Efficient synthesis of 7-amino-3-hydroxyindan-1-one

Article abstract of DOI:10.1080/00397910802419680

An efficient and reliable three-step synthesis of 7-amino-3-hydroxyindan-1- one (7) is described. Compound 7 is a versatile, three-dimensional, three-point scaffold that is useful for the construction of focused compound libraries. Copyright Taylor & Fran

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Efficient Synthesis of 7-
Amino-3-hydroxyindan-1-one
Raj (S. B.) Rajur a , Venugopal N. Rao a , Hwa-Ok
Kim a , Pamela Nagafuji a , Xavier Hearult a , John D.
Williams b & Norton P. Peet a b
a CreaGen Biosciences, Inc. , Woburn,
Massachusetts, USA
b Microbiotix, Inc. , Worcester, Massachusetts, USA
Published online: 27 Jan 2009.
To cite this article: Raj (S. B.) Rajur , Venugopal N. Rao , Hwa-Ok Kim , Pamela
Nagafuji , Xavier Hearult , John D. Williams & Norton P. Peet (2009) Efficient
Synthesis of 7-Amino-3-hydroxyindan-1-one, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 39:4,
626-635, DOI: 10.1080/00397910802419680
To link to this article: http://dx.doi.org/10.1080/00397910802419680
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Synthetic Communications1, 39: 626–635, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802419680
Efficient Synthesis of 7-Amino-3-
hydroxyindan-1-one
Raj (S. B.) Rajur,1 Venugopal N. Rao,1 Hwa-Ok Kim,1
Pamela Nagafuji,1 Xavier Hearult,1 John D. Williams,2
and Norton P. Peet1,2
1CreaGen Biosciences, Inc., Woburn, Massachusetts, USA
2Microbiotix, Inc., Worcester, Massachusetts, USA
Abstract: An efficient and reliable three-step synthesis of 7-amino-3-hydroxyindan-
1-one (7) is described. Compound 7 is a versatile, three-dimensional, three-point
scaffold that is useful for the construction of focused compound libraries.
Keywords: HMBC, hydroxyindanones
INTRODUCTION
Fused-ring systems containing a five-membered ring annellated to a
six-membered ring provide ideal scaffolds for anchoring multiple func-
tionalities that can engage in specific interactions with biological recep-
tors. These biologically important 5,6-fused systems include indoles (1),
isatins (2), benzofuranones (3), indanes (4), indanones (5), and indenes
(6), as shown in Fig. 1.
Recent references describe specific examples of these ring systems
and their utilities. Indole scaffolds interact with protein-coupled amino
acid transporters (PAT1) expressed in several cell types;[1] indoles display
melatonin-like cytoprotective activity;[2] and indoles have also been
shown to bind the colchicine site of tubulin.[3] Isatin derivatives have been
designed to possess antimalarial activity[4] and treat tropical diseases,[5]
Received May 5, 2008.
Address correspondence to Norton P. Peet, Microbiotix, Inc., One Innovation
Drive, Worcester, MA 01605. E-mail: npeet@microbiotix.com
626

7-Amino-3-hydroxyindan-1-one
627
Figure 1. Biologically important 5,6-fused ring systems.
including severe acute respiratory syndrome (SARS) virus[6] and parasitic
diseases that are treatable by inhibiting target cysteine proteinases: cru-
zain, falcipain-2, and rhodesian.[7] Indanes have been used as potassium
channel blockers for the treatment of atrial arrhythmias[8] as well as anti-
bacterial agents by the mimicry of a complementary unit on magainin
2.[9] An indene scaffold has been used to make an avb3 integrin antago-
nist.[10] Interestingly, indanone derivatives, which are known to possess
biological activity,[11] have very recently been synthesized using a triple
cascade process: a Knoevenagel condensation followed by a Nazarov
cyclization and an electrophilic fluorination.[12] In addition, benzofura-
nones have recently been reported as flavopiridol mimics.[13]
The specific scaffold that is the topic of this report is 7-amino-3-
hydroxyindan-1-one (7), as shown in Fig. 1. Note that compound 7 is
a subset of scaffold 5.
Although indanone 7 has been mentioned in the literature, its pre-
paration has not been recorded, and the reported synthesis of its precur-
sor is an experimental procedure that we could not repeat as described. In
addition to the synthesis of indanone 7, we describe the preparation of a
small set of derivatives that were prepared by functionalization of the
amino group.

628
R. (S. B.) Rajur et al.
RESULTS AND DISCUSSION
The preparation of 7-amino-3-hydroxyindan-1-one (7) is shown in
Scheme 1. A solution of 4-nitrophthalic anhydride (8) in methylene chlor-
ide was sequentially treated with ethyl acetoacetate, acetic anhydride, and
triethylamine. The reaction solution was concentrated, and the residue
was reconstituted in water, cooled to 0 ꢀC, and acidified with aqueous
hydrochloric acid. The precipitate was collected and dried to give an
85% yield of pure 10. We were unable to repeat a literature report[14] that
lacked details and did not specify any solvent for this reaction. We deter-
mined that critical features for this successful conversion were (1) the use
of methylene chloride as a solvent; (2) reconstitution of the concentrated
reaction mixture in water; and (3) the precipitation of the desired reaction
product from the cold aqueous solution. We envision that condensation
product 9 is an intermediate in the conversion of 8 to 10. The synthesis of
2-acetyl-1,3-indanedione (12), a compound that is similar to 10, has also
been reported from 8.[15]
Compound 11 is also reported in the old Russian literature in which
they describe a three-step procedure starting from 3-nitrophthalic
anhydride and malonic acid.[16] Our melting point (130–132 ꢀC) for 11
is in good agreement with their reported[16] melting point (133 ꢀC).
However, we were unable to repeat their reported procedure in spite of
several attempts.
Scheme 1. Reagents and conditions: (a) ethyl acetoacetate, acetic anhydride,
triethylamine, dichloromethane, room temperature, 30 min; (b) trifluroacetic,
acetonitrile, room temperature, 45 min; (c) 40 psi H2, 10% Pd=C, methanol, 24 h.

7-Amino-3-hydroxyindan-1-one
629
Hydrolysis and decarboxylation of 10 proceeded smoothly with
trifluoroacetic acid in acetonitrile to give a 91% yield of 4-nitroindan-
1,3-dione (11). Simultaneous reduction of the nitro group and the distal
carbonyl group of 11 by catalytic hydrogenation gave a 76% yield of the
desired three-point scaffold, 7-amino-3-hydroxyindan-1-one (7).
The synthesis of N-substituted derivatives of compound 7 were per-
formed using the straightforward derivatization procedures shown in
Scheme 2. Treatment of 7 with 2-methoxybenzoyl chloride, 2,4-dichloro-
benzoyl chloride, 4-morpholinecarbonyl chloride, and phenylsulfonyl
chloride provided good yields of the respective N-substituted compounds
13–16. Physical constants, spectral data, and percentage yields are shown
for these derivatives in Table 1.
The derivatives of compound 7 shown in Table 1 offered the oppor-
tunity to perform diagnostic NMR experiments to unequivocally deter-
mine the structure of scaffold 7. To our knowledge, this determination
has not previously been reported. Thus, for compound 13, as shown in
Fig. 2, the two possible structures are as shown for compound 13 and, cor-
respondingly, for the scaffold from which they were derived. The possible
structures A and B (Fig. 2) cannot easily be differentiated by simple 1H or
13C NMR spectroscopy; however, the unusually high shift of the amide –
NH (11.92 ppm for this structure vs. 8.5 ppm for N-phenyl acetamide) sug-
gested to us that the carbonyl group was proximal to the amide (e.g.,
structure A). This was confirmed by a heteronuclear multiple bond
Scheme 2. Reagents and conditions: (a) 2-methoxbenzoyl chloride, DIEA, DCE,
room temperature; (b) 2,4-dichlorobenzoyl chloride, DIEA, DCE, room tempera-
ture; (c) 4-morpholinecarbonyl chloride, DIEA, DCE, room temperature; (d)
phenylsulfonyl chloride, DIEA, DCE, room temperature.

630

631

632
R. (S. B.) Rajur et al.
Figure 2. HMBC experiment results.
correlation (HMBC) spectral study. A correlation existed between the
proton at 7.30 ppm and the carbon at 68.1 ppm, but no correlation was
observed between any of the aromatic protons and the carbonyl carbon
at 204.1 ppm. Only in structure A can both of these observations be
accommodated. Thus, these experiments confirm that the structure of
compound 13 is correct as depicted in Table 1 and, importantly, that
the structure of compound 7 is also correct as shown in this report.
CONCLUSION
This report describes a concise and efficient synthesis of 7-amino-3-
hydroxyindan-1-one (7), which will be useful as a three-dimensional,
three-point scaffold for the preparation of biologically active compounds.
In addition, the structure of scaffold 7 has been unambiguously deter-
mined using HMBC. A related scaffold, (chiral) 3-hydroxy-indan-1-
one, is found in indatraline,[17] a nonselective monoamine reuptake
inhibitor. An efficient enzymatic kinetic resolution process has been
described for the preparation of both enantiomers[18] of this scaffold.
This enzymatic transesterification procedure should also be applicable
for the preparation of the enantiomers of 7.
EXPERIMENTAL
All melting points were obtained in open capillary tubes and are uncor-
1
rected. The H spectra were determined on a 400-MHz Inova Varian
FT-NMR, with chemical shifts reported in parts per million (PPM) (d)
relative to tetramethylsilane (TMS) as internal standard. LC=MS were

7-Amino-3-hydroxyindan-1-one
633
measured on a Waters Micromass Quattro Ultima instrument, and both
ultraviolet and ELSD detection modes were used.
Ethyl 4-Nitroindan-1,3-dione-2-carboxylic Acid (10)
To a solution of 3-nitrophthalic anhydride (5.79 g, 30.0 mmol) in methyl-
ene chloride (100 mL), ethyl acetoacetate (4.68 mL, 36.0 mmol) was
added followed by acetic anhydride (5.65 mL, 60.0 mmol). To this reac-
tion mixture triethylamine (12.5 mL, 90.0 mmol) was added dropwise
over a 15-min period. The reaction mixture was stirred for 15 min and
concentrated, and the residue was dissolved in water (250 mL) and cooled
to 0 ꢀC. Acidification by the dropwise addition of 2 N hydrochloric acid
gave an orange precipitate, which was collected and air-dried to give
1
6.75 g (85%) of 10, mp 152–154 ꢀC. H NMR (CDCl3) d: 1.40 (t, 3H),
4.40 (m, 2H), 5.18 (br s, 1H), 7.60–7.98 (m, 3H). LC=MS 264.3 (ESþ),
262.6 (ESꢁ), purity 100% (UV and ELSD).
4-Nitroindan-1,3-dione (11)
To a solution of ester 10 (6.75 g, 25.7 mmol) in acetonitrile (300 mL)
trifluoracetic anhydride (2.17 mL, 28.2 mmol) was added dropwise at rt.
The reaction mixture was stirred for 45 min and concentrated. The resi-
due was triturated with 1:1 chloroform:hexanes to produce a light brown
solid, which was collected and air-dried to give 4.45 g (91%) of 11, mp
130–132 ꢀC (rep.[16] mp 133 ꢀC). 1H NMR (CDCl3) d: 3.38 (m, 2H),
7.98 (t, 1H), 8.10 (d, 1H), 8.22 (d, 1H). LC=MS 190.4 (ESꢁ), purity
100% (UV and ELSD).
7-Amino-3-hydroxyindan-1-one (7)
To a solution of indanedione 11 in methanol (200 mL) under a nitrogen
atmosphere, 10% Pd=C (100 mg) was added. The reaction flask was
flushed with hydrogen, and a hydrogen balloon was added to the neck
of the flask. Stirring was continued for 24 h. The catalyst was removed
by filtration through Celite. The Celite pad was washed with methanol,
and the filtrate was concentrated. Trituration of the residue with chloro-
form gave a light brown solid, which was collected and dried to give
1
1.24 g (76%) of 7, mp 94–96 ꢀC. H NMR (acetone-d6) d: 2.40 (d, 1H),
2.88 (d, 1H), 4.58 (br s, 1H), 2.88 (d, 1H), 4.58 (br s, 1H), 5.22 (m,
1H), 6.24 (br s, 2H), 6.61 (d, 1H), 6.79 (d, 1H), 7.36 (t, 1H). LC=MS
154.3 (ESþ), purity 100% (UV and ELSD).

634
R. (S. B.) Rajur et al.
General Method for the Preparation of Compounds 13–16
A solution of aminoindanone 7 (120 mg, 0.736 mmol) in 1,2-dichloro-
ethane (20 mL) was equally distributed into four Teflon screw-capped
vials (15 mL capacity). To each vial, corresponding acid chlorides of
phenylsulfonyl chloride or 4-morpholinecarbonyl chloride (0.21 mmol
each) were added, followed by diisopropylethylamine (DIEA) (75 mL,
0.037 mmol each). After capping, the solutions were shaken on a reaction
block at room temperature overnight. The solutions were washed with
sat. NaHCO3 (2 mL), H2O (2 mL), and dried (Na2SO4) and purified by
column chromatography [90:10 dichloromethane (DCM):EtOAc or
50:50 hexane:EtOAc] to obtain the corresponding products (82–95%)
as semisolids.
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