TFA-catalyzed ring transformation of 4-hydroxycyclobutenone: A simple and general route for preparation of 3-substituted 4-aminofuran-2(5H )-ones 

Abstract

Following a convenient sequence of alkylation and amination of 3,4-diisopropoxycyclobutene-1,2-dione 11, three typical substituted groups (H, n-Bu, and Ph) and three typical amino groups (unsubstituted, primary and secondary) are easily introduced onto its C-3 and C-4 positions, respectively, to yield 4-substituted 3-aminocyclobutene-1,2-diones 14. Reduction of compounds 14 with NaBH₄ yield 2-substituted 3-amino-4-hydroxycyclobutenones 15 in high yields. By ring transformation of products 15 catalyzed by TFA, a simple and general route for the preparation of 3-substituted 4-aminofuran-2(5H )-ones 4 is developed. A two-step mechanism is proposed to describe the ring transformation of enones 15. The experimental results show that the process in refluxing p-xylene is essential for the initial thermal electrocyclic opening of 15 to yield intermediate hydroxy ketenes 16a and 16b. They are then lactonized in the presence of TFA to give furanones 4 in 51–94% yield.

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Introduction

Although very few derivatives of 4-aminofuran-2(5H )-one occur in nature, their synthetic analogues are widely used in chemical, pharmaceutical and agrochemical research. Some 4-aminofuran-2(5H )-ones have been intermediates in the synthesis of natural products.¹ Many have been patented as prodrugs or insecticides and herbicides ² (for example, see: 1–3 in Chart 1).

Chart 1

Many methods have been developed for the preparation of 4-aminofuran-2(5H )-ones.^3–7 Using cyanohydrin derivatives as starting materials, primary 4-aminofuran-2(5H )-ones, being mono- or bis-substituted at C-5 to meet the requirements of the reaction mechanism, were obtained.⁴ The sequence of aminoaddition on acetylenecarboxylates followed by intramolecular cyclizations afforded 3-unsubstituted primary or secondary 4-aminofuran-2(5H )-ones smoothly.⁵ Although 4-halogeno- or 4-hydroxyfuran-2(5H )-ones can be aminated to yield the corresponding unsubstituted, primary and secondary 4-aminofuran-2(5H )-ones conveniently,^1c,1d,6 the method has been limited by inaccessible precursors.⁸ Very few procedures can be employed for direct alkylation of 4-aminofuran-2(5H )-ones at C-3.^6a,7

To continue our agrochemical research project, a series of 3-substituted 4-aminofuran-2(5H )-ones (4 in Chart 1) were designed as targets for synthesis. Herein, we report a novel and practical route for the synthesis of 3-substituted 4-aminofuran-2(5H )-ones that overcomes some of the limitations to published procedures.

Results and discussion

Strategy

4-Hydroxycyclobutenones with an unsaturated substituent at C-4 (5a–c in Chart 2) undergo thermal electrocyclic ring openings to give a variety of ring-expansion products including highly substituted phenols (6),⁹ quinones (7) ¹⁰ and heteroaromatic compounds (8) (Chart 2).¹¹

Chart 2

The effect of substituents on the direction of conrotation in electrocyclic reactions of 4-hydroxycyclobutenones has been explained and predicted by Houk’s work. The hydroxy group as an electron-donating substituent favors intermediate 9 by outward rotation (Chart 3).¹² For this reason, furan-2(5H )-ones formed by intermediate 10 in thermal electrocyclic reactions were believed to be unusual by-products,¹³ even though they were obtained as sole products in photochemistry or in metal-catalyzed reactions.¹⁴

Chart 3

The thermal electrocyclic opening of 4-substituted 4-hydroxybutenones 5a–c is reversible; hence the final product might arise from trapping intermediate 9 in an equilibrating mixture of 9 and 10. When the reactivity of R in 9 was inhibited by steric hindrance or a hydrogen bond, the corresponding furan-2(5H )-one was obtained by attack of the hydroxy group on the ketene involved in the intermediate 10.^13,15 It clearly implies that the thermolysis of 5d (R = H) should yield a furan-2(5H )-one because only the hydroxy group as trapping group is present in the molecule. As shown in Scheme 1, this transformation has been developed as a key step for the preparation of 3-substituted 4-aminofuran-2(5H )-ones 4 in our synthetic strategy.

Scheme 1

Synthesis of 4-substituted 3-aminocyclobutene-1,2-diones 14

Three typical 4-substituted 3-isopropoxycyclobutene-1,2-diones (12a–c) were chosen as starting materials, which were routinely prepared in 65–90% yield by known procedures ¹⁶ from 3,4-diisopropoxycyclobutene-1,2-dione 11. The vinylogous ester at C-3 in the structures 12a–c made the substitution of the isopropoxy group by various amines very easy.¹⁷ Thus, a mixture of 3-isopropoxy-4-phenylcyclobutene-1,2-dione 12a and ammonium hydroxide (28% solution in water, 13a) in methanol was stirred for 30 min at room temperature, and 3-amino-4-phenylcyclobutene-1,2-dione 14a was separated in 96% yield. To explore the scope of the reaction, allylic, benzyl and cyclic amines (13b–g) were tested and all of them gave excellent yields (14b–g, 88–96%) (Scheme 2).

Scheme 2

Similarly, diones 12b,c were treated with amines 13 to give 14h–o in moderate to high yields (55–98%) (Scheme 2 and Table 1). It was noted that the amination of 4-n-butyl-substituted compound 12b usually gave 4-n-butyl-3-aminocyclobutene-1,2-diones 14h–k in 55–87% yield together with the unsymmetrical squarine by-product in around 10–15% yield.^17a Unfortunately, more than 20% of squarine by-product was produced in the reaction between 12b and 13h (Scheme 3), with the main product being 14k.

Table 1 Substituents and yields of compounds 14, 15, and 4

No.	R	R^2 (R^1 = H) or R^1R^2	14 (%)	15 (%)	4 (%)	Time (t/h) ^a
a Reaction time for 4.
a	Ph	H	96	94	84	4.0
b	Ph	H2C[double bond, length half m-dash]CHCH2	95	91	72	3.0
c	Ph	3-CH3C6H4CH2	95	93	82	2.0
d	Ph	3-CF3C6H4CH2	91	94	80	2.5
e	Ph	4-CF3OC6H4CH2	96	93	70	3.0
f	Ph	(CH2)4	93	89	68	2.5
g	Ph	(CH2)2O(CH2)2	88	82	62	3.0
h	n-Bu	3-CF3OC6H4CH2	87	97	51	3.0
i	n-Bu	4-FC6H4CH2	82	95	69	2.5
j	n-Bu	3-CF3C6H4CH2	82	89	57	3.0
k	n-Bu	(CH2)5	55	89	61	4.0
l	H	4-ClC6H4CH2	90	96	94	0.5
m	H	3-FC6H4CH2	96	94	72	0.25
n	H	(CH2)4	98	92	74	2.5
o	H	(CH2)2O(CH2)2	91	89	69	1.0

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Scheme 3

Synthesis of 2-substituted 3-amino-4-hydroxycyclobutenones 15

In the published procedure, 3-(dibenzylamino)-4-methylcyclobutene-1,2-dione was reduced to 3-(dibenzylamino)-4-hydroxy-2-methylcyclobutenone by Li(t-BuO)₃AlH in 85% yield.^9a Realizing that C-2 ketone in compounds 14 is a vinylogous ketone, we used NaBH₄ to replace Li(t-BuO)₃AlH to furnish this conversion. Typically, when a solution of 3-amino-4-phenylcyclobutene-1,2-dione 14a in methanol was treated with NaBH₄ at 0 °C for 30 min, 3-amino-4-hydroxy-2-phenylcyclobutenone 15a was obtained in 94% yield. In the same way, ketones 14b–o were reduced to the corresponding acyloins 15b–o in 82–97% yield. This new procedure featured short reaction time, low cost and high efficiency (Scheme 4, Table 1).

Scheme 4

Synthesis of 3-substituted 4-aminofuran-2(5H )-ones 4

Following published procedures,^13c,15 4-hydroxy-2-phenyl-3-pyrrolidinocyclobutenone 15f was refluxed in p-xylene until it disappeared completely by TLC. To our disappointment, this process took 46 h and the desired product, 3-phenyl-4-pyrrolidinofuran-2(5H )-one 4f, was separated in 24% yield by column chromatography (Scheme 5). The low yield may reflect the fact that the electrocyclic opening of 15f favors ‘unsuitable’ intermediate 16b by outward rotation obeying Houk’s theory. Then 16b was converted into ‘suitable’ intermediate 16a though a reversible equilibration illustrated in Scheme 6. Finally, an intramolecular cyclization occurred to give target compound 4 by an attack of the hydroxy group on the ketene in 16a.

Scheme 5

Scheme 6

Since the intermediates 16b and 16a were hypothesized, the intramolecular cyclization between ketene and hydroxy group should be the key step to affect the reaction time and yield. It has been well known that the reaction between a ketene and a hydroxy group could be promoted significantly by acids and Lewis acids with variable results.¹⁸ Herein, several typical acids and Lewis acids were employed to test their effects on this conversion. As shown in Table 2, the lactonization can be accelerated by most Lewis acids, but without improvement in the yield. Reagents BF₃–Et₂O and H₂SO₄ induced an alternative result to give the oxidized product 3-phenyl-4-pyrrolidinocyclobutene-1,2-dione 14f (73 and 98% yield respectively) (Scheme 7).

Table 2 Effects of catalysts on the reaction of 15f

Catalysts	mol%	Time (t/h)	4f (%)
a An oxidized product was obtained. b Compound 15f disappeared completely on TLC.
AlCl3	5	18	28 ^b
ZnCl2	5	36	40 ^b
SnCl2	5	3	30 ^b
BF3–Et2O	5	2	75 ^a
H2SO4	100	0.5	98 ^b
HOAc	100	46	34 ^b
TsOH	100	10	42 ^b
TFA	110	2.5	68 ^b
TFA	200	2.0	^b

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Scheme 7

Acetic acid did not benefit either the reaction time or the yield of the reaction. However, the reaction catalyzed by TsOH was completed within 10 h in 42% yield. The best results were obtained in the presence of 1.1 mole equivalents of trifluoroacetic acid (TFA). Thus, a mixture of 15f (1.0 eq.) and TFA (1.1 eq.) in p-xylene was refluxed for 2.5 h gave 4f in 68% yield (Scheme 8). An attempt to decrease the reaction temperature failed. For example, 15f was recovered completely after being refluxed in THF for 12 h, even though 2.0 equivalents of TFA were used. This result strongly supported the two-step mechanism proposed in Scheme 6. Similarly, 14a–o were converted to the corresponding lactones 4a–o in 51–94% yield under the same conditions (Table 1).

Scheme 8

In conclusion, we have developed a simple and general route for preparation of 3-substituted 4-aminofuran-2(5H )-ones. The typical substituted groups, such as H, n-Bu, and Ph on C-3 were introduced easily. The derivatives with unsubstituted, primary and secondary amines substituted on C-4 can all be obtained in satisfactory yields.

Experimental

All mps were determined on a Yanaco melting point apparatus and are uncorrected. IR spectra were recorded on a Nicolet FT-IR 5DX spectrometer for samples as KBr pellets. ¹H NMR spectra were recorded on a Bruker MD500 or MD300 spectrometer with TMS as internal reference in CDCl₃ unless otherwise specified. J-Values are given in Hz. MS spectra were obtained on a VG-ZAB-HS mass spectrometer with 70 eV. Elemental analyses were performed on a Perkin-Elmer 240C instrument and satisfactory results obtained (C ± 0.29, H ± 0.0.24, N ± 0.0.27%) for all new compounds 14a–m, 15a–o, 4a–m and 4o. Light petroleum refers to the fraction with distillation range 60–90 °C.

General procedure for preparation of 4-substituted 3-aminocyclobutene-1,2-diones 14

A mixture of a 4-substituted 3-isopropoxycyclobutene-1,2-dione 12 (10 mmol) and an amine 13 (10 mmol) in methanol (30 cm³) was stirred for 30 min (monitored by TLC). Then it was poured into water (40 cm³) and the resultant mixture was extracted with EtOAc (3 × 40 cm³). The combined organic layers were washed successively with water (40 cm³) and brine (40 cm³) and dried over MgSO₄. The solvent was removed to give the crude product 14, which was purified by chromatography or recrystallization.

3-Amino-4-phenylcyclobutene-1,2-dione 14a. Mp 257 °C (from EtOH–light petroleum) (Found: C, 69.20; H, 4.18; N, 8.09. C₁₀H₇NO₂ requires C, 69.36; H, 4.07; N, 8.09%); ν_max/cm⁻¹ 3316, 3119, 1791, 1721, 1661, 1600; δ_H (CD₃OD) 7.99–7.97 (m, 2H), 7.53–7.47 (m, 3H); m/z 173 (M⁺, 13%), 145 (20), 117 (100), 104 (15), 89 (34), 77 (4), 63 (13), 51 (6).

3-Allylamino-4-phenylcyclobutene-1,2-dione 14b. Mp 189–191 °C (from EtOH–light petroleum); ν_max/cm⁻¹ 1779, 1724; δ_H (acetone-d₆) 8.02–8.00 (m, 2H), 7.54–7.46 (m, 3H), 6.08–6.02 (m, 1H), 5.33 (d, J 17.1, 1H), 5.20 (d, J 9.9, 1H), 4.48 (d, J 4.9, 2H); m/z 213 (M⁺, 27%), 89 (100).

3-(3-Methylbenzylamino)-4-phenylcyclobutene-1,2-dione 14c. Mp 235–237 °C (from EtOH–light petroleum); ν_max/cm⁻¹ 1772, 1718; δ_H (acetone-d₆) 8.01–8.00 (m, 2H), 7.51–7.45 (m, 3H), 7.27–7.23 (m, 3H), 7.14–7.13 (m, 1H), 5.04 (s, 2H), 2.32 (s, 3H); m/z 277 (M⁺, 59%), 105 (100).

3-Phenyl-4-[3-(trifluoromethyl)benzylamino]cyclobutene-1,2-dione 14d. Mp 222–223 °C (from EtOH–light petroleum); ν_max/cm⁻¹ 1773, 1719; δ_H (acetone-d₆) 8.00–7.99 (m, 2H), 7.83–7.79 (m, 2H), 7.69–7.62 (m, 2H), 7.52–7.46 (m, 3H), 5.20 (s, 2H); m/z 331 (M⁺, 20%), 89 (100).

3-Phenyl-4-[4-(trifluoromethoxy)benzylamino]cyclobutene-1,2-dione 14e. Mp 216–218 °C (from EtOH); ν_max/cm⁻¹ 1781, 1722; δ_H (CD₃OD) 7.97–7.96 (m, 2H), 7.53–7.48 (m, 5H), 7.31–7.30 (m, 2H), 5.03 (s, 2H); m/z 347 (M⁺, 21%), 175 (100).

3-Phenyl-4-pyrrolidinocyclobutene-1,2-dione 14f. Mp 132–133 °C (from EtOH–light petroleum); ν_max/cm⁻¹ 1752, 1716; δ_H (acetone-d₆) 7.76–7.75 (m, 2H), 7.51–7.48 (m, 2H), 7.44–7.41 (m, 1H), 4.04 (t, J 5.4, 2H), 3.69 (d, J 5.9, 2H), 2.07–2.05 (m, 4H); m/z 227 (M⁺, 4%), 171 (100).

3-Morpholino-4-phenylcyclobutene-1,2-dione 14g. Mp 146–147 °C (from EtOH–light petroleum); ν_max/cm⁻¹ 1778, 1731; δ_H (acetone-d₆) 7.63–7.44 (m, 5H), 4.11 (s, 2H), 3.85 (s, 4H), 3.70 (s, 2H); m/z 243 (M⁺, 5%), 187 (100).

3-Butyl-4-[3-(trifluoromethoxy)benzylamino]cyclobutene-1,2-dione 14h. Mp 68–71 °C (from C₆H₆–light petroleum); ν_max/cm⁻¹ 1780, 1722; δ_H 7.47–7.14 (m, 4H), 4.89 (d, J 6.3, 1H), 4.67 (d, J 5.9, 1H), 2.54 (t, J 7.5, 2H), 1.63–1.50 (m, 2H), 1.37–1.26 (m, 2H), 0.88 (t, J 7.3, 3H); m/z 327 (M⁺, 9%), 195 (100).

3-Butyl-4-(4-fluorobenzylamino)cyclobutene-1,2-dione 14i. Mp 104–105 °C (from benzene–light petroleum); ν_max/cm⁻¹ 1779, 1715; δ_H 7.32–7.25 (m, 2H), 7.12–7.00 (m, 2H), 4.83 (d, J 6.3, 1H), 4.60 (d, J 5.8, 1H), 2.53 (t, J 7.5, 2H), 1.64–1.53 (m, 2H), 1.38–1.29 (m, 2H), 0.90 (t, J 7.3, 3H); m/z 261 (M⁺, 3%), 109 (100).

3-Butyl-4-[3-(trifluoromethyl)benzylamino]cyclobutene-1,2-dione 14j. Mp 85–88 °C (from benzene–light petroleum); ν_max/cm⁻¹ 1782, 1723; δ_H 7.57–7.43 (m, 4H), 4.91 (s, 2H), 2.52 (t, J 7.5, 2H), 1.62–1.55 (m, 2H), 1.35–1.26 (m, 2H), 0.86 (t, J 7.3, 3H); m/z 311 (M⁺, 4%), 159 (100).

3-Butyl-4-piperidinocyclobutene-1,2-dione 14k. An oil; ν_max/cm⁻¹ 1778, 1731; δ_H 3.94 (s, 2H), 3.52 (s, 2H), 2.65 (t, J 7.6, 2H), 1.74 (s, 6H), 1.67–1.59 (m, 2H), 1.51–1.35 (m, 2H), 0.93 (t, J 7.3, 3H); m/z 221 (M⁺, 4%), 164 (100).

3-(4-Chlorobenzylamino)cyclobutene-1,2-dione 14l. Mp 118–119 °C (from benzene); ν_max/cm⁻¹ 1777, 1741; δ_H 7.93 (s, 1H), 7.39–7.36 (m, 2H), 7.27–7.24 (m, 2H), 4.50 (s, 2H); m/z 221 (M⁺, 3%), 68 (100).

3-(3-Fluorobenzylamino)cyclobutene-1,2-dione 14m. Mp 69–70 °C (from benzene); ν_max/cm⁻¹ 1779, 1751; δ_H 7.93 (s, 1H), 7.40–7.00 (m, 4H), 4.87 (s, 1H), 4.52 (s, 2H); m/z 205 (M⁺, 4%), 68 (100).

3-Pyrrolidinocyclobutene-1,2-dione 14n. Mp 104–105 °C (from benzene–light petroleum) (lit.,¹⁹ 99 °C). Although 14n had a quite different mp from that of the reference material, it had exactly the same spectral data: ν_max/cm⁻¹ 1775, 1745; δ_H 7.90 (s, 1H), 3.90–3.86 (m, 2H), 3.54–3.48 (m, 2H), 2.07–2.05 (m, 4H).

3-Morpholinocyclobutene-1,2-dione 14o. Mp 151–152 °C (from n-PrOH) (lit.,¹⁹ 141 °C). Although 14o had a quite different mp from that of the reference material, it had exactly the same spectral data: ν_max/cm⁻¹ 1779, 1739; δ_H 7.91 (s, 1H), 3.90–3.84 (m, 6H), 3.46–3.40 (m, 2H).

General procedure for preparation of 2-substituted 3-amino-4-hydroxycyclobutenones (15)

To a stirred solution of a 4-substituted 3-aminocyclobutene-1,2-dione 14 (15 mmol) in methanol (50 cm³) was added partly powdered NaBH₄ (1.0 g, 26 mmol) at 0 °C. After the reaction mixture had been kept for another 30 min (monitored by TLC) it was poured into ice–water (60 cm³). The resultant mixture was extracted with EtOAc (3 × 40 cm³) and the combined organic layers were washed successively with water (40 cm³) and brine (40 cm³) and dried over MgSO₄. The solvent was removed to give the crude product 15, which was purified by chromatography or recrystallization.

3-Amino-4-hydroxy-2-phenylcyclobutenone 15a. Mp 232–233 °C (decomp.) (from EtOH–light petroleum) (Found: C, 68.46; H, 5.13; N, 7.93. C₁₀H₉NO₂ requires C, 68.56; H, 5.18; N, 8.00%); ν_max/cm⁻¹ 3285, 3237, 3102, 1734, 1661, 1600; δ_H (CD₃OD) 7.62–7.61 (m, 2H), 7.34–7.31 (m, 2H), 7.19–7.16 (m, 1H), 4.96 (s, 1H); m/z 175 (M⁺, 100%), 147 (66), 130 (56), 118 (96), 102 (94), 89 (86), 77 (35), 63 (43), 51 (39), 44 (37).

3-Allylamino-4-hydroxy-2-phenylcyclobutenone 15b. Mp 187–189 °C (from EtOH–light petroleum); ν_max/cm⁻¹ 3302, 1725; δ_H (acetone-d₆) 7.69–7.67 (m, 2H), 7.32–7.29 (m, 2H), 7.16–7.13 (m, 1H), 6.10–6.06 (m, 1H), 5.32 (d, J 17.1, 1H), 5.17 (d, J 10.1, 1H), 5.11 (s, 1H), 4.29–4.24 (m, 1H), 4.19–4.16 (m, 1H); m/z 215 (M⁺, 61%), 174 (100).

4-Hydroxy-3-(3-methylbenzylamino)-2-phenylcyclobutenone 15c. Mp 202–203 °C (from EtOH–light petroleum); ν_max/cm⁻¹ 3330, 1722; δ_H (acetone-d₆) 7.69–7.68 (m, 2H), 7.26–7.14 (m, 7H), 5.20 (s, 1H), 4.76 (s, 2H), 2.32 (s, 3H); m/z 279 (M⁺, 21%), 105 (100).

4-Hydroxy-2-phenyl-3-[3-(trifluoromethyl)benzylamino]cyclobutenone 15d. Mp 200–201 °C (from EtOH–light petroleum); ν_max/cm⁻¹ 3325, 1727; δ_H (acetone-d₆) 7.85–7.81 (m, 2H), 7.69–7.62 (m, 4H), 7.31–7.28 (m, 2H), 7.16–7.13 (m, 1H), 5.28 (s, 1H), 4.94 (s, 2H); m/z 333 (M⁺, 53%), 159 (100).

4-Hydroxy-2-phenyl-3-[4-(trifluoromethoxy)benzylamino]cyclobutenone 15e. Mp 192–194 °C (from EtOH–light petroleum); ν_max/cm⁻¹ 3316, 1724; δ_H (CD₃OD) 7.63–7.62 (m, 2H), 7.55–7.53 (m, 2H), 7.35–7.27 (m, 4H), 7.20–7.17 (m, 1H), 5.15 (s, 1H), 4.75 (s, 2H); m/z 349 (M⁺, 19%), 175 (100).

4-Hydroxy-2-phenyl-3-pyrrolidinocyclobutenone 15f. Mp 199–201 °C (from EtOH–light petroleum); ν_max/cm⁻¹ 1725; δ_H (acetone-d₆) 7.49–7.47 (m, 2H), 7.32–7.27 (m, 2H), 7.18–7.15 (m, 1H), 5.05 (s, 1H), 4.06–4.02 (m, 1H), 3.71–3.68 (m, 1H), 3.63–3.58 (m, 1H), 3.40–3.36 (m, 1H), 2.05–1.99 (m, 4H); m/z 229 (M⁺, 43%), 70 (100).

4-Hydroxy-3-morpholino-2-phenylcyclobutenone 15g. Mp 195–197 °C (from EtOH–light petroleum); ν_max/cm⁻¹ 3216, 1729; δ_H (acetone-d₆) 7.40–7.19 (m, 5H), 5.11 (s, 1H), 3.80 (br s, 6H), 3.56 (br s, 2H); m/z 245 (M⁺, 48%), 87 (100).

2-Butyl-4-hydroxy-3-[3-(trifluoromethoxy)benzylamino]cyclobutenone 15h. Mp 92 °C (from benzene); ν_max/cm⁻¹ 3225, 1731; δ_H 7.39–7.12 (m, 4H), 6.15 (br s, 1H), 4.99 (s, 1H), 4.55 (d, J 5.5, 2H), 1.90 (t, J 7.8, 2H), 1.25–1.23 (m, 2H), 1.17–1.13 (m, 2H), 0.78 (t, J 7.2, 3H); m/z 329 (M⁺, 15%), 175 (100).

2-Butyl-4-hydroxy-3-(4-fluorobenzylamino)cyclobutenone 15i. Mp 113–114 °C (from benzene); ν_max/cm⁻¹ 3239, 1735; δ_H 7.29–7.25 (m, 2H), 7.04–6.94 (m, 2H), 6.16 (br s, 1H), 4.95 (s, 1H), 4.50 (d, J 5.6, 2H), 1.91 (t, J 7.5, 2H), 1.28–1.14 (m, 4H), 0.80 (t, J 7.3, 3H); m/z 263 (M⁺, 6%), 109 (100).

2-Butyl-4-hydroxy-3-[3-(trifluoromethyl)benzylamino]cyclobutenone 15j. Mp 133 °C (from benzene); ν_max/cm⁻¹ 3234, 1731; δ_H (CD₃OD) 7.69–7.54 (m, 4H), 5.00 (s, 1H), 4.67 (s, 2H), 2.04 (t, J 7.6, 2H), 1.49–1.44 (m, 2H), 1.36–1.29 (m, 2H), 0.90 (t, J 7.3, 3H); m/z 313 (M⁺, 12%), 159 (100).

2-Butyl-4-hydroxy-3-piperidinocyclobutenone 15k. Mp 84–86 °C (from benzene); ν_max/cm⁻¹ 3244, 1737; δ_H 5.05 (s, 1H), 3.65 (s, 2H), 3.48 (s, 2H), 2.11 (t, J 7.6, 2H), 1.70 (s, 6H), 1.50–1.40 (m, 2H), 1.37–1.26 (m, 2H), 0.89 (t, J 7.3, 3H); m/z 223 (M⁺, 0.6%), 57 (100).

3-(4-Chlorobenzylamino)-4-hydroxycyclobutenone 15l. Mp 148–150 °C (from MeOH–water); ν_max/cm⁻¹ 3230, 1728; δ_H (CDCl₃–CD₃OD) 7.35–7.33 (m, 2H), 7.30–7.25 (m, 2H), 4.93 (s, 1H), 4.43–4.35 (m, 1H), 4.27 (s, 2H); m/z 223 (M⁺, 16%), 125 (100).

3-(3-Fluorobenzylamino)-4-hydroxycyclobutenone 15m. Mp 108–111 °C (from benzene); ν_max/cm⁻¹ 3201, 1718; δ_H (CDCl₃–CD₃OD) 7.40–7.32 (m, 1H), 7.13–7.09 (m, 1H), 7.06–7.00 (m, 2H), 4.95 (s, 1H), 4.45–4.37 (m, 1H), 4.10 (s, 2H); m/z 207 (M⁺, 14%), 109 (100).

4-Hydroxy-3-pyrrolidinocyclobutenone 15n. Mp 133–136 °C (from benzene–light petroleum); ν_max/cm⁻¹ 3178, 1729; δ_H 6.04 (br s, 1H), 5.12 (s, 1H), 4.82 (s, 1H), 3.98–3.93 (m, 1H), 3.50–3.45 (m, 1H), 3.39–3.37 (m, 2H), 2.05–2.00 (m, 4H); m/z 153 (M⁺, 67%), 95 (100).

4-Hydroxy-3-morpholinocyclobutenone 15o. Mp 117–119 °C (from benzene–light petroleum); ν_max/cm⁻¹ 3232, 1725; δ_H 6.15 (br s, 1H), 5.17 (s, 1H), 4.93 (s, 1H), 3.86–3.81 (m, 5H), 3.64–3.60 (m, 1H), 3.48–3.41 (m, 2H); m/z 169 (M⁺, 68%), 55 (100).

General procedure for preparation of 3-substituted 4-aminofuran-2(5H )-ones 4

A mixture of a 2-substituted 3-amino-4-hydroxycyclobutenone 15 (15 mmol) and TFA (1.88 g, 16.5 mmol) in anhydrous p-xylene (35 cm³) was refluxed until compound 15 had disappeared completely on TLC. Then it was washed with water (35 cm³) and the organic layer was dried over MgSO₄. The solvent was removed to give the crude product 4, which was purified by chromatography or recrystallization.

4-Amino-3-phenylfuran-2(5H )-one 4a. Mp 198–200 °C (from EtOH–water) (Found: C, 68.66; H, 5.26; N, 8.09. C₁₀H₉NO₂ requires C, 68.56; H, 5.18; N, 8.00%); ν_max/cm⁻¹ 3463, 3299, 3177, 1696, 1641, 1609, 1592; δ_H (acetone-d₆) 7.55–7.52 (m, 2H), 7.38–7.35 (m, 2H), 7.22–7.20 (m, 1H), 6.11 (br s, 2H), 4.74 (s, 2H); m/z 175 (M⁺, 100%), 146 (56), 130 (17), 118 (51), 91 (24), 77 (8), 63 (9).

4-Allylamino-3-phenylfuran-2(5H )-one 4b. Mp 84–85 °C (from benzene–light petroleum); ν_max/cm⁻¹ 1708; δ_H 7.48–7.26 (m, 5H), 5.90–5.82 (m, 1H), 5.52 (br s, 1H), 5.29 (s, 1H), 5.25 (d, J 9.6, 1H), 4.77 (s, 2H), 3.78 (t, J 5.2, 2H); m/z 215 (M⁺, 100%).

4-(3-Methylbenzylamino)-3-phenylfuran-2(5H )-one 4c. Mp 98–99 °C (from EtOAc–light petroleum); ν_max/cm⁻¹ 1713; δ_H 7.48–7.07 (m, 9H), 5.71 (br s, 1H), 4.76 (s, 2H), 4.31 (d, J 6.1, 2H), 2.36 (s, 3H); m/z 279 (M⁺, 18%), 106 (100).

3-Phenyl-4-[3-(trifluoromethyl)benzylamino]furan-2(5H )-one 4d. Mp 125.5–127 °C (from EtOAc–light petroleum); ν_max/cm⁻¹ 1714; δ_H 7.61–7.24 (m, 9H), 5.80 (s, 1H), 4.74 (s, 2H), 4.40 (s, 2H); m/z 333 (M⁺, 40%), 159 (100).

3-Phenyl-4-[4-(trifluoromethoxy)benzylamino]furan-2(5H )-one 4e. Mp 126–127 °C (from benzene–light petroleum); ν_max/cm⁻¹ 1714; δ_H 7.46–7.21 (m, 9H), 5.87 (s, 1H), 4.72 (s, 2H), 4.34 (s, 2H); m/z 349 (M⁺, 72%), 175 (100).

3-Phenyl-4-pyrrolidinofuran-2(5H )-one 4f. Mp 129–131 °C (from EtOAc–light petroleum); ν_max/cm⁻¹ 1710; δ_H 7.34–7.24 (m, 5H), 4.74 (s, 2H), 3.17 (br s, 4H), 1.88 (br s, 4H); m/z 229 (M⁺, 67%), 70 (100).

4-Morpholino-3-phenylfuran-2(5H )-one 4g. Mp 189–190 °C (from benzene–light petroleum); ν_max/cm⁻¹ 1713; δ_H 7.38–7.27 (m, 5H), 4.78 (s, 2H), 3.66 (t, J 4.8, 4H), 3.18 (t, J 4.8, 4H); m/z 245 (M⁺, 56%), 40 (100).

3-Butyl-4-[3-(trifluoromethoxy)benzylamino]furan-2(5H )-one 4h. An oil; ν_max/cm⁻¹ 1725; δ_H 7.41–7.14 (m, 4H), 6.13 (br s, 1H), 4.53 (s, 2H), 4.38 (d, J 6.3, 2H), 2.15 (t, J 7.7, 2H), 1.45–1.38 (m, 2H), 1.29–1.20 (m, 2H), 0.87 (t, J 7.3, 3H); m/z 329 (M⁺, 5%), 175 (100).

3-Butyl-4-(4-fluorobenzylamino)furan-2(5H )-one 4i. An oil; ν_max/cm⁻¹ 1723; δ_H 7.29–7.23 (m, 2H), 7.06–6.96 (m, 2H), 5.97 (br s, 1H), 4.53 (s, 2H), 4.32 (d, J 6.1, 2H), 2.14 (t, J 7.7, 2H), 1.45–1.38 (m, 2H), 1.26 (m, 2H), 0.87 (t, J 7.3, 3H); m/z 263 (M⁺, 7%), 109 (100).

3-Butyl-4-[3-(trifluoromethyl)benzylamino]furan-2(5H )-one 4j. An oil; ν_max/cm⁻¹ 1724; δ_H 7.57–7.48 (m, 4H), 5.94 (s, 1H), 4.54 (s, 2H), 4.41 (s, 2H), 2.16 (t, J 7.7, 2H), 1.46–1.39 (m, 2H), 1.32–1.25 (m, 2H), 0.87 (t, J 7.2, 3H); m/z 313 (M⁺, 9%), 159 (100).

3-Butyl-4-piperidinofuran-2(5H )-one 4k. An oil; ν_max/cm⁻¹ 1730; δ_H 4.56 (s, 2H), 3.94 (s, 1H), 3.52 (s, 1H), 3.33 (s, 2H), 2.65 (t, J 7.6, 1H), 2.31 (t, J 7.3, 1H), 1.74 (s, 6H), 1.47–1.32 (m, 4H), 0.93 (t, J 7.3, 3H); m/z 223 (M⁺, 13%), 180 (100).

4-(4-Chlorobenzylamino)furan-2(5H )-one 4l. Mp 161–162 °C (from CHCl₃–light petroleum); ν_max/cm⁻¹ 1698; δ_H (CDCl₃–CD₃OD) 7.37–7.32 (m, 2H), 7.25–7.23 (m, 2H), 4.70 (s, 2H), 4.26 (s, 2H), 3.97 (s, 1H); m/z 223 (M⁺, 15%), 125 (100).

4-(3-Fluorobenzylamino)furan-2(5H )-one 4m. Mp 165–166.5 °C (from EtOAc–light petroleum); ν_max/cm⁻¹ 1701; δ_H (CDCl₃–CD₃OD) 7.47–7.01 (m, 4H), 4.62 (s, 1H), 4.42 (s, 2H), 4.31 (s, 2H); m/z 207 (M⁺, 20%), 109 (100).

4-Pyrrolidinofuran-2(5H )-one 4n. Mp 119–121 °C (from benzene) (lit.,^6b 120–121 °C).

4-Morpholinofuran-2(5H )-one 4o. Mp 107–109 °C (from benzene); ν_max/cm⁻¹ 1714; δ_H 4.74 (s, 2H), 4.72 (s, 1H), 3.79 (t, J 4.7, 4H), 3.23 (t, J 4.7, 4H); m/z 169 (M⁺, 100%).

Acknowledgements

We are grateful to the Education Ministry of China and the Education Department of Jiangsu Province for financial support.

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Footnote

† Elemental analyses results and detailed IR, MS spectra of new compounds 14a–o, 15a–o, 4a–m and 4o are available as supplementary data. For direct electronic access see http://www.rsc.org/suppdata/p1/b0/b004654j/

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