Synthesis and asymmetric resolution of a dopaminergic compound: 2-amino-5-methoxyindane

Article abstract of DOI:10.1016/j.tetasy.2016.04.005

The racemic synthesis and subsequent resolution of 2-amino-5-methoxyindane enantiomers were achieved starting from 5-bromoindan-2-ol in six steps with 38% total yield. The first step involved the substitution of the Br atom by using NaOMe in the presence of CuI to afford 5-methoxyindan-2-ol. The OH group of 5-methoxyindan-2-ol was converted into its mesylate ester, which was converted into the corresponding azide by reaction with sodium azide. The Pd-C-catalyzed hydrogenation of the azide functional group in the presence of CHCl₃, followed by neutralization of the amine hydrochloride salt with NaOH, furnished the rac-2-amino-5-methoxyindane. Next, rac-2-amino-5-methoxyindane was converted into its diastereomeric amide derivatives by reaction with (R)-mandeloyl chloride. The diastereomeric amide mixture was separated by recrystallization to give the (R,S)- and (R,R)-diastereomers. The absolute configuration of the (R,S)-isomer was determined by X-ray crystallography. The hydrolysis of these diastereomers gave (R)- and (S)-2-amino-5-methoxyindane with high enantiopurity.

Full text of DOI:10.1016/j.tetasy.2016.04.005

Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis and asymmetric resolution of a dopaminergic compound:
2-amino-5-methoxyindane
Yusuf Akbaba a,b, Süleyman Göksu a, , Ertan Sß ahin , Hamdullah Kılıç , Hasan Seçen
⇑
a
a
a
a
Ataturk University, Faculty of Sciences, Department of Chemistry, Erzurum, Turkey
b
Erzurum Technical University, Faculty of Science, Department of Basic Sciences, Erzurum, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
The racemic synthesis and subsequent resolution of 2-amino-5-methoxyindane enantiomers were
achieved starting from 5-bromoindan-2-ol in six steps with 38% total yield. The first step involved the
substitution of the Br atom by using NaOMe in the presence of CuI to afford 5-methoxyindan-2-ol. The
OH group of 5-methoxyindan-2-ol was converted into its mesylate ester, which was converted into
the corresponding azide by reaction with sodium azide. The Pd–C-catalyzed hydrogenation of the azide
Received 1 April 2016
Accepted 15 April 2016
Available online xxxx
3
functional group in the presence of CHCl , followed by neutralization of the amine hydrochloride salt
with NaOH, furnished the rac-2-amino-5-methoxyindane. Next, rac-2-amino-5-methoxyindane was con-
verted into its diastereomeric amide derivatives by reaction with (R)-mandeloyl chloride. The diastere-
omeric amide mixture was separated by recrystallization to give the (R,S)- and (R,R)-diastereomers.
The absolute configuration of the (R,S)-isomer was determined by X-ray crystallography. The hydrolysis
of these diastereomers gave (R)- and (S)-2-amino-5-methoxyindane with high enantiopurity.
Ó 2016 Elsevier Ltd. All rights reserved.
1
. Introduction
Dopamine 1 is a hormone-like neurotransmitter that plays an
enantiomers should facilitate structure–activity studies. Herein
we report an alternative synthesis and a new methodology for
the asymmetric resolution of the title compound starting from a
readily available starting material.
important role in central nervous system-related disorders such
as schizophrenia and Parkinson’s disease.1 Many 2-aminotetralin
and 2-aminoindane derivatives have been reported to have
dopamine-like actions.2 Dopamine-like compounds 2-amino-
2
. Results and discussion
3,4
1
1
5
,2,3,4-tetrahydronaphthalene-6,7-diol 2 (6,7-ADTN), 2-amino-
The starting material rac-7 was prepared by the procedure
5
,6
1
3
,2,3,4-tetrahydronaphthalene-5,6-diol
3
(5,6-ADTN),
and
described in the literature. The introduction of an OMe group
into the aromatic ring was accomplished by substitution of the
bromine atom at the phenyl ring with NaOMe in the presence of
-hydroxy-2-(di-n-propylamino)tetralin (5-OH-DPAT) 47 are
potential agonists at dopamine receptors. The drug rotigotine 5,
Ò
1
3–17
commercially known as Neupro , is used in the treatment of
CuI in DMF–MeOH.
Mesylation of (±)-8 with MeSO
2
Cl fol-
Parkinson’s disease as a transdermal patch (Fig. 1).8 Some com-
lowed by substitution with NaN
3
gave azide (±)-9. The structure
pounds derived from the aminoindane 6 moiety have been
of azide 9 was elucidated based on its physical behavior. Elemental
analysis confirmed the theoretical molecular formula of the com-
pound, while the azide functional group was established by the
reported to show analgesic9 and dopaminergic activities,
10,11
as
1
2
well as activities in treating and preventing psychiatric diseases.
To the best of our knowledge, there is only one report in the
literature on the preparation of (S)-6 via the transformation of
ꢀ1
IR spectral absorptions at 2098 cm . The Pd–C-catalyzed hydro-
genation of (±)-9 in CHCl –MeOH gave (±)-10 as a hydrochloride
3
5
-methoxy-1-indanone into the corresponding racemic a-amino
salt, and (±)-10 was converted into free amine (±)-6 by treatment
with NaOH solution and then used in the next step without further
purification or characterization. It is well known that (R)- or (S)-
mandelic acid is an efficient chiral derivatizing agent, which
enables the resolution of racemates into enantiomers, e.g., the res-
alcohol followed by asymmetric resolution with (R)-mandelic acid
and then hydrogenolysis.11
In light of the limited approach to enantiopure amino-indane
skeletons, efficient and adaptable synthetic routes to such com-
pounds are desirable. A convenient synthesis for amino-indane
1
8
olution of racemic dopaminergic aminotetralins.
When we
applied this methodology to (±)-6, we were not able to separate
stereoisomers with high enantiopurity. Berlingozzi et al.19 reported
resolving DL-amino acids by N-acylation with enantiomerically
⇑
Corresponding author. Tel.: +90 442 231 4389; fax: +90 442 231 4109.
E-mail address: sgoksu@atauni.edu.tr (S. Göksu).
http://dx.doi.org/10.1016/j.tetasy.2016.04.005
957-4166/Ó 2016 Elsevier Ltd. All rights reserved.
0
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2
Y. Akbaba et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
NH
2
HO
HO
NH
2
HO
HO
NH
2
HO
OH
1
2
3
N
N
NH
2
S
MeO
OH
OH
4
5
6
Figure 1. Some selected dopamine 1 and dopaminergic compounds 2–6.
pure O-acetylmandeloyl chloride to give separable amides, which
could be hydrolyzed by HCl to give enantiomerically pure amino
acids. In a similar way, the asymmetric resolution of myo-inositol
derivatives with O-acetylmandeloyl chloride via esterification
amines (S)-6 and (R)-6 with high enantiopurity (>93%). Herein
we have reported a convenient method for the asymmetric resolu-
tion of biologically active aminoindanes, which can be used for fur-
ther synthetic purposes.
20
was also reported by Sureshan et al. Due to the important biolog-
ical activities of 2-aminoindane and 2-aminotetralin derivatives,
applying this methodology to the resolution of dopaminergic
amine compounds would be useful for further synthetic and bio-
logical purposes. In this context, (R)-O-acetylmandeloyl chloride
4
4
. Experimental
.1. General
1
9
was first prepared according to the literature procedure. The
All solvents (AR grade) and reagents were purchased from
reaction of racemic (±)-6 with (R)-O-acetylmandeloyl chloride in
Sigma–Aldrich or Merck in the highest purity available. Reactions
were monitored by thin-layer chromatography (TLC) using alu-
minum-backed Merck Silica-Gel 60 F254 plates. Preparative TLC
was performed using the Silica-Gel 60 HF254+366 (Merck). IR spectra
were recorded on a Mattson 1000 FT-IR spectrometer with KBr pel-
lets. NMR spectra were recorded on either a Varian 400 (at
3
the presence of Et N afforded a diastereomeric amide mixture of
1
1a and 11b, which were easily separated by crystallization with-
out racemization with high enantiopurity (diastereomeric ratios
were 97.2:2.8% for 11a and 96.2:3.8% for 11b according to chiral
1
13
HPLC). H and C NMR spectroscopic data of 11a and 11b clearly
1
13
showed that those compounds were stereoisomers of each other.
In particular, H-C(2), H C(1), H C(3), and CH-OAc gave very similar
2 2
4
4
00 MHz for H and 100 MHz for
C) or a Bruker 400 (at
1
13
00 MHz for H and 100 MHz for C) spectrometer in CDCl unless
3
chemical shifts, coupling constants, and spin systems. Therefore,
the assignment of the absolute configuration of one of these iso-
mers, 11a, was determined by X-ray crystallographic analysis.
stated otherwise. All chemical shifts are reported in ppm and J val-
ues are given in Hz. Interchangeable hydrogens or carbons were
assigned the same letter. Optical rotations were measured with a
Bellingham + Stanley ADP220 spectropolarimeter (589 nm) at
The results of this analysis confirmed that the absolute configura-
1
tion of 11a was (R,S), as shown in Figure 2. The comparison of
H
2
5 °C. A polarimetric Chiralyser detector was used to assess the
1
3
and C NMR spectroscopic data, chiral HPLC chromatograms,
sign of the configuration of the diastereomer and enantiomer
formed. Diastereomeric and enantiomeric excesses were deter-
mined by HPLC analysis on a Thermo Spectra Analysis HPLC Sys-
25
25
D
and specific rotations {½
a
ꢁ
¼ ꢀ38 and ½
aꢁ
¼ ꢀ124} of the two
D
isomers 11a and 11b supported that the structure of stereoisomer
1
1b had an (R,R)-configuration.
tem equipped with
a UV detector using a chiral column
The most crucial step of our synthesis was the hydrolysis of
(
Chiralcel OD), n-hexane–i-PrOH (90:10) as the eluent, and a flow
amides (R,S)-11a and (R,R)-11b to give (S)-6 and (R)-6. For the
hydrolysis of the amides, HCl was the most suitable reagent among
the hydrogen halide acids (HX; X = Cl, Br, I) because HBr and HI
might lead to demethylation of ArOMe. For this reason, we used
aqueous HCl to hydrolyze the amides under several conditions,
but we failed to obtain pure amines. Furthermore, hydrolysis of
the amides (R,S)-11a and (R,R)-11b in aqueous KOH in MeOH or
EtOH, at ambient or reflux temperature also failed. Therefore, we
decided to apply harsh reaction conditions such as heating in a
sealed tube. In a sealed tube, heating the amides with KOH in a
rate of 1 mL/min, with the detection performed at a wavelength
of 220 nm. Diastereomeric and enantiomeric excess were deter-
mined directly from the areas under the curve. Compound 7 was
1
3
synthesized according to the literature procedure.
4
.2. 5-Methoxyindan-2-ol 8
Sodium (2.30 g, 100.0 mmol) in small pieces was added to
refluxing MeOH (80 mL) over 1 h under N . A solution of 5-bro-
moindan-2-ol 7 (5.00 g, 23.5 mmol) in freshly distilled DMF
30 mL) was added to this solution. While the reaction mixture
2
solution of EtOH–H O at 130 °C gave the corresponding amines
2
(
2
D
5
25
D
(
S)-6 {½
a
ꢁ
¼ ꢀ7 (c 1, CHCl
3
)} and (R)-6 {½
aꢁ
¼ þ7 (c 1, CHCl
3
)},
was being heated at reflux, CuI (100 mg) was then added. The reac-
tion mixture was heated for 20 h and then cooled to rt. After most
without any racemization (Scheme 1).
of the solvent was removed under reduced pressure, H
and CH Cl (100 mL) were added to the residue and the organic
layer was separated. The organic layer was washed with H
SO . Evaporation of the solvent
2
O (50 mL)
3
. Conclusion
2
2
2
O
In conclusion, the synthesis of (±)-2-amino-5-methoxyindane
hydrochloride 10 has been achieved starting from 5-bromoindan-
-ol in four steps and with 58% overall yield. The asymmetric res-
(3 ꢂ 50 mL) and dried over Na
2
4
and chromatography of the residue on a short silica gel column
2
(30 g) with hexane–EtOAc (9:1) gave 5-methoxyindan-2-ol 8
2
1
olution of the racemic mixture of (±)-6 with (R)-O-acetylmandeloyl
chloride followed by basic hydrolysis afforded the corresponding
(3.10 g, 80%) as a white solid. Mp 75–77 °C. Lit. mp 72–73 °C.
1
H NMR data of compound 8 are in agreement with data given in
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Y. Akbaba et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
3
Figure 2. (a) ORTEP view of 11a showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 40% probability level. The absolute configuration of the
a
a
stereogenic centers in 11a is (R,S). (b) 1D polymeric H-bonding pattern (dashed lines) along the c-axis in the unit cell. N1AHꢃ ꢃ ꢃO2 = 2.902(7) Å, <(N1AHꢃ ꢃ ꢃO2 ) = 170°
[
Symmetry code (a) y ꢀ 1, ꢀx + y, z ꢀ 1/6].
the literature.22 13C NMR (100 MHz, CDCl
): d 159.2 (C), 142.6 (C),
33.0 (C), 125.7 (CH), 112.8 (CH), 110.7 (CH), 73.8 (C2), 55.6 (OMe),
3.0 (CH ), 42.0 (CH ).
H-4), 6.75 (dd, 1H, H-6, J6,7 = 8.3, J4,6 = 2.4 Hz), 4.34 (m, 1H, H-2),
3.79 (s, 3H, OMe), 3.21 (A part of AB, dd, 1H, J = 12.1,
3
2
1
4
3
2
3
2
2
J = 6.6 Hz), 3.17 (A part of AB, dd, 1H, J = 12.1, J = 6.6 Hz), 2.98
2
3
(
B part of AB, dd, 1H, J = 12.1, J = 4.4 Hz), 2.94 (B part of AB, dd,
2
3
13
4
.3. 2-Azido-5-methoxyindane 9
1H, J = 12.1, J = 4.4 Hz). C NMR (100 MHz, CDCl
41.8 (C), 132.3 (C), 125.4 (CH), 113.2 (CH), 110.4 (CH), 62.4
(CH), 55.6 (OMe), 39.5 (CH ), 38.4 (CH ). Anal. calcd for
10 11 3
C H N O: C, 63.48; H, 5.86; N, 22.21; found: C, 63.48; H, 5.88;
3
): d 159.2 (C),
1
To
a
stirred solution of 5-methoxyindan-2-ol
(0.93 g, 9.20 mmol) in CH Cl (30 mL) was
Cl (1.76 g, 15.34 mmol) in CH Cl drop-
8
(1.00 g,
2
2
6
.09 mmol) and NEt
added a solution of MeSO
3
2
2
2
2
2
N, 22.22.
wise at 0 °C over 15 min. The mixture was stirred at rt for 3.5 h.
After filtration of the reaction mixture and removal of the solvent
4.4. (± ±-2-Amino-5-methoxyindane hydrochloride 10
of the filtrate, freshly distilled DMF (20 mL) and NaN
8.4 mmol) were added to the mixture. The reaction mixture was
stirred at 80 °C for 18 h. The reaction mixture was cooled to rt after
which H O (30 mL) and CH Cl (100 mL) were added. The organic
layer was separated and washed with H
O (3 ꢂ 50 mL). The organic
layer was dried over Na SO and CH Cl was evaporated. Chro-
matography of the crude product on a short silica gel column
3
(1.20 g,
1
Into a 100-mL flask were placed Pd–C (50 mg) and 2-azido-5-
methoxyindane 9 (0.90 g, 4.80 mmol) in MeOH (35 mL) and CHCl
(2 mL). A balloon filled with H gas (3 L) was fitted to the flask. The
mixture was deoxygenated by flushing with H and then hydro-
genated at rt for 24 h. The catalyst was removed by filtration.
Recrystallization of the residue from MeOH–Et O gave (±)-2-
amino-5-methoxyindane hydrochloride 10 (0.90 g 95%). Light yel-
3
2
2
2
2
2
2
2
4
2
2
2
(
20 g), eluting with hexane–EtOAc (9:1), gave 2-azido-5-
ꢀ1
9
1
methoxyindane (9) (0.93 g, 80%). Yellow oil. IR (CH
2
CI
2
, cm ):
low crystal. Mp 234–236 °C. Lit. mp 231–234 °C.
(400 MHz, D O): d 7.13 (d, 1H, H-7, J6,7 = 8.3 Hz), 6.83 (br s, 1H,
H-4), 6.75 (d, 1H, H-6, J6,7 = 8.3 Hz), 4.64 (br s, NH + H O), 4.04
(m, 1H, H-2), 3.68 (s, 3H, OMe), 3.25 (A part of AB, dd, 1H,
H NMR
3
1
001, 2942, 2835, 2098, 1611, 1587, 1492, 1465, 1434, 1321,
2
1
305, 1259, 1195, 1144, 1097, 1032, 1004, 928.
H
NMR
3
2
(
400 MHz, CDCl
3
): d 7.14 (d, 1H, H-7, J6,7 = 8.3 Hz), 6.80 (br s, 1H,
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4
Y. Akbaba et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
i
ii
OH
OH
N
3
Br
MeO
MeO
7
8
9
iii
NH
2
iv
NH2.HCl
MeO
MeO
(±) -6
(±)-10
v
O
O
N
N
H
H
MeO
OAc
+
MeO
OAc
(
R,S)-11a
(R,R)-11b
vi
vi
NH
2
NH
2
MeO
MeO
(S)-6
(R)-6
Scheme 1. Synthesis and resolution of (±)-6. (i) NaOMe, CuI (cat.), MeOH–DMF, 100 °C, 20 h, 80%; (ii) MeSO
, Pd–C (cat.), MeOH–CHCl , 24 h, 25 °C, 95%; (iv) 10% NaOH, MeOH, 0–25 °C; 3 h, 95%; (v) (S)-O-acetyl-mandeloyl chloride, Et
10 mol equiv), EtOH–H O (sealed tube), 130 °C, 80%.
2
Cl, Et
3
N, CH
2
Cl
2
, 0–25 °C, 3.5 h, then NaN
3
, DMF, 90 °C, 80%; (iii)
H
(
2
3
3
N, CH Cl , 0–25 °C, 3 h, 82%; (vi) KOH
2
2
2
2
J = 17.6, 3J = 6.6 Hz), 3.21 (A part of AB, dd, 1H, 2J = 17.6,
added
6.13 mmol) in CH
a
solution of O-acetylmandeloyl chloride (1.30 g,
Cl dropwise at 0 °C over 15 min. The mixture
3
2
3
J = 7.0 Hz), 2.88 (B part of AB, dd, 1H, J = 17.6, J = 3.3 Hz), 2.84
2
2
B part of AB, dd, 1H, J = 17.6, 3J = 3.3 Hz). C NMR (100 MHz,
O): d 158.8 (C), 141.2 (C), 132.0 (C), 126.0 (CH), 113.8 (CH),
10.7 (CH), 55.9 (OMe), 52.2 (CH), 37.6 (CH ), 36.7 (CH ). Anal.
calcd for C10 14ClNO: C, 60.15; H, 7.07; N, 7.01; found: C, 60.16;
H, 7.10; N, 7.04.
2
13
was stirred at rt for 3 h. After the filtration of the reaction mixture
and evaporation of the solvent, the residue was filtered on a short
silica gel column (30 g) eluting with hexane–EtOAc (7:3) to give (R,
S)-11a and (R,R)-11b (1.70 g, 82%). The diastereomeric mixture of
(R,S)-11a and (R,R)-11b was separated by crystallization with
EtOAc–hexane (9:1).
(
D
1
2
2
2
H
4
.5. (± ±-2-Amino-5-methoxyindane 6
4
.6.1. (R±-2-(((S±-5-Methoxy-2,3-dihydro-1H-indan-2-yl±amino±-
Amine hydrochloride 10 (1.00 g. 5.0 mmol) was dissolved in
2-oxo-1-phenylethyl acetate (R,S±-11a
2
D
5
MeOH (50 mL) and cooled to 0 °C. To this solution, a solution of
0% aqueous NaOH (10 mL) was added. The reaction mixture was
stirred at rt for 3 h. After evaporation of MeOH, 50 mL of H O were
added and the organic layer was extracted with EtOAc (3 ꢂ 50 mL).
The organic layer was dried (Na SO ) and evaporation of the sol-
vent gave (±)-2-amino-5-methoxyindane 6 (0.78 g, 95%). Colorless
Colorless crystals. Mp 125–127 °C. ½
a
ꢁ
¼ ꢀ38 (c 1, CHCl
3
) de:
): d 7.42–7.33 (m, 5H, Ph-H),
7.10 (d, 1H, H-7, J6,7 = 8.1 Hz), 6.76 (s, 1H, H-4), 6.73 (d, 1H, H-6,
6,7 = 8.1 Hz) 6.53 (br s, 1H, NH), 6.00 (s, 1H, CHOAc), 4.74–4.69
1
1
92.4%. H NMR (400 MHz, CDCl
3
2
J
2
4
(m, 1H, H-2), 3.77 (s, 3H, OMe), 3.29 (m, 2H, H-1 and H-3), 2.78
1
1
2
1
(dd, 1H, H-1 or H-3 , J = 5.1 Hz, J = 16.4 Hz), 2.67 (dd, 1H, H-1
1
1
2
13
oil. H NMR (400 MHz, CDCl
3
): d 7.07 (d, 1H, H-7, J6,7 = 8.2 Hz), 6.75
or H-3 , J = 4.7 Hz, J = 16.4 Hz), 2.14 (s, 3H, CH
3
).
C NMR
(
s, 1H, H-4), 6.69 (dd, 1H, H-6, J6,7 = 8.2, J4,6 = 2.6 Hz), 3.82–3.78 (m,
(100 MHz, CDCl ): d 169.6 (acetate CO), 168.3 (CONH), 159.3 (C),
142.4 (C), 135.7 (C), 132.7 (C(Ph)), 129.2 (C7), 129.0 (2CH (Ph)),
127.6 (2CH (Ph)), 125.5 (CH (Ph)), 113.0 (CH), 110.4 (CH), 75.8
3
2
H, CHN), 3.76 (s, 3H, OMe), 3.14 (A part of AB, dd, 1H, J = 14.7,
3
J = 6.6 Hz), 3.11 (A part of AB, dd, 1H, 2J = 14.7, 3J = 6.6 Hz), 2.81
(
br s, 2H, NH
2
), 2.80 (m, 1H, H-2), 2.68 (B part of AB, dd, 1H,
(CHOAc), 55.6 (OMe), 51.1 (CNH), 40.5 (CH
(CH ). Anal. calcd for C20 : C, 71.37; H, 6.56; N, 3.96; found:
C, 71.39; H, 6.58; N, 3.94.
2 2
), 39.3 (CH ), 21.2
2
3
3
2
J = 14.7, J = 5.1 Hz), 2.64 (B part of AB, dd, 1H, J = 14.7,
3
H21NO
4
13
J = 4.8 Hz). C NMR (100 MHz, CDCl
33.6 (C), 125.5 (CH), 112.7 (CH), 110.6 (CH), 55.6 (OMe), 53.6
CH), 43.0 (CH ), 41.9 (CH ).
3
): d 159.1 (C), 143.1 (C),
1
(
2
2
4.6.2. (R±-2-(((R±-5-Methoxy-2,3-dihydro-1H-indan-2-yl±
amino±-2-oxo-1-phenylethyl acetate (R,R±-11b
2
D
5
4
.6. The synthesis of diastereomeric amide mixture of (R,S±-11a
Colorless crystals mp: 117–119 °C. ½
aꢁ
¼ ꢀ124 (c 1, CHCl
3
) de:
ꢀ1
and (R,R±-11b
94.4%. IR (CH
1
2 2
CI , cm ): 3297, 3059, 2943, 2840, 1742, 1660,
608, 1539, 1460, 1452, 1372, 1326, 1232, 1145, 1097, 1031.
1
H
To a stirred solution of 2-amino-5-methoxyindane 6 (1.00 g,
3
NMR (400 MHz, CDCl ): d 7.42–7.34 (m, 5H, Ph-H), 7.10 (d, 1H,
6
.13 mmol) and Et
3
N (0.62 g, 6.13 mmol) in CH
2
Cl
2
(30 mL) was
H-7 J6,7 = 8.1 Hz), 6.76 (s, 1H, H-4), 6.74 (d, 1H, H-6, J6,7 = 8.1 Hz),
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Y. Akbaba et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
5
6
.34 (d, 1H, NH, J = 7.7 Hz), 6.00 (s, 1H, CHOAc), 4.77–4.73 (m, 1H,
showed no peaks of chemical significance. Crystal data for 11a:
, crystal system, space group: hexagonal, P6 ; (no:
169); unit cell dimensions: a = 10.4608(2), b = 10.4608(2),
H-2), 3.78 (s, 3H, OMe), 3.31–3.22 (m, 2H, H-1 and H-3), 2.75–2.70
C
20
H
21NO
4
1
1
1
13
(
m, 2H, H-1 and H-3 ), 2.12 (s, 3H, CH
3
). C NMR (100 MHz,
3
CDCl
3
): d 169.5 (acetate CO), 168.2 (CONH), 159.3 (C), 142.3 (C),
c = 28.6779(4) Å,
a = 90, b = 90, c = 120; volume: 2717.74(13) Å ;
3
1
(
(
35.7 (C), 132.7 (C(Ph)), 129.2 (CH), 129.0 (2CH (Ph)), 127.6 (2CH
Ph)), 125.6 (CH (Ph)), 113.0 (CH), 110.4 (CH), 75.7 (CHOAc), 55.7
OMe), 51.1 (CNH), 40.5 (CH ), 39.4 (CH ), 21.3 (CH ). Anal. calcd
: C, 71.37; H, 6.56; N, 3.96; found: C, 71.38; H,
Z = 6; calculated density: 1.244 g/cm ; absorption coefficient:
ꢀ1
0.087 mm ; F(000): 1080; h-range for data collection 2.3–26.4°;
2
2
2
3
refinement method: full-matrix least-square on F ; data/parame-
2
for C20
H21NO
4
ters: 2696/227; goodness-of-fit on F : 0.971; final R-indices
6
.59; N, 3.95.
1 2
[I > 2r(I)]: R = 0.080, wR = 0.189; largest diff. peak and hole:
ꢀ3
0
.353 and ꢀ0.281 e Å . CCDC-1008037 contains the supplemen-
4
.7. Hydrolysis of diastereomeric amides (R,S±-11a and (R,R±-11b
A solution of (R)-2-(((S)-5-methoxy-2,3-dihydro-1H-inden-2-
tary crystallographic data for this paper. These data can be
obtained free of charge via http://www.ccdc.cam.ac.uk/conts/re-
trieving.html (or from the CCDC, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk).
yl)amino)-2-oxo-1-phenylethyl acetate (0.2 g, 0.6 mmol) (R,S)-11
in EtOH (20 mL) was added to a solution of 30% KOH (aq)
(
5
10 mL) in a sealed tube The mixture was stirred at 130 °C for
days. After the evaporation of EtOH, 20 mL of H O were added
to the residue and the organic layer was extracted with CH Cl
3 ꢂ 20 mL). The organic layer was dried (Na SO ) and evaporation
of the solvent gave (S)-5-methoxy-2,3-dihydro-1H-inden-2-amine
S)-6 (0.077 g, 80%). Yellow oil.
Acknowledgement
2
2
2
The authors are indebted to the Scientific and Technological
Research Council of Turkey (TÜBITAK, Grant No. 109T/241) for
financial support of this work.
_
(
2
4
(
Supplementary data
4
.7.1. (S±-5-Methoxy-2,3-dihydro-1H-inden-2-amine (S±-6
2
5
1
Colorless oil. ½
d 7.09 (d, 1H, H-7, J6,7 = 8.1 Hz), 6.76 (s, 1H, H-4), 6.70 (dd, 1H, H-6,
6,7 = 8.1, J4,6 = 2.2 Hz), 3.83–3.77 (m, 1H, CHNH ), 3.76 (s, 3H,
a
ꢁ
3 3
¼ ꢀ7 (c 1, CHCl ). H NMR (400 MHz, CDCl ):
D
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2016.04.
J
2
0
05.
2
3
OMe), 3.14 (A part of AB, dd, 1H, J = 14.7, J = 6.6 Hz), 3.10 (A part
of AB, dd, 1H, J = 14.7, 3J = 6.6 Hz), 2.65 (B part of AB, dd, 1H,
2
References
2
J = 14.7, 3J = 5.1 Hz), 2.61 (B part of AB, dd, 1H, J = 14.7,
2
3
13
J = 4.8 Hz), 1.8 (br s, 2H, NH
2
). C NMR (100 MHz, CDCl
3
): d
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3.
4.
5.
Cannon, J. G. Prog. Drug Res. 1985, 29, 303–414.
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5
59.0 (C), 143.5 (C), 133.9 (C), 125.5 (CH), 112.5 (CH), 110.6 (CH),
5.6 (OMe), 53.8 (CH), 43.6 (CH ), 42.5 (CH ).
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2
3
67.
4
.7.2. (R±-5-Methoxy-2,3-dihydro-1H-inden-2-amine (R±-6
6
.
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1
Colorless oil. ½
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a
ꢁ
3 3
¼ þ7 (c 1, CHCl ). H NMR (400 MHz, CDCl ):
D
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2
3
OMe), 3.15 (A part of AB, dd, 1H, J = 14.7, J = 6.6 Hz), 3.10 (A part
of AB, dd, 1H, J = 14.7, 3J = 6.6 Hz), 2.65 (B part of AB, dd, 1H,
2
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2
J = 14.7, 3J = 5.1 Hz), 2.61 (B part of AB, dd, 1H, 2J = 14.7,
3
13
2 3
J = 4.8 Hz), 1.45 (br s, 2H, NH ). C NMR (100 MHz, CDCl ): d
1
5
59.0 (C), 143.5 (C), 134.0 (C), 125.5 (CH), 112.5 (CH), 110.6 (CH),
5.6 (OMe), 53.8 (CH), 43.7 (CH ), 42.6 (CH ).
2 2
2
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2. Gillen, K. J.; Gillespie, J.; Jamieson, C.; MacLean, J. K. F.; Moir, E. M.; Rankovic, Z.
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.8. Crystallography
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1
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pound 11a was used for data collection on a four-circle Rigaku R-
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1
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k = 0.71073 Å) and oscillation scan technique with
a
D
radiation
w = 5° for
(
2002187875 A 20020705.
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were determined by the least-squares methods on the basis of all
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2
2
0. Sureshan, K. M.; Kiyosawa, Y.; Han, F.; Hyodo, S.; Uno, Y.; Watanabe, Y.
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2
2
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2
3
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5
2
2
4
SHELXS-97 and refined by a full-matrix least-squares procedure
2
4
1
using SHELXL-97. H atoms were positioned geometrically and
refined using a riding model. The final difference Fourier maps
Please cite this article in press as: Akbaba, Y.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.04.005