868, 2229, 1624, 1598, 1538, 1505, 1471, 1400, 1375, 1351, 1307, 1231, 1157, 1095; Anal. Calcd. for C₁₃H₁₄FNO: C 71.21, H 6.44, N 6.39; Found: C 71.15, H 6.45, N 6.35%.

N-Benzyl-3-(3-thienyl)propiolamide (1l). Following the procedure for the preparation of 1g, the reaction of 1.1863 g (6.59 mmol) of ethyl 3-(3-thienyl)propiolate, 2.5 mL of H₂O and 2.5 mL of BnNH₂ afforded 1l with some minor impurity after purification by chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 5/1–3/1). This product was further purified by recrystallization to afford 0.8678 g (54%) of 1l (n-hexane/CH₂Cl₂) as a solid, m.p.: 111.4–112.0 °C (n-hexane/CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃) δ 7.68–7.62 (m, 1H, Ar-H), 7.42–7.27 (m, 6H, Ar-H), 7.20–7.14 (m, 1H, Ar-H), 6.16 (bs, 1H, NH), [4.69 (d, J = 7.2 Hz), 4.54 (d, J = 5.7 Hz), 2H, N-CH₂]; MS (m/z): 242 (M⁺ + 1, 12.00), 241 (M⁺, 64.86), 135 (100); IR (KBr, cm⁻¹): 3215, 3105, 3036, 2847, 2218, 1625, 1558, 1494, 1452, 1420, 1359, 1294, 1225, 1172, 1089, 1030; Anal. Calcd. for C₁₄H₁₁NOS: C 69.68, H 4.59, N 5.80; Found: C 69.79, H 4.72, N 6.03%.

N-Benzyl-3-(2-thienyl)propiolamide (1m). Following the procedure for the preparation of 1g, the reaction of 0.4535 g (2.52 mmol) of ethyl 3-(2-thienyl)propiolate, 1 mL of H₂O and 1 mL of BnNH₂ afforded 0.2171 g (36%) of 1m (eluent: petroleum ether/ethyl acetate = 5/1–3/1) as a solid, m.p.: 107.3–107.6 °C (n-hexane/CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃) δ 7.47–7.21 (m, 7H, Ar-H), 7.07–6.95 (m, 1H, Ar-H), [6.22 (bs), 6.05 (bs), 1H, NH], [4.67 (d, J = 6.3 Hz), 4.54 (d, J = 5.7 Hz), 2H, N-CH₂]; MS (m/z): 242 (M⁺ + 1, 9.74), 241 (M⁺, 50.45), 135 (100); IR (KBr, cm⁻¹): 3273, 3088, 2207, 1625, 1583, 1552, 1496, 1453, 1425, 1366, 1277, 1231, 1180, 1061, 1029, 1009; Anal. Calcd. for C₁₄H₁₁NOS: C 69.68, H 4.59, N 5.80; Found: C 69.74, H 4.60, N 6.12%.

N-(n-Butyl)-3-cyclohexenylpropiolamide (1n). Following the procedure for the preparation of 1g, the reaction of 0.9073 g (5.10 mmol) of ethyl 3-cyclohexenylpropiolate, 2 mL of H₂O and 2 mL of n-BuNH₂ afforded 0.9200 g (88%) of 1n (eluent: petroleum ether/ethyl acetate = 3/1) as a liquid. ¹H NMR (300 MHz, CDCl₃) δ 6.41–6.27 (m, 1H, =CH), 5.80 (bs, 1H, NH), [3.38 (q, J = 6.7 Hz), 3.29 (q, J = 6.7 Hz), 2H, N-CH₂], 2.21–2.02 (m, 4H, CH₂-C=C-CH₂), 1.69–1.45 (m, 6H, 3×CH₂), 1.44–1.25 (m, 2H, MeCH₂), 1.00–0.83 (m, 3H, Me); MS (m/z): 206 (M⁺ + 1, 1.98), 205 (M⁺, 8.93), 133 (100); IR (neat, cm⁻¹): 3263, 3054, 2931, 2862, 2207, 1633, 1538, 1435, 1360, 1348, 1290, 1265, 1226, 1184, 1137, 1077; Anal. Calcd. for C₁₃H₁₉NO: C 76.06, H 9.33, N 6.82; Found: C 76.03, H 9.27, N 6.73%.

Reactions of 2-alkynamides with CO₂

(Z)-3-Benzyl-5-benzylideneoxazolidine-2,4-dione (2a). To the reaction vessel containing K₂CO₃ (54.5 mg, 0.39 mmol) were charged 1a (46.2 mg, 0.20 mmol) and 2 mL of DMSO sequentially under CO₂ atmosphere. The CO₂ gas from a CO₂ balloon was dried by passing through a gas washing bottle with conc. H₂SO₄ and directed through a relief needle fixed with the rubber stopper to the reaction mixture. The resulting solution was heated at 30 °C with stirring. After 11 h, the reaction was quenched with 10 mL of H₂O, extracted with ether (15 mL × 3), washed with brine, and dried over anhydrous Na₂SO₄. After filtration and evaporation, chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 20/1) of the crude product afforded 2a (34.0 mg, 62%) as a solid, m.p.: 158.2–159.2 °C (n-hexane/CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃) δ 7.79–7.70 (m, 2H, Ar-H), 7.50–7.29 (m, 8H, Ar-H), 6.78 (s, 1H, =CH), 4.80 (s, 2H, N-CH₂); ¹³C NMR (75 MHz, CDCl₃): δ 162.0, 152.0, 137.4, 134.3, 131.1, 130.6, 130.5, 129.0, 128.9, 128.8, 128.5, 113.8, 43.8; MS (m/z): 280 (M⁺ + 1, 14.65), 279 (M⁺, 78.90), 118 (100); IR (KBr, cm⁻¹): 1807, 1733, 1674, 1495, 1451, 1433, 1398, 1340, 1309, 1291, 1235, 1170, 1081, 1067; Anal. Calcd. for C₁₇H₁₃NO₃: C 73.11, H 4.69, N 5.02; Found: C 73.20, H 4.72, N 4.96%.

(Z)-5-Benzylidene-3-(n-butyl)oxazolidine-2,4-dione (2b). Following the procedure for the preparation of 2a, the reaction of 40.1 mg (0.20 mmol) of 1b and 55.8 mg (0.40 mmol) of K₂CO₃ in DMSO (2 mL) afforded 39.0 mg (80%) of 2b (eluent: petroleum ether/ethyl acetate = 25/1) as a solid, m.p.: 82.7–83.4 °C (n-hexane/CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃) δ 7.80–7.71 (m, 2H, Ar-H), 7.50–7.36 (m, 3H, Ar-H), 6.76 (s, 1H, =CH), 3.65 (t, J = 7.4 Hz, 2H, N-CH₂), 1.78–1.62 (m, 2H, CH₂), 1.46–1.30 (m, 2H, MeCH₂), 0.96 (t, J = 7.4 Hz, 3H, Me); ¹³C NMR (75 MHz, CDCl₃): δ 162.4, 152.3, 137.5, 131.0, 130.7, 130.4, 129.0, 113.3, 40.0, 29.6, 19.8, 13.5; MS (m/z): 246 (M⁺ + 1, 4.12), 245 (M⁺, 25.65), 118 (100); IR (KBr, cm⁻¹): 1816, 1721, 1666, 1495, 1449, 1413, 1354, 1315, 1264, 1236, 1187, 1082, 1006; Anal. Calcd. for C₁₄H₁₅NO₃: C 68.56, H 6.16, N 5.71; Found: C 68.88, H 6.40, N 5.72%.

(Z)-5-Benzylidene-3-ethyloxazolidine-2,4-dione (2c). Following the procedure for the preparation of 2a, the reaction of 34.2 mg (0.20 mmol) of 1c and 55.4 mg (0.40 mmol) of K₂CO₃ in DMSO (2 mL) afforded 28.4 mg (66%) of 2c (eluent: petroleum ether/ethyl acetate = 25/1) as a solid, m.p.: 123.6–124.3 °C (n-hexane/CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃) δ 7.85–7.68 (m, 2H, Ar-H), 7.52–7.35 (m, 3H, Ar-H), 6.75 (s, 1H, =CH), 3.71 (q, J = 7.2 Hz, 2H, N-CH₂), 1.32 (t, J = 7.2 Hz, 3H, Me); ¹³C NMR (75 MHz, CDCl₃): δ 162.1, 152.0, 137.5, 131.0, 130.7, 130.4, 129.0, 113.2, 35.3, 13.0; MS (m/z): 218 (M⁺ + 1, 5.78), 217 (M⁺, 43.70), 118 (100); IR (KBr, cm⁻¹): 1813, 1735, 1682, 1496, 1452, 1441, 1415, 1372, 1347, 1320, 1246, 1211, 1169, 1115, 1080, 1045; Anal. Calcd. for C₁₂H₁₁NO₃: C 66.35, H 5.10, N 6.45; Found: C 66.31, H 5.33, N 6.46%.

(Z)-3-Allyl-5-benzylideneoxazolidine-2,4-dione (2d). Following the procedure for the preparation of 2a, the reaction of 36.7 mg (0.20 mmol) of 1d and 56.2 mg (0.41 mmol) of K₂CO₃ in DMSO (2 mL) afforded 32.6 mg (72%) of 2d (eluent: petroleum ether/ethyl acetate = 15/1) as a solid, m.p.: 79.7–80.5 °C (n-hexane/CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃) δ 7.84–7.68 (m, 2H, Ar-H), 7.50–7.36 (m, 3H, Ar-H), 6.78 (s, 1H, =CH-Ar), 6.00–5.78 (m, 1H, =CH-CH₂), 5.45–5.25 (m, 2H, =CH₂), 4.25 (d, J = 5.7 Hz, 2H, N-CH₂); ¹³C NMR (75 MHz, CDCl₃): δ 161.8, 151.8, 137.4, 131.1, 130.6, 130.5, 129.5, 129.0, 119.6, 113.6, 42.2; MS (m/z): 230 (M⁺ + 1, 6.03), 229 (M⁺, 41.47), 118 (100); IR (KBr, cm⁻¹): 1816, 1740, 1682, 1452, 1433, 1403, 1351, 1238, 1176, 1101; Anal. Calcd. for C₁₃H₁₁NO₃: C 68.11, H 4.84, N 6.11; Found: C 68.47, H 5.01, N 5.99%.

(Z)-5-Benzylidene-3-isopropyloxazolidine-2,4-dione (2e). Following the procedure for the preparation of 2a, the reaction of 37.6 mg (0.20 mmol) of 1e and 82.9 mg (0.60 mmol) of K₂CO₃ in DMSO (2 mL) afforded 31.5 mg (68%) of 2e (eluent: petroleum ether/ethyl acetate = 25/1) as a solid, m.p.: 123.8–125.0 °C (n-hexane/CH₂Cl₂). The reaction of 37.0 mg (0.20 mmol) of 1e and 132.7 mg (0.41 mmol) of Cs₂CO₃ in DMSO (2 mL) afforded 20.8 mg (46%) of 2e. ¹H NMR (300 MHz, CDCl₃) δ 7.80–7.69 (m, 2H, Ar-H), 7.50–7.36 (m, 3H, Ar-H), 6.72 (s, 1H, =CH), 4.44 (heptet, J = 7.0 Hz, 1H, N-CH), 1.49 (d, J = 7.0 Hz, 6H, 2×Me); ¹³C NMR (75 MHz, CDCl₃): δ 162.2, 151.5, 137.2, 131.0, 130.8, 130.3, 129.0, 112.9, 45.3, 19.4; MS (m/z): 232 (M⁺ + 1, 5.15), 231 (M⁺, 34.78), 118 (100); IR (KBr, cm⁻¹): 1815, 1738, 1686, 1666, 1496, 1452, 1403, 1388, 1371, 1347, 1249, 1207, 1181, 1071, 1021, 1002; Anal. Calcd. for C₁₃H₁₃NO₃: C 67.52, H 5.67, N 6.06; Found: C 67.48, H 5.73, N 6.11%.

(Z)-3-(n-Butyl)-5-(4-n-propylbenzylidene)oxazolidine-2,4-dione (2g). Following the procedure for the preparation of 2a, the reaction of 48.2 mg (0.20 mmol) of 1g and 56.0 mg (0.41 mmol) of K₂CO₃ in DMSO (2 mL) afforded 39.3 mg (69%) of 2g (eluent: petroleum ether/ethyl acetate = 25/1) as a liquid. ¹H NMR (300 MHz, CDCl₃) δ 7.66 (d, J = 8.4 Hz, 2H, Ar-H), 7.23 (d, J = 8.4 Hz, 2H, Ar-H), 6.74 (s, 1H, =CH), 3.64 (t, J = 7.4 Hz, 2H, N-CH₂), 2.61 (t, J = 7.7 Hz, 2H, Ar-CH₂), 1.78–1.57 (m, 4H, 2×MeCH₂), 1.46–1.30 (m, 2H, CH₂), 1.02–0.89 (m, 6H, 2×Me); ¹³C NMR (75 MHz, CDCl₃): δ 162.4, 152.3, 145.8, 136.9, 131.1, 129.1, 128.2, 113.5, 40.0, 37.9, 29.6, 24.2, 19.8, 13.7, 13.5; MS (m/z): 288 (M⁺ + 1, 6.70), 287 (M⁺, 34.43), 160 (100); IR (neat, cm⁻¹): 2960, 2925, 2873, 1822, 1738, 1674, 1608, 1511, 1442, 1404, 1371, 1345, 1301, 1246, 1192, 1162, 1092, 1042; HRMS Calcd for C₁₇H₂₁NO₃ (M⁺): 287.1521, Found: 287.1521.

(Z)-3-(n-Butyl)-5-(4-methylbenzylidene)oxazolidine-2,4-dione (2h). Following the procedure for the preparation of 2a, the reaction of 43.3 mg (0.20 mmol) of 1h and 56.6 mg (0.41 mmol) of K₂CO₃ in DMSO (2 mL) afforded 35.8 mg (69%) of 2h (eluent: petroleum ether/ethyl acetate = 25/1) as a solid, m.p.: 87.0–88.4 °C (n-hexane/CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃) δ 7.64 (d, J = 8.1 Hz, 2H, Ar-H), 7.23 (d, J = 8.1 Hz, 2H, Ar-H), 6.73 (s, 1H, =CH), 3.64 (t, J = 7.4 Hz, 2H, N-CH₂), 2.38 (s, 3H, Ar-Me), 1.77–1.61 (m, 2H, CH₂), 1.46–1.25 (m, 2H, MeCH₂), 0.95 (t, J = 7.2 Hz, 3H, Me); ¹³C NMR (75 MHz, CDCl₃): δ 162.4, 152.3, 141.0, 136.9, 131.0, 129.7, 127.9, 113.4, 39.9, 29.6, 21.5, 19.8, 13.5; MS (m/z): 260 (M⁺ + 1, 4.24), 259 (M⁺, 25.13), 132 (100); IR (KBr, cm⁻¹): 2959, 2877, 1817, 1735, 1675, 1608, 1514, 1440, 1404, 1362, 1345, 1318, 1288, 1239, 1161, 1094, 1065, 1042; Anal. Calcd. for C₁₅H₁₇NO₃: C 69.48, H 6.61, N 5.40; Found: C 69.43, H 6.66, N 5.35%.

(Z)-3-(n-Butyl)-5-(4-methoxybenzylidene)oxazolidine-2,4-dione (2i). Following the procedure for the preparation of 2a, the reaction of 45.7 mg (0.20 mmol) of 1i and 55.1 mg (0.40 mmol) of K₂CO₃ in DMSO (2 mL) afforded 36.7 mg (67%) of 2i (eluent: petroleum ether/ethyl acetate = 25/1–15/1) as a solid, m.p.: 106.0–106.6 °C (n-hexane/CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃) δ 7.73–7.65 (m, 2H, Ar-H), 6.98–6.88 (m, 2H, Ar-H), 6.70 (s, 1H, =CH), 3.84 (s, 3H, OMe), 3.63 (t, J = 7.4 Hz, 2H, N-CH₂), 1.75–1.61 (m, 2H, CH₂), 1.45–1.27 (m, 2H, MeCH₂), 0.95 (t, J = 7.5 Hz, 3H, Me); ¹³C NMR (75 MHz, CDCl₃): δ 162.5, 161.3, 152.4, 136.0, 132.9, 123.4, 114.4, 113.3, 55.3, 39.9, 29.6, 19.8, 13.5; MS (m/z): 276 (M⁺ + 1, 6.32), 275 (M⁺, 36.31), 148 (100); IR (KBr, cm⁻¹): 2979, 2952, 2867, 2835, 1814, 1740, 1678, 1603, 1514, 1447, 1408, 1345, 1307, 1257, 1163, 1095, 1064, 1027; Anal. Calcd. for C₁₅H₁₇NO₄: C 65.44, H 6.22, N 5.09; Found: C 65.38, H 6.30, N 5.03%.

(Z)-3-Benzyl-5-(4-methoxybenzylidene)oxazolidine-2,4-dione (2j). Following the procedure for the preparation of 2a, the reaction of 53.3 mg (0.20 mmol) of 1j and 55.6 mg (0.41 mmol) of K₂CO₃ in DMSO (2 mL) afforded 42.2 mg (68%) of 2j (eluent: petroleum ether/ethyl acetate = 20/1–10/1) as a solid, m.p.: 117.8–118.7 °C (n-hexane/CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃) δ 7.75–7.65 (m, 2H, Ar-H), 7.50–7.40 (m, 2H, Ar-H), 7.40–7.27 (m, 3H, Ar-H), 6.98–6.88 (m, 2H, Ar-H), 6.73 (s, 1H, =CH), 4.78 (s, 2H, N-CH₂), 3.84 (s, 3H, OMe); ¹³C NMR (75 MHz, CDCl₃): δ 162.1, 161.3, 152.1, 135.9, 134.5, 133.0, 128.81, 128.77, 128.4, 123.3, 114.5, 113.8, 55.3, 43.6; MS (m/z): 310 (M⁺+1, 13.88), 309 (M⁺, 68.64), 148 (100); IR (KBr, cm⁻¹): 1805, 1735, 1666, 1601, 1572, 1512, 1455, 1443, 1430, 1401, 1348, 1312, 1259, 1174, 1091, 1070, 1025; Anal. Calcd. for C₁₈H₁₅NO₄: C 68.89, H 4.89, N 4.53; Found: C 69.75, H 5.01, N 4.64%.

(Z)-3-(n-Butyl)-5-(4-fluorobenzylidene)oxazolidine-2,4-dione (2k). Following the procedure for the preparation of 2a, the reaction of 43.2 mg (0.20 mmol) of 1k and 56.2 mg (0.41 mmol) of K₂CO₃ in DMSO (2 mL) afforded 37.2 mg (72%) of 2k (eluent: petroleum ether/ethyl acetate = 25/1) as a solid, m.p.: 102.6–103.8 °C (n-hexane/CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃) δ 7.81–7.69 (m, 2H, Ar-H), 7.18–7.05 (m, 2H, Ar-H), 6.71 (s, 1H, =CH), 3.65 (t, J = 7.4 Hz, 2H, N-CH₂), 1.78–1.60 (m, 2H, CH₂), 1.46–1.28 (m, 2H, MeCH₂), 0.95 (t, J = 7.4 Hz, 3H, Me); ¹³C NMR (75 MHz, CDCl₃): δ 163.6 (d, J = 251.4 Hz), 162.3, 152.2, 137.2 (d, J = 2.7 Hz), 133.1 (d, J = 8.4 Hz), 127.0 (d, J = 3.2 Hz), 116.2 (d, J = 22.7 Hz), 112.0, 40.1, 29.6, 19.8, 13.5; ¹⁹F NMR (282 MHz, CDCl₃): δ −108.0 (standard by frequency conversion of CDCl₃); MS (m/z): 264 (M⁺ + 1, 3.56), 263 (M⁺, 21.57), 136 (100); IR (KBr, cm⁻¹): 2959, 2873, 1819, 1728, 1674, 1602, 1511, 1447, 1416, 1373, 1356, 1310, 1292, 1239, 1186, 1163, 1085, 1058, 1010; Anal. Calcd. for C₁₄H₁₄FNO₃: C 63.87, H 5.36, N 5.32; Found: C 63.98, H 5.41, N 5.23%.

(Z)-3-Benzyl-5-(thiophen-3-ylmethylene)oxazolidine-2,4-dione (2l). Following the procedure for the preparation of 2a, the reaction of 47.9 mg (0.20 mmol) of 1l and 55.1 mg (0.40 mmol) of K₂CO₃ in DMSO (2 mL) afforded 34.8 mg (61%) of 2l (eluent: petroleum ether/ethyl acetate = 15/1) as a solid, m.p.: 155.9–156.4 °C (n-hexane/CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃) δ 7.83–7.75 (m, 1H, Ar-H), 7.52–7.41 (m, 3H, Ar-H), 7.40–7.28 (m, 4H, Ar-H), 6.84 (s, 1H, =CH), 4.78 (s, 2H, N-CH₂); ¹³C NMR (75 MHz, CDCl₃): δ 161.9, 151.9, 136.6, 134.4, 132.0, 130.7, 128.9, 128.8, 128.6, 128.5, 126.7, 107.8, 43.8; MS (m/z): 286 (M⁺ + 1, 16.21), 285 (M⁺, 100); IR (KBr, cm⁻¹): 3102, 3031, 2947, 1808, 1735, 1674, 1518, 1495, 1456, 1438, 1406, 1354, 1343, 1322, 1249, 1212, 1156, 1090, 1069; Anal. Calcd. for C₁₅H₁₁NO₃S: C 63.14, H 3.89, N 4.91; Found: C 63.18, H 4.09, N 4.99%.

(Z)-3-Benzyl-5-(thiophen-2-ylmethylene)oxazolidine-2,4-dione (2m). Following the procedure for the preparation of 2a, the reaction of 47.1 mg (0.20 mmol) of 1m and 81.6 mg (0.59 mmol) of K₂CO₃ in DMSO (2 mL) afforded 30.7 mg (55%) of 2m (eluent: petroleum ether/ethyl acetate = 15/1) as a solid, m.p.: 177.2–178.0 °C (n-hexane/CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃) δ 7.59 (d, J = 4.8 Hz, 1H, Ar-H), 7.53–7.40 (m, 3H, Ar-H), 7.40–7.28 (m, 3H, Ar-H), 7.12 (t, J = 4.4 Hz, 1H, Ar-H), 7.01 (s, 1H, =CH), 4.78 (s, 2H, N-CH₂); ¹³C NMR (75 MHz, CDCl₃): δ 161.5, 151.6, 135.6, 134.4, 133.5, 133.1, 132.0, 128.9, 128.8, 128.5, 128.1, 107.4, 43.8; MS (m/z): 286 (M⁺ + 1, 13.07), 285 (M⁺, 74.61), 124 (100); IR (KBr, cm⁻¹): 3104, 1810, 1728, 1668, 1495, 1457, 1435, 1398, 1344, 1318, 1247, 1231, 1167, 1071, 1051; Anal. Calcd. for C₁₅H₁₁NO₃S: C 63.14, H 3.89, N 4.91; Found: C 63.11, H 3.97, N 5.01%.

Acknowledgements

Financial support from the Major State Basic Research and Development Program (2009CB825300) and Project for Basic Research in Natural Science Issued by Shanghai Municipal Committee of Science (No. 08dj1400100). Shengming Ma is a Qiu Shi Adjunct Professor at Zhejiang University. We thank Mr. Suhua Li in this group for reproducing the results presented in entries 3, 9, and 13 in Table 2.

Notes and references

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3. Using electrochemical method, see: (a) L. Rossi, M. Feroci, M. Verdecchia and A. Inesi, Lett. Org. Chem., 2005, 2, 731; (b) M. A. Casadei, F. M. Moracci, G. Zappia, A. Inesi and L. Rossi, J. Org. Chem., 1997, 62, 6754; (c) M. A. Casadei, S. Cesa, F. M. Moracci, A. Inesi and M. Feroci, J. Org. Chem., 1996, 61, 380; (d) M. A. Casadei, S. Cesa and A. Inesi, Tetrahedron, 1995, 51, 5891; (e) Using strong bases LDA or n-BuLi, see: G. M. Coppola and R. E. Damon, J. Heterocycl. Chem., 1995, 32, 1133; (f) A. R. Katritzky, W.-Q. Fan, A. E. Koziol and G. J. Palenik, Tetrahedron, 1987, 43, 2343; (g) A. R. Katritzky and W.-Q. Fan, Org. Prep. Proced. Int., 1987, 19, 263; (h) G. M. Coppola and R. E. Damon, J. Heterocycl. Chem., 1995, 32, 1133.
4. (a) J. W. Clark-Lewis, Chem. Rev., 1958, 58, 63; (b) P. C. Unangst, D. T. Connor, W. A. Cetenko, R. J. Sorenson, C. R. Kostlan, J. C. Sircar, C. D. Wright, D. J. Schrier and R. D. Dyer, J. Med. Chem., 1994, 37, 322; (c) D. A Heerding, L. T. Christmann, T. J. Clark, D. J. Holmes, S. F. Rittenhouse, D. T. Takata and J. W. Venslavsky, Bioorg. Med. Chem. Lett., 2003, 13, 3771; (d) R. L. Dow, B. M. Bechle, T. T. Chou, D. A. Clark, B. Hulin and R. W. Stevenson, J. Med. Chem., 1991, 34, 1538; (e) Y. Momose, T. Maekawa, T. Yamano, M. Kawada, H. Odaka, H. Ikeda and T. Sohda, J. Med. Chem., 2002, 45, 1518; (f) Y.-L. Li, Y.-X. Song and T.-J. Guo, Cont. Chem. Indu., 2003, 32, 18; (g) Y.-L. Li, W.-R. Miao and Y.-H. Zhou, Chin. J. Pest., 2005, 44, 503.
5. (a) T. L. Patton, J. Org. Chem., 1967, 32, 383; (b) A. Oku, S. Nakaoji, T. Kadono and H. Imai, Bull. Chem. Soc. Jpn., 1979, 52, 2966; (c) A. Zask, J. Org. Chem., 1992, 57, 4558; (d) A. Benavides, R. Martínez, H. A. Jiménez-Vázquez, F. Delgado and J. Tamariz, Heterocycles, 2001, 55, 469.
6. G. Chen, C. Fu and S. Ma, Org. Lett., 2009, 11, 2900.
7. Crystal data for compound 2a: C₁₇H₁₃NO₃, MW = 279.28, monoclinic, space group P2(1)/c, final R indices [I > 2σ(I)], R1 = 0.0411, wR2 = 0.0979, R indices (all data) R1 = 0.0487, wR2 = 0.1027, a = 6.4285(4) Å, b = 31.4664(18) Å, c = 7.0702(4) Å, α = 90°, β = 106.517(2)°, γ = 90°, V = 1371.16(14) ų, T = 173(2) K, Z = 4, reflections collected/unique 15862/2426 (Rint = 0.0299), number of observations [I > 2σ(I)] 2086, parameters: 190. Supplementary crystallographic data have been deposited at the Cambridge Crystallographic Data Center. CCDC 779363.
8. (a) S. A. Jr. Lang and E. Cohen, J. Med. Chem., 1975, 18, 441; (b) Y. Iwanami, Nippon Kagaku Zasshi, 1962, 83, 600; (c) A. Yokoyama, K. Ashida and H. Tanaka, Chem. Pharm. Bull., 1964, 12, 690; (d) H. Jiang, S. Ma, G. Zhu and X. Lu, Tetrahedron, 1996, 52, 10945; (e) H. Imase, K. Noguchi, M. Hirano and K. Tanaka, Org. Lett., 2008, 10, 3563; (f) G. T. Crisp and M. J. Millan, Tetrahedron, 1998, 54, 637.

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Footnote

† Electronic supplementary information (ESI) available: Spectra. CCDC reference number 779363. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c0ob00550a

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