First synthesis of 3-methoxy-4-aminopropiophenone

Article abstract of DOI:10.3184/174751912X13418461206368

The transformation of 3-methoxyphenylacetone to 4-amino-3- methoxypropiophenone is described.

Full text of DOI:10.3184/174751912X13418461206368

JOURNAL OF CHEMICAL RESEARCH 2012
RESEARCH PAPER 543
SEPTEMBER, 543–544
First synthesis of 3-methoxy-4-aminopropiophenone
William J. Vera and Ajoy K. Banerjee*
IVIC, Centro de Quimica, Apartado-21827, Caracas-1020, Venezuela
The transformation of 3-methoxyphenylacetone to 4-amino-3-methoxypropiophenone is described.
Keywords: camptothecins, reduction, irradiation, oxidation, amino ketone
Several routes1 have been developed for the synthesis of
2-amino-5-methoxypropiophenone 1 which is a convenient
starting material for the construction of the A/B ring of the
alkaloid CPT (camptothecin), of CPT-11 (a semi-synthetic
water-soluble derivative of CPT) and of SN-38 (a metabolite
of CPT-11), all three of which have exhibited antitumour
effects. However, to the best of our knowledge, there are no
reports on the synthesis of 3-methoxy-4-aminopropiophenone
2 which on condensation2 with dimethyl acetylenedicarboxyl-
ate and cyclisation is expected to lead to the formation of
kynurenic acid derivatives.3
with copper(II) nitrate hydrate and acetic anhydride in ether
afforded the nitro compound 5 in 53% yield.
Nitration under solvent-free conditions using a mixture of
nitric acid (65%) and sulfuric acid and nitric acid (65%) in the
presence of P2O5 supported on silica gel9 yielded the nitro
compound 5 in low yield. The position of the NO2 at C-4 was
confirmed not only by 1H and 13C NMR spectroscopy but also
by two dimensional (2D HMQC and HMBC) spectroscopy.
In the HMQC spectra, the signals at δ 6.78 and δ 120.2 were
correlated with the proton and carbon at C-6. Similarly the
signals at δ 7.75 and δ 125.7 and the signals at δ 6.84 and δ
113.3 exhibit a correlation between the proton and the carbon
at C-5 and C-2 respectively. In the HMBC spectra, the signals
at δ 2.59 and δ 137.2 showed a correlation between the proton
at C-7 and C-4. Similarly the signals at δ 7.75 and δ 137.2 and
the signals δ 6.84 and δ 137.2 showed a correlation between
the protons and carbons at H-5 and C-4 and H-2 and C-4
respectively. These spectroscopic data lend strong support in
favour of the structure of 5. No trace of 5-methoxy-2-nitropro-
pylbenzene 6 was detected. Oxidation10 of 5 with pyridinium
chlorochromate (PCC) afforded the nitroketone 7 in 43% yield.
Oxidation was also attempted with KMnO4/bentonite in
hexane,11 nitric acid in hexane12 and 2,6-dichloro-5,6-dicyano-
1,4- benzoquinone (DDQ) in THF13 but the yield of the nitro-
ketone could not be improved. The difficulty in obtaining high
yield of the nitroketone can only be explained by assuming
that the nitro group deactivated not only the aromatic ring but
also the benzylic group. The synthesis of the nitroketone 7 had
been reported14 by Katritzky and collaborators by a different
route but without experimental details and spectroscopic data.
Finally the conversion of 7 to the desired aminoketone 2 in
60% yield was accomplished by reduction15 with Pd/C (10%)
and ammonium formate (HCO2NH4). The spectroscopic
data of 2 were consistent with the structure assigned to the
aminoketone.
Kynurenic acid derivatives have been evaluated3 for their
in vitro antagonist activity at the excitatory amino acid recep-
tors that are sensitive to N-methyl-D-aspartic acid, quisqualic
acid and kainic acid. ε-Aminoquinolinecarboxylic acid has
recently been utilised for the synthesis of novel macrocyclic
peptides.4 Keeping in mind the biological properties of
quinolone derivatives we have developed the first synthesis of
the substituted propiophenone 2. The synthetic details are
described in Scheme 1.
Results and discussion
Wolff–Kishner reduction of the commercially available of
3-methoxyphenylacetone 3 under microwave irradiation5 led
to the known compound 4 in 82% yield. Although 4 has been
synthesised by different methods6,7 our method is different and
easy to manipulate compared to those reported. Nitration8 of 4
Scheme 1
* Correspondent. E-mail: aabanerje@gmail.com

544 JOURNAL OF CHEMICAL RESEARCH 2012
chromatography plate. Elution with hexane: ether (9:1) afforded the
nitroketone 7 (307 mg, 43%) as a pale yellow crystalline solid, m.p.
65–67 °C (from hexane); MS (m/z): 210 (M++1), 209 (M+); 1H NMR:
δ 7.84 (d, 1H, J = 8.3 Hz), 7.66 (d, 1H, J = 1.5 Hz), 7.56–7.53 (dd, 1H,
J = 8.3 Hz, J = 15 Hz) (H at C-5, C-2 and C-6), 3.99 (s, 3H, MeO),
3.01 (q, 2H, J = 7 Hz) (H at C-8), 1.22 (t, 3H. J = 7 Hz) (H at C-9);
13C NMR: δ 199 (C-7), 152.8 (C-3), 142.2 (C-4), 140.9 (C-1), 125
(C-5), 119.8 (C-6), 112.6 (C-2), 56.7 (C-10), 32.3 (C-8), 7.9 (C-9).
Anal. Calcd for C10H11O4N: C, 57.41; H, 5.26. Found: C, 57.23; H,
5.38%.
In conclusion the synthesis of the 3-methoxy-4-aminopro-
piophenone is described for the first time from commercially
available methoxyphenylacetone 3. Its transformation into the
kynurenic acid derivative following the literature procedure2,3
will be attempted shortly.
Experimental
Melting points were determined on an Electrothermal melting point
apparatus and are uncorrected. Infrared spectra were recorded on a
Nicolet-Fourier Transform (FT) instrument and NMR (1H and 13C)
spectra were recorded on a Bruker AM-300 spectrometer in CDCl3.
Chemical shifts (δ) are expressed in ppm. Mass spectra (MS) were
determined on a Dupont 21-492B. Column chromatography was
carried out on silica gel 60 (Merck). The organic extracts (ether or
chloroform) were washed with brine, dried (MgSO4) and evaporated
under reduced pressure. TLC plates were coated with silica gel 60F254
and the spots were visualised using UV light. Elemental analyses
were performed on a Carlo-Erba 1108 elemental analyser. Microwave
irradiations were carried out with a microwave oven (2.45 GHz,
300W) (Trade Mark Discover, CEM).
3-Methoxy-4-aminopropiophenone (2): Ammonium formate (177 mg,
2.8 mmol) was added to a solution of the nitroketone 7 (125 mg,
0.59 mmol) in methanol (2 mL). After stirring for 10 min under nitro-
gen, Pd–C (10%, 67 mg) was added. The reaction mixture was heated
using a microwave oven at 45W for 20 min. The catalyst was removed
by filtration and washed with methanol. The filtrate was concentrated
under reduced pressure and the resulting residue on purification using
a preparative chromatography plate (hexane: ether 9:1), afforded the
aminoketone 2 (63 mg, 60%) as pale yellow crystalline solid, m.p.
89–92 °C (from hexane); IR (cm−1): 3437–3338 (NH2), 1660 (CO);
1
MS (m/z): 179 (M+); H NMR: δ 7.46–7.43 (m, 2H), 6.63 (d, 1H,
J = 8.5 Hz) (H at C-6, C-2, C-5), 4.26 (bs, 2H, NH2), 3.88 (s, 3H,
OMe), 2.89 (q, 2H, J = 7.3 Hz), 1.18 (t, 3H, J = 7.3 Hz) (H at C-8 and
C-9); 13C NMR: δ 199.4 (C-7), 146.5 (C-3), 141.4 (C-4), 127.5 (C-1),
123.4 (C-6), 112.6 (C-2), 109.3 (C-5), 55.6 (C-10), 31.0 (C-8), 8.9
(C-9). Anal. Calcd for C10H13O2N: C, 67.03; H, 7.26. Found: C, 66.84;
H, 7.38%.
3-Methoxypropylbenzene (4): A solution of 3-methoxyphenylace-
tone 3 (1.01 g, 6.1 mmol) in diethylene glycol (DEG) (12 mL) was
treated with KOH (2.22 g, 39.6 mmol) and 80% hydrazine monohy-
drate (N2H4.H2O) (1.10 mL, 22.8 mmol) and was irradiated in a
microwave oven at 100W for 20 min at 112 °C and then for 30 min at
180 °C. The reaction mixture was cooled to room temperature, diluted
with water (30 mL) and extracted with ether (150 mL). The ethereal
extract was washed, dried and evaporated to afford an oil which was
chromatographed (hexane) to yield 4 (750 mg, 82%) as a colourless
Received 30 May 2012; accepted 22 June 2012
Paper 1201344 doi: 10.3184/174751912X13418461206368
Published online: 28 August 2012
1
oil. MS (m/z): 150 (M+) (100%); H NMR: δ 7.27 (t, 1H, 5-H, J =
7.6 Hz), 6.88–6.80 (m, 3H, H-2, H-6, H-4), 3.86 (s, 3H, OMe), 2.66
(t, 2H, J = 7.8 Hz), 1.78–1.68 (m, 2H), 1.04 (t, 3H, J = 7 Hz) (H-7,
H-8, H-9); 13C NMR: δ 159.6 (C-3), 144.2 (C-1), 129.1 (C-5). 120.9
(C-6), 114.2 (C-2), 110.8 (C-4), 54.9 (C-10), 38.1 (C-7), 24.4 (C-8),
13.7 (C-9). Anal. Calcd for C10 H14O: C, 79.95; H, 9.39. Found: C,
80.16; H, 9.24%.
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3-Methoxy-4-nitropropiophenone (7): Pyridinium chlorochromate
(3.84 g, 17.8 mmol) was added to a solution of the nitro compound 5
(661 mg, 3.4 mmol) in benzene (40 mL). The mixture was stirred,
heated under reflux for 24 h, cooled and filtered through a short pad of
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