Synthesis of optically pure 1-amino-3-aryl indanes exemplified by (+)-indatraline

Article abstract of DOI:10.1055/s-0030-1260823

A versatile procedure for the synthesis of optically pure 1-amino-3-aryl indanes is presented, exemplified by the synthesis of the triple uptake inhibitor (+)-indatraline (1). Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1260823

LETTER
1753
Synthesis of Optically Pure 1-Amino-3-aryl Indanes Exemplified by
(+)-Indatraline
Synthesisof
O
ptic
i
allyPu
e
l
-3-aryl
s
Indanes Grøn Nørager,a,b Linda Luise Reeh Lorentz-Petersen,a,c Lars Ole Lyngsø,d Jan Kehler,a Karsten Juhl*a
a
Discovery Chemistry and DMPK, H., Lundbeck A/S, Otilliavej 9, 2500 Valby, Denmark
Fax +45(364)38237; E-mail: kaju@lundbeck.com
b
c
d
Department of Chemistry, Aarhus University, Langelandsgade 140, 8000 Aarhus C, Denmark
Department of Chemistry, Technical University of Denmark, Bldg. 201, Kemitorvet, 2800 Kgs. Lyngby, Denmark
Process Research, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark
Received 25 February 2011
which we envisioned could act as a handle for an enzy-
matic resolution, thus introducing enantioselectivity to
our synthesis. The cis-indanol 2 would be obtained by a
diastereoselective ketone reduction of the racemic 3-aryl-
1-indanone 3. This intermediate would be synthesized by
a rhodium-catalyzed conjugate addition of an arylboronic
acid to 1-indenone (4), which could be obtained from the
commercially available 1-indanone.
Abstract: A versatile procedure for the synthesis of optically pure
1-amino-3-aryl indanes is presented, exemplified by the synthesis
of the triple uptake inhibitor (+)-indatraline (1).
Key words: indane, indatraline, enzymatic resolution, conjugate
addition, rhodium
The 1-aryl indane motif is a common scaffold, which is
found in several compounds of interest to medicinal
chemists. The scaffold has been used in drug candidates
aiming at modulating a diverse group of target structures,
e.g. the dopamine,1 serotonin2 and neurokinin-2 recep-
tors,3 as well as the monoamine transporters.4 Among
these drug candidates are (+)-indatraline (Lu 19-005, 1) a
potent reuptake inhibitor of serotonin, noradrenalin and
dopamine that has been investigated as a potential drug
for the treatment of major depressive disorder and cocaine
addiction.4,5
NHMe
OH
Ar
Ar
2
(+)-indatraline (1)
1. reduction
2. enzymatic
resolution
O
O
In this letter, we report a method for the synthesis of opti-
cally pure 1-amino-3-aryl indanes, illustrated by the syn-
thesis of (+)-indatraline (1). Earlier syntheses of this
scaffold have primarily been based on assembling of the
indane motif by cyclization reactions, e.g. by intramolec-
ular electrophilic aromatic substitution.5,6 These cycliza-
tion reactions have required harsh, strongly acidic
conditions resulting in limited scope tolerance, especially
of substituents at the C4–C7 positions. Heck cross-cou-
pling,7 Claisen-type cyclization8and iodide(III)-mediated
ring contraction9 have also been applied in the syntheses
of 1-amino-3-aryl indanes. To expand the scope of toler-
ated substrates we set out to develop a mild procedure that
would also allow easy variation of the 3-aryl moiety. We
envisaged that this could be achieved by starting from 1-
indanone, where the bicyclic moiety is already formed,
thus circumventing the scope limitations associated with
the ring-closing reactions. Related approaches have previ-
ously been reported by Itoh et al.8 and Cossy et al.10
Ar
4
( )-3
Scheme 1 Retrosynthetic analysis of (+)-indatraline (1)
The starting point of our synthesis was 3-bromo-1-in-
danone (5), which can be prepared from 1-indanone by a
Wohl–Ziegler bromination.11The first steps were an elim-
ination reaction followed by a conjugate addition. Addi-
tion of one equivalent of triethylamine in THF at room
temperature led to complete elimination of hydrogen bro-
mide within an hour. The elimination occurred so cleanly
that the crude 1-indenone (4) could be used directly in the
next step after filtration and evaporation of solvent.
Avoidance of purification of the 1-indenone was desired,
as 1-indenones are generally unstable, readily polymeriz-
ing.12
Inspired by the work of Miyaura and Hayashi,13 we devel-
oped a method for transformation of the enone 4 into the
3-aryl-1-indanone 3 using a rhodium-catalyzed conjugate
addition of 3,4-dichlorophenylboronic acid. Enone 4 was
treated with a mixture of 3 mol% of bis(norborna-
diene)rhodium(I) tetrafluoroborate and racemic BINAP,
one equivalent of triethylamine and two equivalents of
arylboronic acid in 1,4-dioxane–water (9:1). Heating at
Scheme 1 outlines our approach to the synthesis of (+)-
indatraline (1). Functional group interconversion of the
amine to the alcohol would result in a secondary alcohol,
SYNLETT 2011, No. 12, pp 1753–1755
x
x
.x
x
.2
0
1
1
Advanced online publication: 28.06.2011
DOI: 10.1055/s-0030-1260823; Art ID: D06511ST
© Georg Thieme Verlag Stuttgart · New York

1754
N. G. Nørager et al.
LETTER
100 °C for four hours resulted in 74% of 3 over the two chromatographic separation. Acylation in diisopropyl
steps. An excess of boronic acid was required to counter ether at room temperature overnight resulted in a 45%
decomposition of the aryl substrate via protonolysis of ei- yield of the non-acylated S-enantiomer with an enantio-
ther the boron–phenyl or rhodium–phenyl bonds.13a To meric excess of more than 99%.
explore the scope of boronic acids tolerated by this proce-
dure, a simple phenylboronic acid, as well as an electron-
O
O
O
rich 4-methoxyphenylboronic acid, were screened. They
were both tolerated, albeit in lower yields than the 3,4-
dichlorophenylboronic acid (Table 1). In our initial syn-
thetic strategy, we envisioned that this conjugate addition
could be made enantioselective if catalyzed using an
enantiopure chiral catalyst. A related conjugate addition
of a boronic acid to an inden-1-one catalyzed by a chiral
rhodium(I)-chiraphos complex has previously been re-
ported to proceed in 27% yield with an enantiomeric ex-
cess of 8%.8 Despite a substantial screening of chiral
ligands only low enantioselectivity was obtained. The best
selectivity was observed when (R)-BINAP was used, as
shown in Table 1. Thus, we decided to introduce enantio-
selectivity later in the synthesis instead.
O
Novozym 435®
i-Pr2O, r.t., o.n.
45% yield, 99% ee
Ar
Ar
2
( )-2
Scheme 2 Enzymatic resolution of ( )-2
The synthesis of (+)-indatraline (1), was concluded by a
methylamine substitution of the hydroxyl group with ste-
reoinversion of the benzylic C1-centre. To obtain com-
plete stereoinversion an azide substitution–reductive
alkylation procedure was tested. The hydroxyl group was
activated as the corresponding phosphate moiety and sub-
stituted by an in situ generated azide nucleophile follow-
ing a protocol reported by Thompson et al.16 The azide
was subsequently reductively alkylated in a one-pot reac-
tion using dimethylboron bromide.17 A NOESY experi-
ment verified that the pure trans configuration had been
formed. However, a moderate yield of 60% for the two
steps was obtained.
Table 1 Exploration of the Scope of Tolerated Boronic Acids
ArB(OH)2 (2 equiv)
[Rh(ndb)2] BF (3 mol%)
( )-BINAP (3 mol%)
O
O
dioxane–H2O (9:1)
Et3N, 100 °C, 4 h
Ar
4
Indanone
3a
( )-3
Thus, a simple one-pot mesylation–nucleophilic substitu-
tion procedure developed by Froimowitz et al. was tested
as well.5,6c The alcohol was mesylated with three equiva-
lents of mesyl chloride and triethylamine in THF at –20
°C. After one hour the mesylated intermediate was treated
with a large excess (20 equivalents) of methylamine at
–20 °C. Reaction overnight led to a 97:3 (trans/cis) mix-
ture of the 1-amino-3-aryl indane 1. Subsequent separa-
tion of the diastereomers by crystallization in ethyl
acetate–heptane resulted in an 80% yield of the pure trans
(+)-indatraline (1). To verify the absolute configuration of
the product it was recrystallized as the L-(+)-tartaric acid
salt from diethyl ether–methanol; mp 159–162 °C (lit. mp
Ar
Yielda
ee of (R)-BINAPb
Ph
43%
74%
55%
34%
25%
22%
3b
3,4-Cl2C6H3
3-OMeC6H4
3c
a Yield of isolated product with ( )-BINAP as ligand.
b Enantiomeric excess from separate experiment with (R)-BINAP as
ligand. Enantiomeric excess was measured using chiral HPLC.
Indanone 3 was subsequently diastereoselectively re-
duced with two equivalents of sodium borohydride in
THF–water (10:1) at –15 °C overnight. The cis isomer of
the 3-aryl-1-indanol 2 was formed with a diastereomeric
excess of 92%. The two diastereomers could be separated
by flash chromatography resulting in pure cis-2 in 91%
yield. The cis configuration was verified using NOESY
spectroscopy.
159–162 °C);6a specific rotation: [a]D +29.5 (c = 1.0,
20
MeOH) {lit. [a]D20 +33.5 (c = 1.0, MeOH)}.6a
In conclusion we have synthesized enantiopure (+)-inda-
traline (1), in a yield of 24% over five steps starting from
3-bromo-1-indanone (Scheme 3). The two key steps of
the synthesis were a rhodium-catalyzed conjugate addi-
tion of an arylboronic acid, and an enzymatic resolution
introducing enantioselectivity. The main advantage com-
pared to earlier reported syntheses is avoidance of the
scope limitations associated with the ring-closing reac-
tions. Mild conditions and reagents were used throughout
the synthesis, ensuring a broad scope of tolerated sub-
strates. Additionally, the developed conjugate addition
was shown to tolerate simple phenyl groups as well as
electron-poor and electron-rich aryl groups. The enzymat-
ic resolution generates pure samples of both enantiomers,
thus synthesis of both the (+)- and (–)-enantiomers is pos-
sible using this procedure.
At this point enantioselectivity was introduced to the syn-
thesis by enzymatic resolution of 2 (Scheme 2).14 No-
vozym 435®, which is a lipase capable of enantioselective
acylation of secondary alcohols, was used. The Kazlaus-
kas’ Model, which states that the lipase distinguishes be-
tween the pair of enantiomers on basis of the relative size
of the aliphatic substituents, was used to predict the selec-
tivity of the acylation.15 Thus, in this case the R-enantio-
mer would be acylated. Vinyl butyrate was chosen as the
acylation reagent, as the aliphatic chain would incorporate
a significant structural difference between the original and
the acylated enantiomer, thus facilitating the following
Synlett 2011, No. 12, 1753–1755 © Thieme Stuttgart · New York

LETTER
Synthesis of Optically Pure 1-Amino-3-aryl Indanes
1755
(3) Guillon, J.; Dallemagne, P.; Léger, J.-M.; Sopkova, J.; Bovy,
P. R.; Jarry, C.; Rault, S. Bioorg. Med. Chem. 2002, 10,
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O
(4) Hyttel, K.; Larsen, J.-J. J. Neurochem. 1985, 44, 1615.
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Ar =
Br
Cl
5
Cl
1. Et3N
2. ArB(OH)2
[Rh(ndb)2] BF4
( )-BINAP
74% yield
O
OH
Ar
NaBH4
91% yield
Ar
( )-3
( )-2
(8) Itoh, T.; Mase, T.; Nishikata, T.; Iyama, T.; Tachikawa, H.;
Kobayashi, Y.; Yamamotod, Y.; Miyaurad, N. Tetrahedron
2006, 62, 9610.
vinyl butyrate
Novozym 435®
45% yield
99% ee
(9) Silva, L. F. Jr.; Siqueira, F. A.; Pedrozo, E. C.; Vieira, F. Y.
M.; Doriguetto, A. C. Org. Lett. 2007, 9, 1433.
(10) Cossy, J.; Belotti, D.; Maguer, A. Synlett 2003, 1515.
(11) Podgorsek, A.; Stavber, S.; Zupan, M.; Iskra, J. Tetrahedron
Lett. 2006, 47, 1097.
NHMe
Ar
OH
1. MsCl, Et3N
2. MeNH2
80% yield
Ar
2
(12) Marvel, C. S.; Hinman, C. W. J. Am. Chem. Soc. 1954, 76,
(+)-indatraline (1)
5435.
(13) See for example: (a) Takaya, Y.; Ogasawara, M.; Hayashi,
T. J. Am. Chem. Soc. 1998, 120, 5579. (b) Hayashi, T.;
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Soc. 2002, 124, 5052. (c) Itooka, R.; Iguchi, Y.; Miyaura, N.
J. Org. Chem. 2003, 68, 6000.
Scheme 3 The complete synthetic pathway
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
(14) Ghanem, A. Tetrahedron 2007, 63, 1721; and references
therein.
(15) See for example: (a) Kazlauskas, R. J.; Weissfloch, A. N. E.;
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Gupta, A. K. J. Am. Chem. Soc. 1994, 116, 3180.
(16) Thompson, A. S.; Humphrey, G. R.; DeMarco, A. M.;
Mathre, D. J.; Grabowski, E. J. J. J. Org. Chem. 1993, 58,
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Synlett 2011, No. 12, 1753–1755 © Thieme Stuttgart · New York

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