A simple method for the synthesis of 2-amino-1(4′-methoxyphenyl)-propane

Article abstract of DOI:10.1081/SCC-100105672

Synthesis of 2-amino-1-(4′-methoxyphenyl)-propane (II) starting from p-anisaldehyde (1) in 67% overall yield is described. Key reactions involved Horner-Wadswoth-Emmons olefination of 1 to form the ester 2 and Hoffmann degradation of amide 5 to obtain the amine II.

Full text of DOI:10.1081/SCC-100105672

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A SIMPLE METHOD FOR THE SYNTHESIS OF 2-
AMINO-1-(4′-METHOXYPHENYL)-PROPANE
Hari Babu Mereyala a & Sreenivasulu Reddy Koduru a
a Organic Chemistry Division-III, Indian Institute of Chemical Technology, Hyderabad, 500
007, India
Version of record first published: 16 Aug 2006.
To cite this article: Hari Babu Mereyala & Sreenivasulu Reddy Koduru (2001): A SIMPLE METHOD FOR THE SYNTHESIS OF 2-
AMINO-1-(4′-METHOXYPHENYL)-PROPANE, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 31:19, 3005-3010
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SYNTHETIC COMMUNICATIONS, 31(19), 3005–3010 (2001)
A SIMPLE METHOD FOR THE
SYNTHESIS OF 2-AMINO-1-
(40-METHOXYPHENYL)-PROPANE
Hari Babu Mereyala* and Sreenivasulu Reddy Koduru
Organic Chemistry Division-III, Indian Institute of
Chemical Technology, Hyderabad 500 007, India
ABSTRACT
Synthesis of 2-amino-1-(40-methoxyphenyl)-propane (II)
starting from p-anisaldehyde (1) in 67% overall yield is
described. Key reactions involved Horner–Wadswoth–
Emmons olefination of 1 to form the ester 2 and Hoffmann
degradation of amide 5 to obtain the amine II.
b-Arylethylamine functionality is essential to many amphetamine drugs
that offer high selectivity for b2-adrenoceptors.1 A variety of b2-adrenoceptor
agonists have been prepared for treatment of asthma and chronic bronchitis.2
Among them formoterol (I) offers high selectivity for b2-adrenoceptors and
has excellent safety, tolerance profile and has been commercialized in racemic
form.3 Synthesis of I requires preparation of 2-amino-1-(40-methoxyphenyl)-
propane (II) by a process which is amenable to scale up, avoids use of hazar-
dous reagents, elevated temperature and pressure. Synthetic procedures to
prepare b-phenyl ethylamine II describes Henry reaction of p-anisaldehyde
*Corresponding author. E-mail: haribabu@iict.ap.nic.in
3005
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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BABU MEREYALA AND REDDY KODURU
(1) to obtain the key intermediate b-nitrostyrene4 III followed by hydrogena-
tion at high pressure in presence of Pd/C5 or RED-AL4b or by refluxing with
LiAlH4 in Et2O4f to obtain the amine II in 70–85% yield in one approach and
in the second III was converted to the keto compound IV by reaction with
Fe/aq. HCl4a, or NaH2PO2.H2O/Raney–Ni at pH 56 or HClO74 or Zn–TFA.8
The keto compound IV was converted to the corresponding oxime V9b by
reaction with NH2OH.HCl followed by reduction with Raney–Ni at high
pressure4a to obtain the amine II in 40–43% overall yield.
We report herein a simple laboratory method for the preparation of
amine II. Horner–Wadsworth–Emmons reaction of 1 with ethyl-(2-di-
methoxyphosphinyl)-2-propanoate10 (1.1 mol equiv.) and NaOtBu (1.5 mol
equiv.) in toluene at room temperature for 15 min gave the a/b-unsaturated
ester 2 which on catalytic hydrogenation (1 atm.) with 10% Pd/C in MeOH
for 4 h gave the saturated ester 3, while progress of the reaction was mon-
itored by HPLC (experimental). Hydrolysis of 3 with aq. NaOH (20%) and a
catalytic amount of cetrimide at reflux temperature for 5 h gave the acid deri-
vative 4. Compound 4 was transformed to the amide 5 (mp: 119–121ꢀC) by
reaction with SOCl2 followed by quenching with methanolic ammonia sol-
ution at À5ꢀC. Hoffman degradation of amide 5 by reaction with NaOBr at
70ꢀC for 2 h gave the amine II in 67% overall yield from p-anisaldehyde (1).
In conclusion a simple, high yielding laboratory method for the pre-
paration of racemic amphetamine derivative II has been achieved starting
from p-anisaldehyde.
EXPERIMENTAL
Flame dried glassware, commercially available solvents and reagents
were used without further purification unless otherwise stated. Melting

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2-AMINO-1-(40-METHOXYPHENYL)-PROPANE
3007
Scheme.
1
points were measured using capillary tubes and are uncorrected. H NMR
spectra were measured with a Varian Gemini (200 MHz) spectrometer with
a tetramethyl silane as an internal standard for solutions in deuterochloro-
form. IR spectra were taken with a Perkin Elmer 1310 spectrometer. Mass
spectra were obtained on a VG 70-70H instrument.
Ethyl-3-(40-methoxyphenyl)-2-methyl-2-propenoate (2)
To a solution of p-anisaldehyde 1 (32 g, 0.24 mol), toluene (160 mL)
and ethyl-(2-dimethoxyphosphinyl)-2-propanoate (58.8 g, 0.28 mol) was
added NaOtBu (33.6 g, 0.35 mol) at 0ꢀC under N2 atmosphere during half
an hour. The reaction mixture was brought to room temperature and stirred
for 15 min. Progress of the reaction was monitored by t.l.c. [AcOEt :
Hexane; 1:4] from the appearance of a faster moving spot. After completion
of the reaction, the reaction mixture was neutralised with 10% aq. HCl. The
toluene layer was separated, washed with water (2 Â 100 mL), dried
(Na2SO4) and concentrated to obtain the title compound 2 in quantitative
yield as a syrup (51.6 g). IR (neat): 1694, 1600, 1514, 1200, 1050, 965, 870 cmÀ1
;
1H NMR (CDCl3): d 1.35 (t, 3H, J ¼ 6.5 Hz, -CH2-CH3), 2.15 (s, 3H, -CH3),

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BABU MEREYALA AND REDDY KODURU
3.85 (s, 3H, -OCH3), 4.25 (q, 2H, OCH2-CH3), 6.91 (d, 2H, J ¼ 10 Hz, Ar-
H), 7.35 (d, 2H, Ar-H), 7.62 (s, 1H, H-3); EI MS( m/z, %): 220 (Mþ, 100%);
Anal. Calcd. (Found) for C13H16O3: C, 70.89 (70.72); H, 7.32 (7.37).
Ethyl-3-(40-methoxyphenyl)-2-methyl-propanoate (3)
To a solution of 2 (32 g, 0.145 mol) in MeOH (160 mL) was added
Pd/C 10% (1.0 g) and subjected to hydrogenation (1 atm.) for 4 h.
Progress of the reaction was monitored by HPLC (Eluant: 70% CH3CN
in H2O, 2 had a retention time of 8.3 min and compound 3 of 7.3 min). After
completion of the reaction, the catalyst was filtered off and the filtrate was
concentrated to obtain the title compound 3 in quantitative yield (31.8 g) as
1
a syrup. IR (neat): 1725, 1513, 1450, 1247, 1176, 1003, 800 cmÀ1. H NMR
(CDCl3): d 1.12 (t, 3H, J ¼ 6.0 Hz, -CH2-CH3), 1.21 (d, 3H, J ¼ 6.5 Hz, -
CHCH3), 2.50–2.75 (m, 2H, Ph-CH2), 2.80–3.10 (m, 1H, -CH-CH3), 3.72 (s,
3H, -OCH3), 4.08 (q, 2H, O-CH2-CH3), 6.81 (d, J ¼ 8.0 Hz, 2H, Ar-H), 7.08
(d, 2H, Ar-H); EI MS( m/z, %): 222 (Mþ, 26%); Anal. Calcd. (Found) for
C13H18O3: C, 70.24 (70.01); H, 8.16 (8.11).
3-(40-Methoxyphenyl)-propanoic Acid (4)
To a solution of 3 (25 g, 0.11 mmol) in THF (93 mL) was added NaOH
(8.96 g in 46 mL H2O) (0.22 mol), citrimide (0.2 g) and refluxed for 5 h. The
progress of the reaction was monitored by t.l.c. [AcOEt : Hexane; 2:3] from
the appearance of a slower moving spot. After completion of the reaction,
THF was removed on a rotary evaporator and the reaction mixture was
acidified with 10% aq. HCl and extracted into CH2Cl2 (125 mL). The
organic layer was separated, washed with water (2 Â 100 mL), dried
(Na2SO4) and concentrated to obtain the title compound 4 in quantitative
yield (21.5 g) as a syrup. IR (neat): 1710, 1600, 1513, 1450, 1247, 1098,
1035 cmÀ1
;
1H NMR (CDCl3): d 1.15 (d, 3H, J ¼ 5.9 Hz, -CH2-CH3),
2.10–3.10 (m, 3H), 3.78 (s, 3H, -OCH3), 6.78 (d, 2H, J ¼ 5.9 Hz, Ar-H),
7.06 (d, 2H, Ar-H); EI MS( m/z, %): 194 (Mþ, 8%). Anal. Calcd.
(Found) for C11H14O3: C, 68.02 (68.19); H, 7.27 (7.21).
3-(40-Methoxyphenyl)-2-methyl-propanamide (5)
A solution of 4 (20 g, 0.10 mol) in SOCl2 (14.6 mL, 0.20 mol) was
heated to reflux for 2 h. After completion of the reaction, thionyl chloride

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2-AMINO-1-(40-METHOXYPHENYL)-PROPANE
3009
was distilled off to obtain a residue which was dissolved in MeOH (60 mL),
cooled to À5ꢀC under nitrogen atmosphere and a 5% solution of ammonia
in MeOH (3.50 g in 70 mL MeOH, 0.20 mol) was added dropwise under
efficient stirring at À5ꢀC. After completion of the reaction, methanol was
removed on a rotary evaporator to obtain a solid which was filtered, washed
with water (100 mL) and dried to obtain the title compound 5 in quantitative
yield (19.30 g). mp: 119–121ꢀC; IR (KBr): 3388, 3200, 1662, 1600, 1498,
1
1459, 1247, 1035 cmÀ1. H NMR (CDCl3): d 1.18 (d, 3H, J ¼ 5.0 Hz, -CH-
CH3), 2.62 (dd, 1H, J2,3a ¼ 5.0 Hz, Jgem ¼ 12.5 Hz, Ph-CH2), 2.88 (dd, 1H,
J2,3b ¼ 7.5 Hz, Ph-CH2), 3.78 (s, 3H, -OCH3), 6.78 (d, 2H, J ¼ 6.5 Hz, Ar-H),
7.08 (d, 2H, Ar-H); EI MS( m/z, %): 193 (Mþ, 10%). Anal. Calcd. (Found)
for C11H15O2N: C, 68.37 (68.11); H, 7.82 (7.73); N, 7.25 (7.19).
2-Amino-1-(40-methoxyphenyl)-propane (II)
To a stirred solution of sodium hypobromite [Br2 (4.6 mL, 0.09 mol),
NaOH (18.72 g, 0.48 mol) in 150 mL water] was added a finely divided amide
5 (15 g, 0.078 mol) at 0ꢀC during 10 min. The reaction mixture was heated to
70ꢀC for 2 h. The progress of the reaction was monitored by t.l.c.
(BuOH : EtOH : NH3, 7:2.6:0.3 mL). After completion of the reaction, the
reaction mixture was extracted into CH2Cl2 (75 mL). Organic layer was
separated, washed with water (2 Â 75 mL), dried (Na2SO4) and concentrated
to obtain the title compound II as a syrup (9.6 g, 75%) that exhibited com-
1
parable H NMR spectrum with that reported in literature.4f,11a For the
purpose of characterisation II was also converted to the corresponding
hydrochloride11b [10.5 g, 65%, mp: 208–210ꢀC (lit.4a 208ꢀC)] by treating
with 5% HCl in MeOH.
ACKNOWLEDGMENTS
KSR thanks Director, IICT for funding this project.
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Received in the UK September 29, 2000

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