JOURNAL OF CHEMICAL RESEARCH 2009 421
CH30~CN
M n.
CH30
Br
7
8
~h
Fig.2
Reagents and conditions: (a) Br2/CH3COOH, 50°C, 6 h; (b) Cyanoacetic acid/Ammonium
h; (c) NaBHJNaHC03, r.t., 12 h; (d) dimethylacetamide, 170°C, 2 h; (e) dimethylacetamide, 170°C, 2 h; (f) CH3CN/NaOH, reflux, 8 h;
reflux, 2 h; (h) NaNH2/liquid NH3, -45°C, 2 h.
acetate/Xylene/Pyridine,
reflux, 12
(g) NaBHJPyridine/CH30H,
IR spectra were determined as KBr pellets on a Shimadzu model 470
spectrometer. 'H NMR spectra were recorded using a Bruker AV 400
of CO2 ceased after 30 min. The reaction mixture was poured
into water (500 mL) and set aside overnight. The crystals which
separated were collected, washed with water, and recrystallised
from ethanol to obtain colourless crystals of 7. Yield 91.8 g (71%).
m.p. 147-148°C.
MHz spectrometer in CDCI and DMSO-d6 with tetramethylsilane as
3
the internal standard. The mass spectra were recorded on Shimadzu
QP 2010 system. Elemental analyses were performed on a Vario EL
III elemental analyser. All the products except for compound 7 were
known compounds and the data (m.p., 'H NMR) accord with that
reported in the literature.
Route
B
procedure: 2-Bromo-4,5-dimethoxybenzaldehyde
4
(200.0 g, 0.82 mol) was dissolved in acetonitrile (800 mL) and heated
to reflux. Then sodium hydroxide (39.3 g, 0.98 mol) was added in
batches, and the reaction mixture was refluxed for 8 h. After the
solvent was removed in vacuo, the residue was diluted with water
(800 mL), and the product was extracted with ethyl acetate
(600 mL x 3). The organic layer was washed with water (300 mL
2-bromo-4,5-dimethoxybenzaldehyde
(4): Bromine (30.8 mL,
0.6 mol) was added dropwise with stirring at room temperature over
30 min to a solution of 3,4-dimethoxybenzaldehyde (3, 100.0 g,
0.60 mol) in acetic acid (400 mL). The reaction mixture was stirred
at 50°C for 6 h. After cooling to room temperature, water (500 mL)
was added, the precipitate was filtered, and the excess bromine was
washed away with water several times. The product was dried under
vacuum to give the crude product 4 as white solid. This product was
used directly in the next step. Crude yield 126.6 g (87%); m.p. 151-
152°C (lit.8: m.p. 148-150°C).
x
2), and dried over MgS04• The solvent was removed under
vacuum, followed by recrystallisation of the residue from EtOH to
give compound 7. Yield 156.0 g (71%). m.p. 147-148°C. IR (cm-'):
2230 (CN), 1612 (C=C). 'H NMR: 1) 3.84 (s, 6H), 5.68 (d, 1H,
J= 16.4 Hz), 6.88 (s, 1H), 7.00 (s, 1H), 7.66 (d, 1H, J= 16.4 Hz).
MS (EI, m/z): 267/269 (M+, 100/98),252,224,
145, 130, 117, 102,
3-(2-Bromo-4,5-dimethoxyphenyl}-2-cyanoacrylic
Ammonium acetate (41.6g, 0.54 mol) was added in portions to
solution of 2-bromo-4,5-dimethoxybenzaldehyde (122.0 g,
acid
(5):
75. Ana!. Calcd. for CllHIOBrN02: C, 49.28; H, 3.76; N, 5.22. Found:
C, 49.02; H, 3.98; N, 4.99%.
a
4
0.50 mol) and cyanoacetic acid (46.8 g, 0.55 mol) in xylene (500 mL)
and pyridine (100 mL) at room temperature. This reaction mixture was
then heated under reflux for 12 h using a Dean and Stark apparatus.
After the calculated amount of water had separated, the mixture
was cooled and acidified with 10% HC!. Yellow crystals separated
out slowly, and were collected, Recrystallisation from EtOH to give
the title compound 5 as pale yellow needles. Yield 89.0 g (64%);
m.p. 266-268°C (lit.6: m.p. 272-272.5°C).
2-Bromo-4, 5-dimethoxyhydrocinnamonitrile (8)
Route A procedure:
A suspension of 3-(2-bromo-4,5-dimethoxy-
phenyl)-2-cyanopropionic acid 6 (120.0 g, 0.38 mol) in dimethyl-
acetamide (500 mL) was heated at 170°C for 2 h. The evolution ofthe
calculated amount of CO2 ceased after 30 min. The reaction mixture
was poured into water (500 mL), and set aside overnight. The crystals
which separated were collected, washed with water, and recrystallised
from ethanol to obtain a white powder 8. Yield 83.9 g (81.4%).
m.p. 76-78°C (lit.6: m.p. 79-80°C). Purity by HPLC: 96.5%.
3-(2-Bromo-4,5-dimethoxyphenyl}-2-cyanopropionic
acid (6):
3-(2-Bromo-4,5-dimethoxyphenyl)-2-cyanoacrylic
acid 7 (120.0 g,
Route
(80.0 g, 0.30 mol) was dissolved in a mixture of methanol (320 mL)
and pyridine(80 mL). NaBH (22.8 g, 0.60 mol) was added in
B
procedure: 2-Bromo-4,5-dimethoxycinnamonitrile
7
0.38 mol) was added to a saturated NaHC0
3
solution (800 mL) at
room temperature. Then sodium borohydride (28.9 g, 0.76 mol) was
added in small portions, producing effervescence and the stirring was
continued for 4 h. Acidification with 10% HCI solution produced
white crystals. The precipitate was collected to give the title product
6 as colourless crystals. Yield 86.4 g (72%); m.p. 165-167°C (lit.6:
m.p. 166-168°C). IR (cm-'): 2228 (CN). 'H NMR: 1) 3.16-3.28
(m,2H), 3.74 (s, 3H), 3.77 (s, 3H), 4.28 (t, 1H, J = 8.4 Hz), 7.08
(s, 1H), 7.14 (s, 1H), 13.84 (brs, 1H).
4
small portions. The reaction mixture was refluxed for 2 h. When the
reaction was complete it was cooled to room temperature, and 10%
HCI solution was added to acidifY the reaction mixture. The product
was extracted with ethyl acetate (150 mL x 3), and the organic layer
separated and washed with water (120 ml x 2), and dried over MgS04•
The solvent was evaporated under reduced pressure, and the residue
was recrystallised from EtOH to provide 8 as white crystals. Yield
65.7 g(81 %);m.p. 75-77°C(lit.6: m.p.79-80°C). IR(cm-'): 2239 (CN).
'H NMR: 1)2.57 (t, 2H, J = 7.3 Hz), 2.93 (t, 2H, J = 7.3 Hz), 3.78 (s,
3H), 3.79 (s, 3H), 6.73 (s, 1H), 6.94 (s, 1H); Purity by HPLC: 97.5%.
2-Bromo-4,5-dimethoxycinnamonitrile (7)
Route A procedure: A suspension of cyanoacrylic acid 5 (150.0 g, 0.48
mol) in dimethylacetamide (500 mL), was heated at 170°C. Evolution
Zhao, Sheng Yin
