JOURNAL OF CHEMICAL RESEARCH 2008 171
the crude product. Recrystallisation from 50% ethanol yielded a
pure product, m.p. 158–159°C (lit.5 150–151°C). Anal.: calcd for
C9H7NO4: C, 55.96; H, 3.65; N, 7.25. Found: C, 56.06; H, 3.64; N,
7.11. MS: calcd. 193.0373, found 193.0372. [When the reaction was
carried out in O-18 labelled water and analysed by ( + )SIMS, the
product showed an MH+ ion at m/e 198 indicating the presence of
two O-18 atoms.] UV: λmax, ε: 276 nm, 1400 M-1cm-1 (95% ethanol).
1H NMR, 500 MHz, DMSO-d6: δ 7.53 (1H, dd, Jm = 0.8 Hz, Jo = 7.1
were dissolved in 10 ml DMSO. Then 1.4 g (0.01 mol) potassium
carbonate was added and the mixture stirred at RT overnight.
The orange reaction mixture was diluted with 500 ml ethyl acetate
and kept at 5°C overnight. The ethyl acetate was decanted from the
precipitated oil, the oil washed with fresh ethyl acetate several times,
and finally with ether. The dried residue was then taken up in 30 ml
cold water. Conc. HCl, 1.5 ml, was slowly added with stirring.
This gives an opalescent supernatant layer and a brown sticky
precipitate. The opalescent material was decanted from the
brown material and allowed to crystallise for a few hours at 5°C.
The crude product was filtered and washed with cold water. The
yield was about 1.5 g (60%). The product, N-(1-hydroxy-2-oxo-2-
phenylethyl)maleamic acid (NHOPM), was purified by crystallisation
from chloroform. M.p. 110–111°C. Anal.: calc. for C12H11NO5.1/
4H2O; C, 56.80; H, 4.57; N, 5.52. Found: C, 56.70; H, 4.21; N, 5.49.
MS: calcd for M + Na, 272.056, found, 272.052. 1H NMR, 600 MHz,
DMSO-d6: δ 6.32 (1H, d, J = 12.2 Hz), 6.36(1H, d, J = 12.2 Hz),
6.41 (1H, dd, J = 7.3 Hz), 6.89 (1H, d, J = 7.1 Hz), 7.55 (2H, dd,
J = 7.7 Hz), 7.67 (1H, dd, J = 7.3 Hz), 8.00 (2H, d, J = 7.3 Hz),
9.47(1H, d, J = 8.3 Hz), 13.5(1H, br). IR: Nujol: 3388, 3323, 3238,
1699, 1627, 1532, 1282, 1259, 1219, 1104, 1095, 1070, 1059, 992,
977, 855, 836, 762, 707 cm-1.
Oxidation of NHOPM with periodate: NHOPM (125 mg,
0.5 mmol) was added to a solution of 150 mg NaIO4(0.7 mmol) in
5 ml water at 5°C. Sodium bicarbonate (42 mg, 0.5 mmol) was added
with stirring. The pH should be about 4. A precipitate of benzoic
acid forms gradually. After 1 h, 2 drops of 1M sulfuric acid were
added and the benzoic acid filtered on a Büchner. The cold solution
was then extracted three times with ether to remove any remaining
benzoic acid. The pH of the solution was readjusted to pH 4 with solid
sodium bicarbonate and then taken to dryness on a rotary evaporator
at 30°. The sodium salt of N-formylmaleamic acid was extracted
from the residue of sodium iodate by trituration with methanol.
Removal of the methanol by rotary evaporation yielded the sodium
salt of N-formylmaleamic acid contaminated with a little sodium
iodate.28 The material was purified by extraction with ethanol
(in which sodium iodate is less soluble) followed by drying in vacuo
(oil pump). The yield was 60–70%. Anal.: calcd. for C5H4NO4Na.0.5
H2O with 1.35% NaIO3: C, 33.95; H, 2.83; N, 7.92. Found: C, 34.02;
H, 3.19; N, 7.45. This quantity of sodium iodate was confirmed
by iodometric titration. (Note that iodate and periodate may be
distinguished by the pH-dependencies of their reactions with
iodide.29)
Hz), 7.61 (1H, ddd, Jm = 1.4 Hz, Jo = 7.6 Hz), 7.67 (1H, ddd, Jm
=
1.4 Hz, Jo = 7.5 Hz), 7.91 (1H, dd, Jm = 1.0 Hz, Jo = 7.0 Hz), 9.04
(1H, br), 11.53 (1H, d, 9.2 Hz), 13.3 (1H, br). 13C NMR,125.7 MHz,
DMSO-d6:δ 127.6, 129.6, 129.7, 130.4, 132.1, 136.2, 163.5, 166.9,
170.6.. IR: Nujol and Fluorolube mulls: 3400, 3288, 3206, 2920,
2675, 2553, 1725, 1680, 1487, 1246, 1193, 713 cm-1. The ammonium
salt was crystallised from propan-1-ol, m.p. 142–143°C. Anal: calcd.
for C9H10N2O4: C, 51.43; H, 4.79; N, 13.33. Found: C, 5l.63; H, 4.93;
N, 13.16. 13C NMR, δ 125.7 MHz, DMSO-d6: 128.1, 129.4, 130.7,
132.6, 133.3, 138.6, 166.8, 174.0, 175.7.
N-Formylbenzamide (with Dong): Formamidine acetate (2.1 g,
0.02 mol) was dissolved in 4 ml water. Acetone (26 ml) was
added and then sodium bicarbonate (1.7 g, 0.02 mol). The two-
phase mixture was stirred on ice while 2.3 ml (0.02 mol) benzoyl
chloride was added dropwise during 10 min. An initial flocculent
precipitate was gradually replaced by a granular one. This precipitate
was removed by filtration after one hour. Most of the acetone
was removed by rotary evaporation. The residue was partitioned
between methylene chloride and dilute sodium bicarbonate to
remove benzoate. The methylene chloride layer was washed with
water, dried with magnesium sulfate, and evaporated to yield 0.6 g
(20%) of crude material. Crystallisation from 100 ml hexane gave
0.3 g of fine needles, m.p. 100–110°C. A second crystallisation from
60 ml hexane gave pure material which sintered at 100°C and melted
at 105–108°C (lit.4,6,17 106–108°C, 112–113°C, 111–113°C). MS:
calcd. 149.0475, found 149.0477. 1H NMR, 500 MHz, CDCl3: δ 7.55
(2H, ddd, J = 8.6, 1.3 Hz), 7.66(1H, ddd, J = 8.7, 1.3 Hz), 7.94 (2H,
dd, J = 7, 1.3 Hz), 9.4(2H, br). IR: Nujol mull: 3272, 1725, 1686,
1672, 1251, 1157, 1061, 885, 701 cm-1.
4-Chloro-N-formylbenzamide (with Zechinati): Formamidine
acetate, 2.1 g (0.02 mol) and sodium bicarbonate, 2 g(0.024 mol)
were added to a solution of 4-chlorobenzoyl chloride (3.5 g, 0.02 mol)
in 30 ml methylene chloride. The mixture was stirred for 20 h at
room temperature with the exclusion of moisture. The solvent was
removed by rotary evaporation. Acetone (30 ml) was added together
with additional formamidine acetate (1.1 g) and sodium bicarbonate
(1 g). After stirring for 1 h, the acetone was removed and the residue
dissolved in ethyl acetate. The solution was washed with dilute
sodium bicarbonate, water, and dried with magnesium sulfate.
Rotary evaporation yielded 2.0–2.35 g (54–64%) of crude product.
Trituration with ethanol removed a 4-chlorobenzamide impurity.
Recrystallisation from toluene gave a pure product, m.p. 191–
194°C (lit.27 95–96°C, which may be a misprint as the nmr data are
misassigned).Anal. Calcd. for C8H6O2NCl: C, 52.33; H, 3.09; N, 7.63.
Found: C, 52.40; H, 3.09; N, 7.51. 1H NMR, 600 MHz, CDCl3: δ 7.53
(2H, d, J = 8.4 Hz), 7.90 (2H, d, J = 8.4 Hz), 9.37 (1H, d, J = 9.6 Hz),
9.55 (1H, s). IR, Nujol: 3263, 1738, 1693, 1593, 1255, 1222, 1091,
1066, 849, 748 cm-1.
MS.: Calcd.for M + H 166.012, found 166.006. UV(water): (λmax
,
nm; ε, M-1cm-1;)227, 10,500. For comparative purposes(sodium salts
in water): N-formylfumaramic acid:225, 20,600; maleamic acid: 201,
1
10,000; fumaramic acid: 210, 18,950. H NMR, 600 MHz, DMSO-
d6: δ 5.69 (1H, d, J = 13.2 Hz), 6.34 (1H, dd, J = 13.3, 1.1 Hz) (the
four bond coupling establishes this resonance as H-3), 9.05 (1H, d,
J = 8.9 Hz), 16.3(1H, br.). D2O: δ 5.98 (1H, d, J = 12.2 Hz), 6.58
(1H, d, J = 12.2 Hz), 8.98 (1H, s). 13C NMR, 150.9 MHz, DMSO-
d6(doublets using gated decoupling):δ 126.9 (J = 161 Hz), 144.2
(J=156Hz),164.2(J=202Hz),167.2(J=14.4Hz),167.6(J=11.6Hz).
IR, Nujol: 1719, 1680, 1588, 1548, 1531, 1353, 1232, 862 cm-1.
We are grateful to E. Cupler, S. El-Khoury, A. Yahner,
S. Buchholz, B. Zechinati, andY. Dong for many contributions.
We also thank Dr. C. E. Cottrell for suggesting the gated
decoupling experiment.
N-Formylmaleamic acid; (a) By reaction of maleic anhydride and
formamidine acetate:21
Formamidine acetate (1.0 g, 0.01 mol) was added to 50 ml of acetone
containing 4% water. Maleic anhydride (0.01 mol) was added
with stirring to yield a clear solution. After 10 min, the acetone
and water were removed by rotary evaporation and then the acetic
acid was removed with an oil pump. This yields about 0.6 g of a
white solid which, by NMR analysis, contains 30–40% of N-
formylmaleamic acid together with maleic and maleamic acids in
smaller amounts. The only method of purification found was ion-
exchange column chromatography. An AG-l-X4 column in the
chloride form using a KCl eluant resolved the three components at
pH 4. Maleamic acid elutes first followed by N-formylmaleamic acid
and finally maleic acid. Water was removed from the column eluates
by rotary evaporation. N-formylmaleamic acid was then extracted
by ethanol. Alternatively, if LiCl was used as the eluant, Sephadex
could be used to separate the salt from the product. Spectroscopic data
follow the description of the alternate synthesis of N-formylmaleamic
acid below.
Received 16 February 2008; accepted 17 March 2008
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(b) By reaction of maleamic acid and phenylglyoxal: Maleamic
acid (1.15 g, 0.01 mol) and phenylglyoxal (1.52 g, 0.01 mol)
PAPER: 08/5098