Synthesis of 3-diaminomethylene-2(3H)-furanones by reaction of 2-amino-4,5-dihydro-3-furancarboxamides with amines

Article abstract of DOI:10.1007/s007060200036

The reaction of 2-amino-4,5-dihydro-3-furancarboxamides with morpholine in the presence of acetic acid in pyridine or under the influence of ammonium acetate gave the corresponding 3-diaminomethylene-4,5-dihydro-2(3H)-furanones; 4,5-dihydro-2-morpholino-3-furancarboxamides were not isolated. One of the former reacted with benzylamine to give (E)- and (Z)-3-(amino-(benzylamino)-methylene)-4,5-dihydro-4-phenyl-2(3H)-furanones and 2-benzylamino-4,5-dihydro-4-phenyl-3-furancarboxamide.

Full text of DOI:10.1007/s007060200036

Monatshefte fuÈr Chemie 133, 643±651 ꢀ2002)
Synthesis of 3-Diaminomethylene-2ꢀ3H)-
furanones by Reaction of 2-Amino-4,5-
dihydro-3-furancarboxamides with Amines
Ã
and Yoshinobu Tagawa
Kenji Yamagata , Fumi Okabe, Motoyoshi Yamazaki,
Faculty of Pharmaceutical Sciences, Fukuoka University, 814-0180 Fukuoka, Japan
Summary. The reaction of 2-amino-4,5-dihydro-3-furancarboxamides with morpholine in the pres-
ence of acetic acid in pyridine or under the in¯uence of ammonium acetate gave the corresponding
3-diaminomethylene-4,5-dihydro-2ꢀ3H )-furanones; 4,5-dihydro-2-morpholino-3-furancarboxamides
were not isolated. One of the former reacted with benzylamine to give ꢀE )- and ꢀZ )-3-ꢀamino-
ꢀbenzylamino)-methylene)-4,5-dihydro-4-phenyl-2ꢀ3H )-furanones and 2-benzylamino-4,5-dihydro-
4-phenyl-3-furancarboxamide.
Keywords. Furancarboxamides; Furanones; Amines; Michael addition; Recyclization.
Introduction
Earlier, we have reported on the reaction of 2-amino-4,5-dihydro-3-furancarboni-
triles ꢀ1) with amines such as morpholine, pyrrolidine, and piperidine to give 4,5-
dihydro-2-morpholino-ꢀ2-pyrrolidino and 2-piperidino)-3-furancarbonitriles [1, 2].
This reaction probably occurs via Michael addition to the ꢀ,ꢁ-unsaturated nitrile
moiety of 1 with amine to form the intermediate adduct which undergoes elimina-
tion of ammonia to give the observed products. The reaction suggests the pos-
sibility that when 2-amino-4,5-dihydro-3-furancarboxamides 3 are treated with
amines, the Michael adduct initially formed may undergo elimination of ammonia
to furnish the corresponding 2-amino-4,5-dihydro-3-furancarboxamides. Thus, we
have investigated the reaction of 3 with amines.
Results and Discussion
The required tetrahydro-2-oxo-4-phenyl- and -5-phenyl-3-furancarbonitriles ꢀ2a
and 2b) [3, 4] were obtained by reaction of 2-amino-4,5-dihydro-4-phenyl- and -5-
phenyl-3-furancarbonitriles ꢀ1a and 1b) [5] with hydrochloric acid. The starting
materials 3 were prepared from 2 and concentrated ammonium hydroxide
according to Ref. [6] ꢀScheme 1).
Ã
Corresponding author. E-mail: yamagata@fukuoka-u.ac.jp

644
K. Yamagata et al.: Synthesis of Diaminomethylenefuranones
Scheme 1
When a mixture of 3a, morpholine, and acetic acid in pyridine was heated at
80ꢀC, 3-diaminomethylene-4,5-dihydro-4-phenyl-2ꢀ3H )-furanone ꢀ4a) was ob-
tained in 75% yield, and the expected 4,5-dihydro-2-morpholino-4-phenyl-3-
furancarboxamide could not be isolated ꢀScheme 2). The structure of 4a was
deduced from satisfactory elemental analyses and spectroscopic data. The mass
spectrum and the results of elemental analyses of 4a indicate that both 4a and 3a
have the same molecular composition C11H12N2O2. The IR spectrum of 4a displays
a band due to a lactone carbonyl group conjugated with an enamine group [7] at
1660 cmÀ1. Similarly, the reaction of 3b with morpholine afforded 3-diamino-
methylene-4,5-dihydro-5-phenyl-2ꢀ3H )-furanone ꢀ4b). In order to con®rm the struc-
ture of 4a, we carried out the reaction shown in Scheme 3. The reaction of 4a with
benzoyl chloride gave 3-ꢀamino-ꢀbenzamido)-methylene)-2ꢀ3H )-furanone 5.
Hydrolysis of 5 with hydrochloric acid provided N-benzoyl-3-furancarboxamide
6 which was converted into methyl 2-oxo-4-phenyl-3-furancarboxylate 7 [8] by
treatment with concentrated hydrochloric acid and methanol. The structure of 7 was
con®rmed by direct comparison with an authentic sample which was synthesized by
the following methods: methyl 2-amino-4-phenyl-3-furancarboxylate 8 was pre-
pared from 2a and a catalytic amount of sodium methoxide according to Ref. [9].
Hydrolysis of 8 with hydrochloric acid provided the desired compound 7.
The formation of 4 can be explained by the mechanism shown in Scheme 2.
The Michael addition of morpholine to 3 gives the adduct A which undergoes
recyclization to provide B. B in turn is transformed into the intermediates 11 by
elimination of ammonia. The conjugated addition of ammonia to 11 produces the
adduct C which undergoes elimination of morpholine to yield 4.
Subsequently, we examined the reaction of the intermediates 11 with ammonia
in the presence of acetic acid in order to prove whether or not compounds 4 are
formed. Compounds 11 were prepared by successive treatment of 2 with
trimethylsilylmorpholine and water. The IR spectra of 11 showed a primary
amino bands near 3300 cmÀ1, but lacked a characteristic nitrile band. The reaction
of 11 with ammonium acetate afforded 4 in good yields. In a similar manner, the
reaction of 3 with ammonium acetate resulted in the formation of the same
compounds 4. Probably, this recyclization takes place through the adduct D.
Finally, we have examined the reaction of 3a with benzylamine in order to
explore the scope of this type of reaction. The reaction of 3a with benzylamine

Scheme 2
Scheme 3

646
K. Yamagata et al.
Scheme 4
yielded a 1:1 mixture of 3-ꢀamino-ꢀbenzylamino)-methylene)-2ꢀ3H )-furanones ꢀ9
and 90, 57%) and 2-benzylamino-3-furancarboxamide 10 ꢀ11%), and 4a could not
be isolated. An analogous reaction has also been observed by Wamhoff et al. when
dealing with the reaction of ethyl 2-amino-4,5-dihydro-3-furancarboxylates and
methylamine [7]. The 1H NMR spectrum of 10 in deuteriochloroform indicates that
10 consists of an approximately 4:1 tautomeric mixture of the enamine ꢀE) and
imine ꢀF) forms ꢀScheme 4). Separation of 9 and 90 was attempted by column chro-
matography, but was not successful. When a mixture of 9=90 and ammonium
acetate in pyridine was heated, no reaction occurred, and 9=90 were recovered
unchanged. Compound 10 was easily hydrolyzed to 2-oxo-3-furancarboxamide 12
when heated with hydrochloric acid. Compound 12 was also obtained by treatment
of 3a with hydrochloric acid.
Experimental
1
All melting points are uncorrected. IR spectra were taken with a Jasco A-302 spectrometer. H and
1
13C NMR spectra were measured on Jeol JNM-A500 instrument ꢀ500.00 MHz for H, 125.65 MHz
for 13C) with TMS as internal standard; 13C signal assignments were con®rmed by the DEPT tech-
nique. Mass spectra were recorded with a Jeol JMS-HX110 equipment at 70 eV. Elemental analyses
were performed using a MT-6 elemental analyzer ꢀYanaco); the data were found to be within 0.3% of
the calculated values.
Tetrahydro-2-oxo-3-furancarbonitriles ꢀ2); general procedure
A mixture of 18.60 g ꢀ100 mmol) 1 and 150 cm3 5% HCl was stirred at room temperature for 1 h. The
precipitate was collected by ®ltration, washed with H2O, and dried to give 2.

Synthesis of Diaminomethylenefuranones
647
Tetrahydro-2-oxo-4-phenyl-3-furancarbonitrile ꢀ2a; C11H9NO2)
Yield: 16.82 g ꢀ90%); colorless needles; m.p.: 94±95ꢀC ꢀacetone=petroleum ether) ꢀRef. [3]: m.p.:
1
126±128ꢀC); IR ꢀKBr): ꢂ ˆ 2250 ꢀCꢁN), 1790 ꢀCˆO) cmÀ1; H NMR ꢀCDCl3, ꢃ): 3.80 ꢀd, J ˆ
11.6 Hz, 0.8H, 3-H), 4.01 ꢀddd, J ˆ 4.0=6.4=8.6 Hz, 0.2H, 4-H), 4.06 ꢀd, J ˆ 8.6 Hz, 0.2H, 3-H), 4.08
ꢀddd, J ˆ 8.0=10.4=11.6 Hz, 0.8H, 4-H), 4.34 ꢀdd, J ˆ 9.5=10.4 Hz, 0.8H, 5-H), 4.66 ꢀdd, J ˆ 4.0=
9.7 Hz, 0.2H, 5-H), 4.72 ꢀdd, J ˆ 6.4=9.7 Hz, 0.2H, 5-H), 4.75 ꢀdd, J ˆ 8.0=9.5 Hz, 0.8H, 5-H), 7.28±
‡
7.50 ꢀm, 5H, aryl) ppm; MS ꢀFAB): m=z ꢀ%) ˆ 188 ꢀ62) [M ‡ H].
Tetrahydro-2-oxo-5-phenyl-3-furancarbonitrile ꢀ2b; C11H9NO2)
Yield: 16.31 g ꢀ87%); colorless needles; m.p.: 134±136ꢀC ꢀacetone=petroleum ether) ꢀRef. [3]: m.p.:
113±115ꢀC); IR ꢀKBr): ꢂ ˆ 2270 ꢀCꢁN), 1770 ꢀCˆO) cmÀ1; 1H NMR ꢀDMSO-d6, ꢃ): 2.55±2.70 ꢀm,
1H, 4-H), 3.00±3.10 ꢀm, 1H, 4-H), 4.62 ꢀdd, J ˆ 7.9=9.8 Hz, 0.2H, 3-H), 4.71 ꢀdd, J ˆ 8.2=12.5 Hz,
0.8H, 3-H), 5.55 ꢀdd, J ˆ 5.5=10.7 Hz, 0.8H, 5-H), 5.83 ꢀdd, J ˆ 5.2=8.0 Hz, 0.2H, 5-H), 7.40±7.50
‡
ꢀm, 5H, aryl) ppm; MS ꢀFAB): m=z ꢀ%) ˆ 188 ꢀ37) [M ‡ 1].
2-Amino-4,5-dihydro-3-furancarboxamides ꢀ3); general procedure
A mixture of 3.74 g ꢀ20 mmol) 2 and 20 cm3 concentrated ammonium hydroxide was stirred at room
temperature for 1 h. The reaction mixture was cooled and diluted with H2O. The resulting precipitate
was collected by ®ltration, washed with H2O, and dried to give 3.
2-Amino-4,5-dihydro-4-phenyl-3-furancarboxamide ꢀ3a; C11H12N2O2)
Yield: 3.89 g ꢀ95%); colorless columns; m.p.: 177±178ꢀC ꢀacetone); IR ꢀKBr): ꢂ ˆ 3480, 3450,
1
3285, 3190 ꢀNH), 1655 ꢀCˆO) cmÀ1; H NMR ꢀDMSO-d6, ꢃ): 4.04 ꢀdd, J ˆ 4.5=8.0 Hz, 1H, 5-H),
4.22 ꢀdd, J ˆ 4.5=8.0 Hz, 1H, 4-H), 4.61 ꢀt, J ˆ 8.0 Hz, 1H, 5-H), 5.60 ꢀs, 2H, NH2), 6.96 ꢀs, 2H,
NH2), 7.19±7.24 ꢀm, 3H, aryl), 7.28±7.31 ꢀm, 2H, aryl) ppm; 13C NMR ꢀDMSO-d6, ꢃ): 45.0 ꢀC-4),
77.0 ꢀC-3), 79.0 ꢀC-5), 126.4, 127.0, 128.3, 145.2 ꢀC aryl), 166.5 ꢀC-2), 168.7 ꢀCˆO) ppm; MS ꢀEI):
‡
m=z ꢀ%) ˆ 204 ꢀ52) [M ].
2-Amino-4,5-dihydro-5-phenyl-3-furancarboxamide ꢀ3b; C11H12N2O2)
Yield: 3.29 g ꢀ81%); colorless prisms; m.p.: 134±135ꢀC ꢀacetone); IR ꢀKBr): ꢂ ˆ 3480, 3445 ꢀsh),
3280, 3160 ꢀNH), 1660 ꢀCˆO) cmÀ1; 1H NMR ꢀDMSO-d6, ꢃ): 2.63 ꢀdd, J ˆ 7.1=12.5 Hz, 1H, 4-H),
3.18 ꢀdd, J ˆ 9.8=12.5 Hz, 1H, 4-H), 5.56 ꢀdd, J ˆ 7.1=9.8 Hz, 1H, 5-H), 6.01 ꢀs, 2H, NH2), 6.82 ꢀs,
2H, NH2), 7.32±7.39 ꢀm, 5H, aryl) ppm; 13C NMR ꢀDMSO-d6, ꢃ): 36.2 ꢀC-4), 72.8 ꢀC-3), 80.9 ꢀC-5),
125.4, 127.8, 128.4, 141.9 ꢀC aryl), 164.8 ꢀC-2), 169.0 ꢀCˆO) ppm; MS ꢀFAB): m=z ꢀ%) ˆ 205 ꢀ100)
‡
[M ‡ H].
3-Diaminomethylene-4,5-dihydro-2(3H)-furanones ꢀ4); general procedure
Procedure A: To an ice-cooled and stirred solution of 4.08 g ꢀ20 mmol) 3 and 1.92 g ꢀ22 mmol)
morpholine in 15 cm3 pyridine, 1.32 g ꢀ22 mmol) acetic acid were added. The mixture was stirred at
80ꢀC for 3 h. The solvent was removed, and 50 cm3 H2O were added to the residue. The precipitate
was collected, washed with H2O, and dried. Yields: 4a ꢀ3.04 g, 75%) and 4b ꢀ1.22 g, 30%).
Procedure B: A mixture of 1.37 g ꢀ5 mmol) 11 and 0.42 g ꢀ5.5 mmol) ammonium acetate in 5 cm3
pyridine was stirred at 60ꢀC for 3 h. The solvent was removed, and 20 cm3 H2O were added to the
residue. The precipitate was collected, washed with H2O, and dried. Yields: 4a ꢀ0.92 g, 90%) and 4b
ꢀ0.60 g, 59%).

648
K. Yamagata et al.
Procedure C: A mixture of 2.04 g ꢀ10 mmol) 3 and 0.85 g ꢀ11 mmol) ammonium acetate in
10 cm3 pyridine was stirred at 80ꢀC for 3 h. The solvent was removed, and 50 cm3 H2O were added
to the residue. The precipitate was collected, washed with H2O, and dried. Yields: 4a ꢀ1.74 g, 85%)
and 4b ꢀ1.20 g, 59%).
3-Diaminomethylene-4,5-dihydro-4-phenyl-2(3H)-furanone ꢀ4a; C11H12N2O2)
Colorless columns; m.p.: 207±208ꢀC ꢀacetone); IR ꢀKBr): ꢂ ˆ 3490, 3430, 3225, 3155 ꢀNH), 1660
ꢀCˆO) cmÀ1; 1H NMR ꢀDMSO-d6, ꢃ): 3.79 ꢀdd, J ˆ 3.0=8.9 Hz, 1H, 4-H), 4.14 ꢀdd, J ˆ 2.8=8.9 Hz,
1H, 5-H), 4.38 ꢀt, J ˆ 8.9 Hz, 1H, 5-H), 5.57 ꢀs, 2H, NH2), 6.63 ꢀs, 2H, NH2), 7.18±7.30 ꢀm, 5H,
aryl) ppm; 13C NMR ꢀDMSO-d6, ꢃ): 42.6 ꢀC-4), 70.6 ꢀC-3), 71.8 ꢀC-5), 126.2, 126.7, 128.2, 145.7 ꢀC
‡
aryl), 158.3 ꢀˆCꢀNH2)2), 173.0 ꢀC-2) ppm; MS ꢀEI): m=z ꢀ%) ˆ 204 ꢀ88) [M ].
3-Diaminomethylene-4,5-dihydro-5-phenyl-2(3H)-furanone ꢀ4b; C11H12N2O2)
Colorless prisms; m.p.: 176±177ꢀC ꢀacetone); IR ꢀKBr): ꢂ ˆ 3510, 3450, 3350, 3200 ꢀNH), 1665
ꢀCˆO) cmÀ1; 1H NMR ꢀDMSO-d6, ꢃ): 2.50 ꢀdd, J ˆ 6.4=12.5 Hz, 1H, 4-H), 3.11 ꢀdd, J ˆ 9.5=12.5 Hz,
1H, 4-H), 5.30 ꢀdd, J ˆ 6.4=9.5 Hz, 1H, 5-H), 5.91 ꢀs, 2H, NH2), 6.50 ꢀs, 2H, NH2), 7.27±7.38 ꢀm,
5H, aryl) ppm; 13C NMR ꢀDMSO-d6, ꢃ): 34.2 ꢀC-4), 64.8 ꢀC-3), 75.0 ꢀC-5), 125.2, 127.3, 128.3,
‡
143.5 ꢀC aryl), 157.8 ꢀˆCꢀNH2)2), 172.3 ꢀC-2) ppm; MS ꢀFAB): m=z ꢀ%) ˆ 205 ꢀ100) [M ‡ H].
3-(Amino-(benzamido)-methylene)-4,5-dihydro-4-phenyl-2(3H)-furanone
ꢀ5; C18H16N2O3)
To an ice-cooled and stirred suspension of 2.04 g ꢀ10 mmol) 4a in 10 cm3 pyridine, 1.55 g ꢀ11 mmol)
benzoyl chloride were added. The mixture was heated at 50ꢀC for 1 h. The solvent was removed, and
50 cm3 H2O were added to the residue. The precipitate was collected, washed with H2O, and dried.
Yield: 2.62 g ꢀ85%); pale yellow needles; m.p.: 174±175ꢀC ꢀacetone); IR ꢀKBr): ꢂ ˆ 3480, 3340
1
ꢀNH), 1775, 1630 ꢀCˆO) cmÀ1; H NMR ꢀCDCl3, ꢃ): 4.10 ꢀdd, J ˆ 6.1=9.5 Hz, 1H, 4-H), 4.31 ꢀdd,
J ˆ 6.1=9.5 Hz, 1H, 5-H), 4.71 ꢀt, J ˆ 9.5 Hz, 1H, 5-H), 5.00±6.70 ꢀbr, 2H, NH2), 7.40±7.60 ꢀm, 8H,
aryl), 8.01±8.03 ꢀm, 2H, aryl), 12.46 ꢀs, 1H, NH) ppm; 13C NMR ꢀCDCl3, ꢃ): 43.7 ꢀC-4), 73.7 ꢀC-5),
78.3 ꢀC-3), 127.3, 127.7, 128.0, 129.0, 129.5, 132.5, 133.1, 141.2 ꢀC aryl), 153.0 ꢀˆCꢀNH2)NH),
‡
167.7, 174.9 ꢀCˆO) ppm; MS ꢀFAB): m=z ꢀ%) ˆ 309 ꢀ100) [M ‡ H].
N-Benzoyltetrahydro-2-oxo-4-phenyl-3-furancarboxamide ꢀ6; C18H15NO4)
To a stirred suspension of 1.54 g ꢀ5 mmol) 5 in 10 cm3 acetone, 10 cm3 10% HCl were added. The
mixture was stirred at room temperature for 15 h, cooled, and poured onto 30 cm3 H2O. The pre-
cipitate was collected, washed with H2O, and dried.
Yield: 1.44 g ꢀ93%); colorless needles; m.p.: 179±180ꢀC ꢀacetone=petroleum ether); IR ꢀKBr):
1
ꢂ ˆ 3360 ꢀNH), 1770, 1750, 1695 ꢀCˆO) cmÀ1; H NMR ꢀCDCl3, ꢃ): 4.36 ꢀt, J ˆ 9.8 Hz, 1H, 5-H),
4.41 ꢀdt, J ˆ 8.6=10.1 Hz, 1H, 4-H), 4.64 ꢀd, J ˆ 10.1 Hz, 1H, 3-H), 4.75 ꢀt, J ˆ 8.6 Hz, 1H, 5-H),
7.30±7.60 ꢀm, 8H, aryl), 7.85±7.90 ꢀm, 2H, aryl), 9.61 ꢀs, 1H, NH) ppm; 13C NMR ꢀCDCl3, ꢃ):
43.3 ꢀC-4), 54.1 ꢀC-3), 72.8 ꢀC-5) 127.4, 127.8, 128.1, 129.0, 129.2, 132.4, 133.5, 137.3 ꢀC aryl),
‡
164.8, 165.6, 172.7 ꢀCˆO) ppm; MS ꢀFAB): m=z ꢀ%) ˆ 310 ꢀ59) [M ‡ H].
Methyl tetrahydro-2-oxo-4-phenyl-3-furancarboxylate ꢀ7; C12H12O4)
Procedure A: A mixture of 1.55 g ꢀ5 mmol) 6 and 10 cm3 concentrated HCl in 10 cm3 MeOH was
re¯uxed for 6 h. The solvent was removed, and 30 cm3 cold H2O were added to the residue. The

Synthesis of Diaminomethylenefuranones
649
mixture was extracted with CH2Cl2. The extract was washed with H2O, dried over Na2SO4, and
concentrated. The residue was chromatographed on silica gel with CH2Cl2 as the eluent to give 7
ꢀ0.71 g, 65%).
Procedure B: A suspension of 1.10 g ꢀ5 mmol) 8 and 10 cm3 5% HCl was stirred at room
temperature for 0.5 h. The oily product was extracted with CH2Cl2. The extract was washed with
H2O, dried over Na2SO4, and concentrated. The residue was chromatographed on silica gel with
CH2Cl2 as the eluent to give 7 ꢀ0.97 g, 88%).
Colorless prisms; m.p.: 60±61ꢀC ꢀEt2O=petroleum ether); IR ꢀKBr): ꢂ ˆ 1788, 1732
1
ꢀCˆO) cmÀ1; H NMR ꢀCDCl3, ꢃ): 3.73 ꢀd, J ˆ 10.1 Hz, 1H, 3-H), 3.80 ꢀs, 3H, CH3), 4.19±4.25
ꢀm, 1H, 4-H), 4.28 ꢀt, J ˆ 8.8 Hz, 1H, 5-H), 4.72 ꢀdd, J ˆ 8.0=8.8 Hz, 1H, 5-H), 7.25±7.39 ꢀm, 5H,
‡
aryl) ppm; MS ꢀFAB): m=z ꢀ%) ˆ 221 ꢀ100) [M ‡ H].
Methyl 2-amino-4,5-dihydro-4-phenyl-3-furancarboxylate ꢀ8; C12H13NO3)
A mixture of 5.61 g ꢀ30 mmol) 2a and 0.16 g ꢀ3 mmol) MeONa in 20 cm3 MeOH was heated at 60ꢀC
for 7 h. The mixture was cooled, and 0.16 g ꢀ3 mmol) acetic acid were added. The solvent was re-
moved, and 50 cm3 H2O were added to the residue. The mixture was extracted with CH2Cl2. The
extract was washed with H2O, dried over Na2SO4, and concentrated. The residue was chro-
matographed on alumina with CH2Cl2 as the eluent to give 8.
Yield: 5.48 g ꢀ83%); colorless prisms; m.p.: 150±151ꢀC ꢀCH2Cl2=petroleum ether); IR ꢀKBr):
ꢂ ˆ 3470, 3250 ꢀNH), 1660 ꢀCˆO) cmÀ1; 1H NMR ꢀCDCl3, ꢃ): 3.50 ꢀs, 3H, CH3), 4.54 ꢀdd, J ˆ 3.9=
8.1 Hz, 1H, 4-H), 4.29 ꢀdd, J ˆ 3.9=8.1 Hz, 1H, 5-H), 4.70 ꢀt, J ˆ 8.1 Hz, 1H, 5-H), 5.75 ꢀs, 2H, NH2),
‡
7.15±7.30 ꢀm, 5H, aryl) ppm; MS ꢀFAB): m=z ꢀ%) ˆ 220 ꢀ100) [M ‡ H].
Reaction of 3a with benzylamine
To an ice-cooled and stirred solution of 2.04 g ꢀ10 mmol) 3a and 1.18 g ꢀ11 mmol) benzylamine in
10 cm3 pyridine, 0.66 g ꢀ11 mmol) acetic acid were added. The mixture was stirred at 60ꢀC for 3 h.
The solvent was removed, and 30 cm3 H2O were added to the residue. The mixture was extracted
with CH2Cl2. The extract was washed with H2O, dried over Na2SO4, and concentrated. The residue
was chromatographed on alumina with CH2Cl2:acetone ˆ 4:1 as the eluent to give a mixture of 9, 90,
and 10. Fractional recrystallization from acetone=petroleum ether gave colorless needles ꢀ9 and 90,
1.67 g, 57%) and colorless columns ꢀ10, 0.33 g, 11%).
(E)- and (Z)-3-(Amino-(benzylamino)-methylene)-4,5-dihydro-
4-phenyl-2(3H)-furanones ꢀ9 and 90; C18H18N2O2)
M.p.: 135±137ꢀC; IR ꢀKBr): ꢂ ˆ 3460, 3430, 3370, 3260 ꢀNH), 1670 ꢀCˆO) cmÀ1
;
1H NMR
ꢀCDCl3, ꢃ): 3.91 ꢀbr s, 1H, NH2), 3.97 ꢀdd, J ˆ 5.7=8.3 Hz, 0.5H, 4-H), 3.99 ꢀdd, J ˆ 5.2=8.3 Hz,
0.5H, 4-H), 4.27 ꢀdq, J ˆ 5.1=13.1 Hz, 1H, benzylic H), 4.21 ꢀdd, J ˆ 5.7=8.3 Hz, 0.5H, 5-H), 4.22
ꢀdd, J ˆ 5.2=8.3 Hz, 0.5H, 5-H), 4.26 ꢀbr t, J ˆ 5.1 Hz, 0.5H, NH), 4.36 ꢀdq, J ˆ 6.2=15.3 Hz, 1H,
benzylic H), 4.59 ꢀt, J ˆ 8.3 Hz, 1H, 5-H), 6.14 ꢀbr s, 1H, NH2), 7.40±7.70 ꢀm, 10H, aryl), 8.71 ꢀbr t,
‡
J ˆ 6.2 Hz, 0.5H, NH) ppm; MS ꢀFAB): m=z ꢀ%) ˆ 295 ꢀ100) [M ‡ H].
2-Benzylamino-4,5-dihydro-4-phenyl-3-furancarboxamide ꢀ10; C18H18N2O2)
1
M.p.: 110±112ꢀC; IR ꢀKBr): ꢂ ˆ 3490, 3270, 3120 ꢀNH), 1660 ꢀCˆO) cmÀ1; H NMR ꢀCDCl3, ꢃ):
3.66 ꢀd, J ˆ 7.3 Hz, 0.2H, 3-H), 4.13±4.18 ꢀm, 0.2H, 4-H), 4.17 ꢀdd, J ˆ 6.1=8.9 Hz, 0.8H, 4-H), 4.26
ꢀdd, J ˆ 7.2=8.9 Hz, 0.2H, 5-H), 4.31 ꢀdd, J ˆ 6.1=9.5 Hz, 0.8H, 5-H), 4.36 ꢀbr s, 1.6H, NH2), 4.49 ꢀd,
J ˆ 6.7 Hz, 1.6H, benzylic H), 4.55 ꢀq, J ˆ 13.7 Hz, 0.4H, benzylic H), 4.64 ꢀdd, J ˆ 8.0=8.9 Hz,

650
K. Yamagata et al.
0.2H, 5-H), 4.75 ꢀdd, J ˆ 8.9=9.5 Hz, 0.8H, 5-H), 5.44 ꢀbr s, 0.2H, NH2), 7.26±7.36 ꢀm, 10H, aryl),
‡
7.77 ꢀbr s, 0.2H, NH2), 8.15 ꢀbr s, 0.8H, NH) ppm; MS ꢀFAB): m=z ꢀ%) ˆ 295 ꢀ100) [M ‡ H].
Tetrahydro-2-oxo-4-phenyl-3-furancarboxamide ꢀ12; C11H11NO3)
Procedure A: A mixture of 0.59 g ꢀ2 mmol) 10 and 5 cm3 5% HCl was stirred at 40ꢀC for 2 h. The
product was extracted with CH2Cl2. The extract was washed with H2O, dried over Na2SO4, and
concentrated. The residue was chromatographed on silica gel with CH2Cl2:acetone ˆ 4:1 as the
eluent to give 12 ꢀ0.23 g, 56%).
Procedure B: A mixture of 1.02 g ꢀ5 mmol) 3a and 5 cm3 5% HCl was stirred at room
temperature for 0.5 h. The precipitate was collected, washed with H2O, and dried to give 12 ꢀ0.74 g,
72%).
Colorless columns; m.p.: 119±121ꢀC ꢀacetone=petroleum ether); IR ꢀKBr): ꢂ ˆ 3470, 3360 ꢀNH),
1
1755, 1700 ꢀCˆO) cmÀ1; H NMR ꢀCDCl3, ꢃ): 3.58 ꢀd, J ˆ 8.9 Hz, 1H, 3-H), 4.25±4.35 ꢀm, 2H,
4-H, 5-H), 4.72 ꢀt, J ˆ 8.0 Hz, 1H, 5-H), 5.73 ꢀbr s, 1H, NH), 6.69 ꢀbr s, 1H, NH), 7.25±7.30 ꢀm, 3H,
‡
aryl), 7.35±7.40 ꢀm, 2H, aryl) ppm; MS ꢀFAB): m=z ꢀ%) ˆ 206 ꢀ100) [M ‡ H].
3-(Amino-(morpholino)-methylene)-4,5-dihydro-2(3H)-furanones ꢀ11);
general procedure
A solution of 3.74 g ꢀ20 mmol) 2 and 3.50 g ꢀ22 mmol) trimethylsilylmorpholine in 20 cm3 CH2Cl2
was stirred at room temperature for 48 h. The mixture was washed with H2O, dried over Na2SO4, and
concentrated. The residue was chromatographed on alumina with CH2Cl2 as the eluent to give 11.
3-(Amino-(morpholino)-methylene)-4,5-dihydro-4-phenyl-2(3H)-furanone
ꢀ11a; C15H18N2O3)
Yield: 1.49 g ꢀ27%); colorless columns; m.p.: 134±135ꢀC ꢀacetone=petroleum ether); IR ꢀKBr):
ꢂ ˆ 3300, 3220 ꢀNH), 1630 ꢀCˆO) cmÀ1
;
1H NMR ꢀCDCl3, ꢃ): 3.00±3.40 ꢀm, 8H, 4CH2
morpholine), 3.83 ꢀdd, J ˆ 6.7=8.3 Hz, 1H, 5-H), 4.36 ꢀdd, J ˆ 6.7=8.9 Hz, 1H, 4-H), 4.54 ꢀdd,
J ˆ 8.3=8.9 Hz, 1H, 5-H), 6.32 ꢀs, 2H, NH2), 7.16±7.33 ꢀm, 5H, aryl) ppm; 13C NMR ꢀCDCl3, ꢃ):
46.3 ꢀC-4, NCH2), 66.0 ꢀOCH2), 72.6 ꢀC-5), 75.8 ꢀC-3), 127.1, 127.3, 128.7, 142.9 ꢀC aryl), 161.2
‡
ꢀˆC±NH2), 176.5 ꢀC-2) ppm; MS ꢀFAB): m=z ꢀ%) ˆ 275 ꢀ100) [M ‡ H].
3-(Amino-(morpholino)-methylene)-4,5-dihydro-5-phenyl-2(3H)-furanone
ꢀ11b; C15H18N2O3)
Yield: 3.81 g ꢀ70%); colorless columns; m.p.: 144±146ꢀC ꢀacetone=petroleum ether); IR ꢀKBr):
ꢂ ˆ 3390, 3240 ꢀNH), 1640 ꢀCˆO) cmÀ1; 1H NMR ꢀCDCl3, ꢃ): 2.77 ꢀdd, J ˆ 7.0=12.9 Hz, 1H, 4-H),
3.24 ꢀdd, J ˆ 8.6=12.9 Hz, 1H, 4-H), 3.23±3.30 ꢀm, 4H, 2CH2 morpholine), 3.67±3.71 ꢀm, 4H, 2CH2
morpholine), 5.36 ꢀdd, J ˆ 7.0=8.6 Hz, 1H, 5-H), 6.14 ꢀs, 2H, NH2), 7.30±7.40 ꢀm, 5H, aryl) ppm; 13
C
NMR ꢀCDCl3, ꢃ): 37.0 ꢀC-4), 46.8 ꢀNCH2), 66.6 ꢀOCH2), 72.8 ꢀC-3), 77.0 ꢀC-5), 125.4, 127.8, 128.5,
‡
142.1 ꢀC aryl), 160.5 ꢀˆC±NH2), 175.6 ꢀC-2) ppm; MS ꢀFAB): m=z ꢀ%) ˆ 275 ꢀ100) [M ‡ H].
References
[1] Yamagata K, Takaki M, Yamazaki M ꢀ1992) Liebigs Ann Chem 1109
[2] Yamagata K, Akizuki K, Yamazaki M ꢀ1998) J Prakt Chem 340: 51
[3] Hashem AI, Shaban ME ꢀ1981) Indian J Chem 20B: 807
[4] Allegretti M, D'Annibale A, Trogolo C ꢀ1993) Tetrahedron 49: 10705

Synthesis of Diaminomethylenefuranones
651
[5] Matsuda T, Yamagata K, Tomioka Y, Yamazaki M ꢀ1985) Chem Pharm Bull 33: 937
[6] a) Campaigne E, Ho J, Bradford M ꢀ1970) J Heterocycl Chem 7: 257; b) Campaigne E, Ellis RL,
Bradford M ꢀ1969) J Heterocycl Chem 6: 159
[7] Huang Z, Wamhoff H ꢀ1984) Chem Ber 117: 622
[8] Hussain SMMT, Ollis WD, Smith C, Stoddart JF ꢀ1975) J Chem Soc Perkin Trans 1, 1480
[9] Campaigne E, Ellis RL, Bradford M, Ho J ꢀ1969) J Med Chem 12: 339
Received October 4, 2001. Accepted October 10, 2001