Synthesis of 2-amino-1-indanone from DL-phenylalanine

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Synthesis of 2-Amino-1-indanone from
DL-Phenylalanine
a
a
a
a
Rong Zhao , Peijiang Guo , Junyu Dong , Xiaoping Zhang ,
a
a
a
Xiaofei Sun , Yun Tian & Qingle Zeng
a
College of Materials and Chemistry & Chemical Engineering,
Chengdu University of Technology, Chengdu, P. R. China
Version of record first published: 02 Aug 2011.
To cite this article: Rong Zhao , Peijiang Guo , Junyu Dong , Xiaoping Zhang , Xiaofei Sun , Yun Tian &
Qingle Zeng (2011): Synthesis of 2-Amino-1-indanone from DL-Phenylalanine, Organic Preparations and
Procedures International: The New Journal for Organic Synthesis, 43:4, 377-380
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Organic Preparations and Procedures International, 43:377–380, 2011
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2011.582014
Synthesis of 2-Amino-1-indanone from
DL-Phenylalanine
Rong Zhao, Peijiang Guo, Junyu Dong, Xiaoping Zhang,
Xiaofei Sun, Yun Tian, and Qingle Zeng
College of Materials and Chemistry & Chemical Engineering, Chengdu
University of Technology Chengdu, P. R. China
2
-Amino-1-indanone is a cyclic vicinal amino ketone. Such compounds are of great interest
1
–3
as pharmaceutical agents and as intermediates in natural product synthesis. There are four
main methods to synthesize this compound. One is an anionic cyclization of N-protected
o-bromophenylalanine ester by lithium-bromine exchange followed by internal trapping of
the lithiated intermediate by the carboxylate group under rigorously anhydrous, anaerobic
◦
4
operation at -78 C. The N-protected o-bromophenylalanine ester requires at least three
steps for its preparation. Another method is an intramolecular Friedel-Crafts acylation of the
5
N-carboxyanhydrideofphenylalanine, inwhichtheanhydridemust bepreparedbyreaction
of phenylalanine with phosgene or triphosgene or by reaction of l-N-methoxycarbonyl
5
phenylalanine with PBr3. The third route is a Friedel-Crafts acylation of the N-protected
(
α-aminoacyl)benzotriazole of phenylalanine, obtained from phenylalanine via a two-step
6
reaction, with AlCl3 to give N-protected 2-amino-1-indanone. The fourth method is an
intramolecular Friedel-Crafts cyclization of N-phthaloylphenylalanine acid chloride to give
N-protected 2-amino-1-indanone.7 In this procedure, N-methoxycarbonyl or N-phthaloyl
protected phenylalanine must first be converted to its acid chloride with thionyl chloride.
The acid chlorides are moisture sensitive and apt to emit volatile, corrosive hydrogen
chloride gas. In continuation of our interest in the synthesis and transformations of amino
–12
1
3–16
acids,
Scheme 1).
Polyphosphoric acid (PPA) is known to be an excellent Br o¨ nsted acid for cyclodehy-
we now describe a new route to 2-amino-1-indanone from dl-phenylalanine
(
1
7–19
dration, Friedel-Crafts acylation and alkylation.
Although PPA is frequently used in
Friedel-Crafts acylation, it has not been investigated in the synthesis of 2-amino-1-indanone.
There are four advantages for PPA-catalyzed Friedel-Crafts acylation: (1) Transformation
from N-phthaloylphenylalanine into its acid chloride is avoided; (2) Yield from N-protected
phenylalanine to N-protected 2-amino-1-indanone is much higher (75%); (3) No volatile
Submitted November 10, 2010.
Address correspondence to Qingle Zeng, College of Materials and Chemistry & Chemical
Engineering, Chengdu University of Technology, Chengdu 610059, P. R. China. E-mail: qinglezeng@
hotmail.com
377

378
Zhao et al.
O
O
HO
O
N
O
HO
O
PPA
O
o
o
NH2 150 C, vacuo
130 C
O
1
O
O
AcOH, HCl
NH Cl
N
3
reflux
O
O
2
3
Scheme 1
Synthesis of 2-Amino-1-indanone hydrochloride (3)
corrosive gas is produced; and (4) No organic solvents are used in the Friedel-Crafts
acylation.
Our synthesis commenced with the preparation of N-phthaloylphenylalanine (1). Com-
mercially available dl-phenylalanine20 and phthalic anhydride were heated to melting un-
der low vacuum to speed removal of water generated in the process and thus to accelerate
21
the condensation at a relatively low temperature. When N-phthaloylphenylalanine (1)
◦
was heated at 130 C in PPA, as catalyst and solvent, 2-phthalimido-1-indanone (2) was
obtained with good yield (75%). Finally, 2-phthalimido-1-indanone (2) was hydrolyzed
with acetic acid and concentrated hydrochloric acid under reflux for ten hours to give 2-
8
amino-1-indanone hydrochloride (3). Attempted cleavage with hydrazine hydrate led to a
homogeneous mixture from which it was difficult to remove water. The overall yield from
dl-phenylalanine was 40%.
Experimental section
The purity of all the synthesized compounds was checked by thin-layer chromatography
(TLC) using various non-aqueous solvents. Melting points were measured on an Electro-
thermal digital melting point apparatus and are not corrected. The IR spectra were recorded
1
on a Bruker Tensor-27 FT-IR spectrophotometer in KBr discs. H NMR spectra were ob-
tained on a Bruker Advance 300 MHz NMR spectrometer at 300 MHz in CDCl3 containing
tetramethylsilane (TMS) as an internal standard. The chemicals were purchased from
Aldrich, Aladdin, or Kelong Chemical Companies, and used without further purification.
Synthesis of N-Phthaloylphenylalanine (1).
dl-Phenylalanine (3.30 g, 20.0 mmol) and phthalic anhydride (3.25 g, 22.0 mmol) were
added into a round bottom flask fitted with a magnetic stirring assembly. The flask was
connected to a water aspirator (with about 40 mmHg vacuum), and heated in an oil bath

Synthesis of 2-Amino-1-indanone from DL-Phenylalanine
379
◦
at 150 C. Soon the solid mixture was fused and some water drops were condensed at the
top of the flask. After 50 min, the flask was removed from the oil bath and cooled to
room temperature. The excess crystalline phthalic anhydride on the wall of the flask was
removed by cotton wool dipped in ethyl acetate. The solid crude product at the bottom of
the flask was purified by recrystallization from ethanol/water (3/2) to give white needle
◦
21
crystalline solid of N-phthaloylphenylalanine 1 (5.156 g, 87% yield), mp. 184–185 C [lit.
◦
−1
1
1
3
5
84–186 C]. IR (neat), ν (cm ): 3271, 1771, 1749, 1698. H NMR (300MHz, CDCl3): δ
.60 (d, J = 9.0 Hz, 2H), 5.23 (t, J = 9 Hz, 1H), 6.4 (br, COOH, 1H), 7.11–7.19 (m, Ar–H,
H), 7.70 (dd, J1 = 5.4Hz, J2 = 3.0 Hz, 2H), 7.78 (dd, J1 = 5.4 Hz, J2 = 3.0 Hz, 2H). The
1
21
IR and H NMR spectra are consistent with literature data.
Synthesis of 2-Phthalimido-1-indanone (2)
N-Phthaloylphenylalanine (1) (3.01 g, 10.2 mmol), PPA (20 ml) was added to a 250 ml flask
fitted with a magnetic stirring assembly and a reflux condenser. The flask was heated in an
◦
oil bath at 130 C for 3 h. Then the flask was cooled to room temperature, and water (60 ml)
was added to quench the reaction. The resulting solution was transferred to a separatory
funnel, and extracted with dichloromethane (3 × 30 ml). The combined organic layer was
washed with water (10 ml), saturated sodium bicarbonate (10 ml), saturated sodium chloride
(10 ml), and then dried over anhydrous magnesium sulfate. The filtrate was concentrated on
a rotary evaporator. The resulting solid was purified by silica gel column chromatography
with petroleum and ethyl acetate (4/1) as eluent to give 2-phthalimido-1-indanone (2) as
◦
7
◦
a white solid (2.1030 g, 75% yield), mp. 203–205 C [lit. mp. 203–204 C]; IR (neat), ν
(
1
7
−1
1
cm ): 1780, 1723, 1602; H NMR (300 MHz, CDCl3): δ 3.40 (dd, J1 = 16 Hz, J2 = 6 Hz,
H), 3.60 (dd, J1 = 16 Hz, J2 = 8.4 Hz, 1H), 5.09 (dd, J1 = 8.4 Hz, J2 = 6 Hz, 1H),7.43 –
1 8
.87(m, 8 H). The H NMR and IR spectra are consistent with the literature data.
Synthesis of 2-Amino-1-indanone Hydrochloride (3)
-Phthalimido-1-indanone 2 (0.800 g), conc. hydrochloric acid (3 ml) and acetic acid
2
(
5 ml) were added into a 100 ml flask fitted with a magnetic stirring assembly and a reflux
◦
condenser. The flask was heated on an oil bath at 110 C for ten hours. After cooling to
room temperature, water (50 ml) was added to the flask, and white emulsion appeared
immediately. The mixture was filtered by gravity to remove the white solid, phthalic acid.
The filtrate was extracted twice with ethyl acetate (20 ml) and the ethyl acetate extract was
discarded. The aqueous layer was concentrated on a rotary evaporator to remove water.
The resulting solid was washed with diethyl ether (5 ml) to give 2-amino-1-indanone
◦
8
hydrochloride 3 as a white crystalline solid (0.3286 g, 62% yield), mp. 167–170 C (lit.
1
◦
−1
1
68–175 C); IR (neat), ν (cm ): 2973, 1715, 1591; H NMR (300 MHz, CDCl3), δ (ppm):
3
.18 (dd, J1 = 17.1 Hz, J2 = 5.1 Hz, 1H), 3.72 (dd, J1 = 17.1 Hz, J2 = 5.1 Hz, 1H), 4.34
1
(dd, J1 = 8.1Hz, J2 = 5.4 Hz, 1H), 7.46–7.80 (m, 4H). The H NMR and IR spectra are
8
basically consistent with the literature data.

380
Zhao et al.
Acknowledgments
We thank the National Science Foundation of China (Grant No. 20672088), Ministry of
Human Resources and Social Security of the People’s Republic of China, and Incuba-
tion Program for Excellent Innovation Team of Chengdu University of Technology for
financial support. We sincerely appreciate the help of Prof. J.-P. Anselme (University of
Massachusetts Boston) for the careful revision of this manuscript.
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