The synthesis of novel cis-α-substituted-β-aminotetralins

Article abstract of DOI:10.1081/SCC-120021500

Teteralones were converted, in 1 to 3 steps, to α-substituted tetralones. Subsequent reductive amination with ammonium acetate/sodium cyanoborohydride gave the corresponding α-substituted-β-aminotetralins, on a multigram scale, with minimal chromatography for the entire transformation.

Full text of DOI:10.1081/SCC-120021500

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The Synthesis of Novel cis-α-Substituted-β-
aminotetralins
Mark A. Youngman a , Nicole M. Willard a , Scott L. Dax a & James J. McNally a
a Johnson & Johnson Pharmaceutical Research and Development , LLC , Spring House,
Pennsylvania, USA
Published online: 17 Aug 2006.
To cite this article: Mark A. Youngman , Nicole M. Willard , Scott L. Dax & James J. McNally (2003) The Synthesis of Novel
cis-α-Substituted-β-aminotetralins, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 33:13, 2215-2227, DOI: 10.1081/SCC-120021500
To link to this article: http://dx.doi.org/10.1081/SCC-120021500
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 13, pp. 2215–2227, 2003
The Synthesis of Novel
cis-a-Substituted-b-aminotetralins
Mark A. Youngman, Nicole M. Willard, Scott L. Dax,
*
and James J. McNally
Johnson & Johnson Pharmaceutical Research and
Development, LLC, Spring House, Pennsylvania, USA
ABSTRACT
Teteralones were converted, in 1 to 3 steps, to a-substituted
tetralones. Subsequent reductive amination with ammonium
acetate/sodium cyanoborohydride gave the corresponding a-substi-
tuted-b-aminotetralins, on a multigram scale, with minimal chroma-
tography for the entire transformation.
The b-aminotetralin ring system is an important pharmacophoric
element in medicinal chemistry. In essence, b-aminotetralins embody a
ring-constrained version of the ubiquitous phenethylamine moiety and
thus it is not surprising that the b-aminotetralin motif is present in
*Correspondence: James J. McNally, Johnson
& Johnson Pharmaceutical
Research and Development, LLC, Welsh and McKean Roads, Spring House,
PA, 19477, USA; E-mail: jmcnally@prdus.jnj.com.
2215
DOI: 10.1081/SCC-120021500
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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2216
Youngman et al.
well-known modulators of biogenic amine receptors. Hydroxylated
N,N-dialkylated b-aminotetralins are illustrative; 7-hydroxy-2-N,N-
dipropylaminotetralin (7-OH-DPAT) is
a
selective D3 agonist,[1]
8-hydroxy-2-N,N-dipropylaminotetralin is a selective 5-HT1A agonist,[2]
and other structurally-related congeners exhibit a spectrum of CNS activ-
ities.[3] More recently, certain aminotetralins have been reported to antag-
onize the effects of nicotine on acetylcholine receptors.[4] In conjunction
with these areas of research, the preparation of b-aminotetralins substi-
tuted with simple alkyl substituents in the a-position have been described.
We recently reported on novel structurally-diverse aminotetralin-
derived series of neuropeptide Y Y5 receptor antagonists.[5–7] During
the course of this work and as described herein, we investigated and
developed several efficient routes for the preparation of a-substituted-b-
aminotetralins 1 (Fig. 1). Specifically we have been able to install a host
of aryl, heteroaryl, and alkyl a-substituents onto the b-aminotetralin
nucleus. Optimization of our chemical processes leads to moderate
yields of novel a-substituted-b-aminotetralins that can be readily pre-
pared on a multigram scale with minimal chromatographic purification.
Since we desired access to an array of structurally-diverse b-amino-
tetralins, we decided to explore several different synthetic strategies. The
most versatile route is centered upon conversion of b-tetralone to corre-
sponding pyrrolidinyl enamine and subsequent C-alkylation (Sch. 1).
Several b-tetralones were acquired from commercial sources (R1¼H,
6-OMe, 7-OMe) while others needed to be synthesized using the metho-
dology developed by Stjernlof et al.[8] Thus 6-methoxy-b-tetralone (2:
R1¼–OCH3) was treated with an excess of pyrrolidine in a variety of
solvents (methanol, benzene, tetrahydrofuran), to afford enamine 3,
which was used without purification. This material was dissolved in acet-
onitrile and then treated with a benzylic, allylic, or alkyl halide to afford
the desired C-alkylated iminium salt 4. Only reactive alkylating agents
Figure 1.

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cis-a-Substituted-b-aminotetralins
2217
Scheme 1.
underwent efficient reaction; for example, phenethyl halides and simple
alkyl halides formed intractable mixtures of product, starting material
and by-products. Mild acidic hydrolysis liberated the a-substituted-b-
tetralone 5 in high yields (Sch. 1), which in some cases were used as is,
and in other cases were separated from baseline impurities by a quick
flash chromatography.
A variety of reductive amination conditions were explored for the
conversion of the b-teralone, 5, to the corresponding b-tetralin, 1. These
conditions included a variety of primary and secondary amines and
ammonium acetate as well as a selection of reducing agents including
borohydride reagents (sodium, sodium cyano, and sodium triacetoxy)
as well as catalytic hydrogenation conditions.
Most of these conditions gave unacceptable yields and mixtures of
aminotetralin products, however, reductive amination using sodium cya-
noborohydride and ammonium acetate gave the most encouraging
results. Aminotetralins, 1, were formed in modest yields, mixed with
the product resulting from bis-alkylation of ammonia, 6 (Sch. 1).
Optimization of this transformation proved to be successful. Treatment
of the b-tetralone with a large excess of ammonium acetate (15-fold) and
sodium cyanoborohydride (3-fold) in refluxing methanol, produced good
yields of the desired b-aminotetralins. In most cases, treatment of a tetra-
hydrofuran solution of the a-substituted-b-aminotetralin with ethereal
hydrochloric acid allowed for the isolation of the pure cis-isomer as a
stable, crystalline hydrochloride salt. This procedure works well with a
variety of 5-, 6-, 7-, or 8-substituted b-tetralones (Table 1). Both electron-
donating and electron-withdrawing substituents on the aryl portion of
the tetralin ring are well tolerated, as well as a variety of substituents in
the a-position (Tables 1 and 2).

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2218
Youngman et al.
Table 1. Conversion of tetralones, 2, to a-substituted-b-tetralones,
5, and subsequent conversion to a-substituted-b-aminotetralins, 1.
Yield (%)
2 to 5
Yield (%)
5 to 1
R1
R2
H
P
Ph
h0
66
54
86
28
47
58
85
464
61
51
58
51
51
48
32
5-Cl
6-Cl
7-Cl
8-Cl
6-OMe
6-F
Ph
Ph
Ph
Ph
Ph
CH¼CH2
6-OMe
Scheme 2.
Our program required the synthesis of several heterocyclic deriva-
tives, in which the alkylation of the enamine, 3, was difficult to achieve
due to poor yields, the unavailability and/or the instability of the requi-
site alkyl halide. Employing a slightly different synthetic route (Sch. 2)
circumvented these problems. Condensation of the b-tetralone with
the appropriate aldehyde gave, in good yields, a mixture of the
corresponding E and Z unsaturated ketones, 7. Hydrogenation of the
mixture gave the a-substituted-b-tetralone in good yield, which could
then be converted to the desired b-aminotetralin using the conditions
previously described. However, we have found that subjecting the
mixture of E and Z unsaturated ketones to the reductive amination

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cis-a-Substituted-b-aminotetralins
2219
Table 2. Conversion of tetralones, 2, to unsaturated a-substituted-b-tetralones,
7, and subsequent reductive amination to 1.
Yield (%) Yield (%) Yielda (%)
R1
R2
2 to 7
7 to 1
2 to 1
cis/transb
6-OMe 1-trityl-4-imidazolyl
66
—
—
92
79
—
—
52
—
47
47
—
81/19
75/25
83/17
all cis
6-OMe
6-F
6-OMe
3-thienyl
3-pyridyl
C3H5-c
aIn these cases the intermediates, 7, were not isolated, and the crude mixture was
converted to the product, 1.
bRatio of cis vs. trans isomers in the isolated product.
conditions effected both reductions in one step, in essentially the same
yield.
In this manner we synthesized compounds, which were inaccessible
via the methods described in scheme 1, including the compounds listed in
Table 2. Note that in the cases where a (heterocycle)methyl group
occupies the a-position, conversion to the hydrochloride salts formed
amorphous solids. While, in these cases, we were able to isolate mixtures
of cis and trans products, we were unable to isolate the cis-product by
crystallization.
CONCLUSION
Using the chemistry developed and described above, we were able
to prepare gram quantities of novel a-substituted-b-tetralones from
b-tetralones in two or three steps, which in most cases, involved
no chromatographic purifications. These a-substituted-b-tetralones
could be converted to the corresponding a-susbstituted-b-aminotetra-
lins. The cis isomer was the major product, and in most cases could
be isolated by a single crystallization of the hydrochloride salt. These
intermediates can serve as phenethylamine biosteres and have been
used to prepare medicinally important small-molecules such as
neuropeptide Y Y5 antagonists.
EXPERIMENTAL
All compounds were identified by a variety of methods including
nuclear magnetic resonance spectroscopy, mass spectrometry and in

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2220
Youngman et al.
some cases, infrared spectroscopy and elemental analysis. Nuclear mag-
netic resonance (300 MHz NMR) data is reported in parts per million
downfield from tetramethylsilane. Mass spectra data is reported in
mass/charge (m/z) units.
1-Benzyl-3,4-dihydro-1H-naphthalen-2-one (5, R15H, R25Ph).
Under an atmosphere of argon, a solution of b-tetralone (6.33 mL,
47.8 mmol) and pyrrolidine (4.4 mL, 52.6 mmol) in methanol (120 mL)
was stirred at room temperature for 1 h. A colorless crystalline solid
developed, which darkens when exposed to air. The solvent was evapo-
rated in vacuo, and the residue taken up in 1,2-dichloroethane (DCE)
(ꢀ50 mL), and the solvent evaporated in vacuo (to remove excess pyrro-
lidine) to give 1-(3,4-dihydro-naphthalen-2-yl)-pyrrolidine, 3 (R15H), as
a gray solid, 9.66 g (100%). 1H NMR (CDCl3): ꢀ 1.86–1.93 (m, 4H), 2.46
(t, 2H), 2.81 (t, 2H), 3.23–3.27 (m, 4H), 5.12 (s, 1H), 6.78–6.85 (m, 2H),
and 6.97–7.05 (m, 2H). MS: m/z 200 (MHþ). The purity was estimated to
be 95% by HPLC analysis, and the crude product was used in the
subsequent reaction. Enamine 3 (R15H), (9.5 g, 47.7 mmol) was dissolved
in acetonitrile (100 mL), and treated with benzyl bromide (6.25 mL,
52.5 mmol). After stirring the solution for 1 h, the solvent was evaporated
in vacuo, and the residue crystallized from diethyl ether, to give 1-(1-
benzyl-3,4-dihydro-1H-naphthalen-2-ylidene)-pyrrolidinium bromide, 4
1
(R15H, R25Ph), as a pale gray hygroscopic solid. H NMR (DMSO-
d6): ꢀ 1.79–1.86 (m, 1H), 1.90–2.02 (m, H), 2.97–3.10 (m, 3H), 3.18–3.27
(m, 2H), 3.34–3.47 (m, 3H), 3.86–3.97 (m, 1H), 4.00–4.16 (m, 1H),
4.18–4.25 (m, 1H), 4.50 (t, 1H), 6.94 (d, 1H), 7.11–7.17 (m, 3H),
and 7.22–7.43 (m, 5H). MS: m/z 200 (Mþ). Purity of the product
was estimated to be 97% by HPLC. The solid was dissolved in
dichloromethane (70 mL), water (70 mL), methanol (150 mL), and
acetic acid (10 mL). The resultant solution was stirred overnight
at room temperature. An aqueous layer had developed, and was sepa-
rated. The aqueous layer was washed with DCM, and the combined
organic solutions were washed with saturated aqueous sodium bicarbo-
nate and dried over sodium sulfate. The solvent was evaporated and
the residue purified by flash chromatography, using ethyl acetate/hexanes
(5/95% v/v to 10/90) as the eluant, to give the product as an oil,
4.5 g (40%). 1H NMR (CDCl3): ꢀ 2.45–2.63 (m, 3H), 2.78–2.86
(m, 1H), 3.19–3.22 (m, 2H), 3.73 (t, 1H), 6.86–6.93 (m, 3H), and
7.11–7.23 (m, 6H).
cis-1-Benzyl-1,2,3,4-tetrahydro-naphthalen-2-ylamine hydrochloride
(1, R15H, R25Ph). A solution of 5 (R15H, R25Ph) (4.4 g, 18.6 mmol)
and ammonium acetate (21.5 g, 280 mmol) in methanol was treated with
sodium cyanoborohydride (5.84 g, 93 mmol) and heated to reflux for 8 h.

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cis-a-Substituted-b-aminotetralins
2221
The solution was cooled and diluted with water (ꢀ200 mL). Sodium
hydroxide (50%) was added until the solution became basic, and the
product was extracted into DCM (200 mL), dried over sodium sulfate,
and the solvent evaporated in vacuo. The residue was taken up in THF,
and converted at room temperature to the hydrochloride salt by the
addition of ethereal hydrochloride (1 N). The product crystallized from
the solution to give the product as a colorless solid, 3.25 g (64%).
1H NMR(DMSO-d6):
ꢀ 2.02–2.16 (m, 2H), 2.38–2.46 (m, 1H),
2.87–3.07 (m, 2H), 3.17–3.21 (m, 1H), 3.31 (m, 1H), 3.55 (br m, 1H),
6.02 (d, 1H), 6.75 (t, 1H), 7.04–7.12 (m, 4H), 7.20–7.28 (m, 3H), and 8.61
(br s, 2H). MS: m/z 238 (MHþ). HRMS; C17H20N Calcd. for 238.159575
(obs. 238.160666).
5-Chloro-b-tetralone, 2 (R155-Cl), and 7-chloro-b-tetralone, 2 (R157-
Cl). Thionyl chloride (12.7 mL, 174 mmol) was added to a solution of
3-chlorophenyl acetic acid (9.9 g, 58 mmol) in DCE (150 mL), and the
resultant solution was heated to reflux for 4 h. The solvent was evapo-
rated in vacuo to give the corresponding acid chloride, which was used
without purification in the subsequent step. 3-Chlorophenylacetyl chlor-
ide was dissolved in DCM (50 mL) and added via an addition funnel,
over 20 min, to a suspension of aluminum chloride (17 g, 127 mmol) in
DCM (200 mL) at ꢁ10 to 0ꢂC. Ethylene gas was bubbled into the mix-
ture, for 20 min, causing the temperature to rise to ꢀ5ꢂC, then drop back
to ꢁ5ꢂC. Ethylene gas was allowed to bubble slowly through the mixture
for an additional hour. The mixture was treated with ice (200 g). The
organic layer was separated, washed successively with 1 N hydrochloric
acid, saturated aqueous sodium bicarbonate, and dried over magnesium
sulfate. The solvent was evaporated in vacuo, and the individual products
were isolated by silica gel chromatography using 10% ethyl acetate in
hexanes as the eluant to give 5-chloro-b-tetralone, 1.74 g (17%). 1H NMR
(CDCl3): ꢀ 2.57 (t, 2H), 3.24 (t, 2H), 3.59 (s, 2H), 7.04 (d, 1H), 7.16 (t,
1H), and 7.29 (d, 1H). 7-Chloro-b-tetralone, 4.3 g (41%), was isolated as
1
well. H NMR (CDCl3): ꢀ 2.57 (t, 2H), 3.04 (t, 2H), 3.57 (s, 2H), 7.12 (s,
1H), and 7.17 (s, 2H). 6-Chloro-b-tetralone, 8-chloro-b-tetralone, and 6-
fluoro-b-tetralone were synthesized in the same manner from 4-chloro-
phenylacetic acid, 2-chlorophenylacetic acid, and 4-fluorophenylacetic
acid, respectively.
cis-1-Benzyl-5-chloro-1,2,3,4-tetrahydro-naphthalen-2-ylamine hydro-
chloride (1, R155-Cl, R25Ph). Prepared from 2 (R155-Cl) in the same
manner as 1 (R15H). 1H NMR (DMSO-d6): ꢀ 2.11 (m, 2H), 2.44 (t, 1H),
2.73–2.86 (m, 1H), 3.01–3.07 (m, 1H), 3.21 (d, 1H), 3.24 (m, 1H),
3.52–3.63 (m, 1H), 5.96 (d, 1H), 6.81 (t, 1H), 7.10 (d, 1H), 7.17–7.30

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2222
Youngman et al.
(m, 4H), and 8.70 (br s, 2H). MS: m/z 272 (MHþ). HRMS; C17H19ClN
Calcd. for 272.120602 (obs. 272.120501).
cis-1-Benzyl-6-chloro-1,2,3,4-tetrahydro-naphthalen-2-ylamine hydro-
chloride (1, R156-Cl, R25Ph). Prepared from 2 (R156-Cl) in the same
manner as 1 (R15H). 1H NMR (DMSO-d6): ꢀ 2.02 (m, 2H), 2.41 (t, 1H),
2.83–3.10 (m, 2H), 3.18 (d of d, 1H), 3.30 (m, 1H), 3.52–3.56 (m, 1H),
5.98 (d, 1H), 6.52 (d of d, 1H), 7.09 (d, 1H), 7.21–7.29 (m, 3H), and 8.62
(br s, 3H). MS: m/z 272 (MHþ). HRMS; C17H19ClN Calcd. for
272.120602 (obs. 272.121077).
cis-1-Benzyl-7-chloro-1,2,3,4-tetrahydro-naphthalen-2-ylamine hydro-
chloride (1, R157-Cl, R25Ph). Prepared from 2 (R157-Cl) in the same
1
manner as 1 (R15H). H NMR (DMSO-d6): ꢀ 2.02–2.11 (m, 2H), 2.41
(t, 1H), 2.80–2.92 (m, 1H), 2.97–3.05 (m, 1H), 3.20 (d of d, 1H), 3.34
(m, 1H), 3.53–3.63 (m, 1H), 5.90 (s, 1H), 7.09 (d, 2H), 7.14 (s, 2 H),
7.23–7.40 (m, 3H), and 8.63 (br s, 1H). MS: m/z 272 (MHþ). HRMS;
C17H19ClN Calcd. for 272.120602 (obs. 272.121018).
cis-1-Benzyl-8-chloro-1,2,3,4-tetrahydro-naphthalen-2-ylamine hydro-
chloride (1, R1 5 8-Cl, R2 5 Ph). Prepared from 2 (R1 5 8-Cl) in
the same manner as 1 (R1 5 H). 1H NMR (DMSO-d6): ꢀ 2.05–2.13
(m, 2H), 2.53 (m, 1H), 2.86–2.97 (m, 1H), 3.03–3.18 (m, 1H), 3.25 (d
of d, 1H), 3.48–3.58 (m, 1H), 3.81–3.87 (m, 1H), 6.93–6.97 (m, 2H),
7.02–7.07 (m, 1H), 7.12–7.17 (m, 5H), and 8.66 (br s, 3H). MS: m/z
272 (MHþ). HRMS; C17H19ClN Calcd. for 272.120602 (obs.
272.120898).
cis-1-Benzyl-6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylamine hydro-
chloride (1, R1 5 6-OMe, R2 5 Ph). Prepared from 2 (R1 5 6-OMe) in the
same manner as 1 (R1 5 H). 1H NMR (CDCl3): ꢀ 2.05–2.30 (m, 2H),
2.50–2.60 (m, 1H), 2.83–3.03 (m, 3H), 3.30–3.40 (m, 2H), 3.71 (s, 3H),
6.00 (d, 1H), 6.35 (d of d, 1H), 6.60 (d, 1H), 7.02–7.16 (m, 5H), 8.53 (bs,
1H), and 8.96 (bs, 2H). MS: m/z (MHþ) 268. HRMS; C18H22NO Calcd. for
268.170140 (obs. 268.171181).
cis-1-Benzyl-6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamine hydro-
chloride (1, R1 5 6-F, R2 5 Ph). Prepared from 2 (R1 5 6-F) in the same
manner as 1 (R1 5 H). 1H NMR (DMSO-d6): ꢀ 1.96–2.13 (m, 2H), 2.40 (t,
1H), 2.82–3.12 (m, 2H), 3.17 (dd, 1H), 3.28–3.37 (m, 1H), 3.47–3.60 (br
m, 1H), 5.98 (m, 1H), 6.62 (m, 1H), 6.98 (m, 1H), 7.08 (d, 2H), 7.18–7.30
(m, 3H), and 8.64 (br s, 3H). MS: m/z 256 (MHþ). HRMS; C17H19FN
Calcd. for 256.150153 (obs. 256.150147).
cis-1-Allyl-6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylamine hydro-
chloride(1, R156-OMe, R25CH5CH2). Prepared from 2 (R156-OMe) in
the same manner as 1 (R15H), substituting allyl bromide for benzyl
bromide. 1H NMR (DMSO-d6): ꢀ 1.91–2.10 (m, 3H), 2.54 (m, 1H),

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cis-a-Substituted-b-aminotetralins
2223
2.77–2.96 (m, 2H), 3.00–3.06 (m, 1H), 3.42–3.50 (m, 1H), 3.71 (s, 3H),
4.98 (d, 1H), 5.00 (s, 1H), 5.72–5.83 (m, 1H), 6.64 (s, 1H), 6.67 (d, 1H),
6.94 (d, 1H), and 8.4 (br s, 3H). MS: m/z 218 (MHþ). HRMS; C14H20NO
Calcd. for 218.154489 (obs. 218.154932).
cis-6-Methoxy-1-(1-trityl-1H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-
naphthalen-2-ylamine (1, R156-OMe, R251-trityl-4-imidozolyl). 6-
Methoxy-b-tetralone (5.78 g, 32.8 mmol) was dissolved in 125 mL benzene
with stirring. To this solution was added 1-tritylimidazole-4-carboxalde-
hyde (10.03 g, 29.6 mmol) and catalytic piperidine (0.081 mL, 0.82
mmol). This suspension was heated under Dean-Starke conditions
under a nitrogen atmosphere for 22 h. The organics were removed in
vacuo and the residue was purified by chromatography on silica gel
eluted with hexanes to hexanes:ethyl acetate (1:1), to give the product 7
(R156-OMe, R251-trityl-4-imidazolyl), a 1:1 mixture of Z and E isomers,
as a yellow foam.
All of the product from the previous reaction was dissolved in
300 mL ethyl acetate and hydrogenated with 10% palladium on charcoal
(0.739 g) for 24 h at which time an additional amount of the catalyst
(0.753 g) was added and the hydrogenation was continued for another
5 days. The material was then filtered through a pad of celite. The solvent
was evaporated in vacuo and the residue was triturated in 100 mL metha-
nol. The product was collected by filtration, washed with methanol, and
dried under vacuum to give a light yellow powder 10.60 g (66%), 5
(R156-OMe, R251-trityl-4-imidazolyl).
A mixture of tetralone 5 (R156-OMe, R251-trityl-4-imidazolyl) from
the previous reaction (7.53 g, 15.1 mmol) was suspended as a slurry in
250 mL methanol with stirring. Ammonium acetate (17.68 g,
229.4 mmol) and sodium cyanoborohydride (4.77 g, 75.9 mmol) was
added and the mixture was heated to reflux for 2 h. The solvent was
evaporated in vacuo to yield a residue that was subsequently suspended
in 500 mL water and made basic with 100 mL 1 N NaOH. This aqueous
mixture was extracted three times with 250 mL methylene chloride. The
combined organics were washed twice with 100 mL brine and dried over
MgSO4. The solvent was evaporated in vacuo, and the residue was
purified by silica gel chromatography using a gradient of DCM to
DCM/methanol/NH4OH (85/15/1) to give the product, 1 (R156-OMe,
R251-trityl-4-imidazolyl), as an off white powder, 5.93 g, (79%). NMR
(CDCl3): 7.43–7.28 (m, 10H), 7.10 (m, 6H), 6.84 (d, 1H), 6.60 (m, 2H),
6.35 (s, 1H), 3.77 (s, 3H), 3.42–3.17 (m, 2H), 3.02 (m, 1H), 2.89–2.75 (m,
3H), 1.93 (br m, 1H), 1.74 (br m, 1H). MS: m/z 500.2 (MHþ). HPLC
(220 nm): 81% cis, 19% trans. HRMS; C34H34N3O Calcd. for
500.270188 (obs. 500.272296).

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2224
Youngman et al.
cis-6-Methoxy-1-thiophen-3-ylmethyl-1,2,3,4-tetrahydro-naphthalen-2-
ylamine hydrochloride (1, R156-OMe, R253-thienyl). 6-Methoxy-b-
tetralone (12.55 g, 71.2 mmol) was dissolved in 200 mL benzene with
stirring. To this solution was added thiophene-3-carboxaldehyde
(5.6 mL, 63.9 mmol) and catalytic piperidine (0.176 mL, 1.78 mmol).
This solution was heated under Dean-Starke conditions under a nitrogen
atmosphere for 20 h. The solvent was evaporated in vacuo and the residue
was purified by chromatography on silica gel using a gradient of hexanes
to hexanes:ethyl acetate (9:1) to yield the product 5 (R156-OMe, R253-
thienyl) as a 4:1 mixture of Z and E isomers 17 g, (88%) as an orange oil.
All of the product from the previous reaction (17 g, 63 mmol) was
dissolved in 500 mL methanol with stirring. Ammonium acetate (74.81 g,
970.6 mmol) and sodium cyanoborohydride (20.48 g, 325.9 mmol) was
added to the methanol solution and the mixture was heated to reflux for
2.5 h. The solvent was evaporated in vacuo to yield a residue, that was
suspended as a slurry in 500 mL water and then made basic with 50 mL
50% NaOH. This aqueous mixture was extracted three times with 250 mL
methylene chloride. The combined organics were washed twice with
100 mL brine and dried over MgSO4. The crude material was purified
via silica gel chromatography using a gradient of DCM to DCM/MeOH/
NH4OH (90/10/1), to give the aminotetralin as a dark oil. The oil was
dissolved in ethyl ether and treated with an excess of ethereal HCl.
Evaporation of the solvent gave a solid which was triturated in 200 mL
hot ethyl acetate, cooled, filtered, and dried in vacuo to yield the product
HCl salt, 1 (R156-OMe, R253-thienyl), as a powder 10.43 g, (53%). NMR
(DMSO-d6): ꢀ 75% cis, 25% trans, 8.43 (br s, 3H), 7.50 (m, 1H), 7.02 (m,
2H), 6.68 (m, 1H), 6.47 (dd, 1H), 6.18 (d, 1H), 3.67 (s, 3H), 3.58–3.12 (m,
3H), 3.11–2.55 (m, 3H), and 2.12–1.90 (m, 2H). MS: m/z 274.1 (MHþ).
HRMS; C16H19NOS Calcd. for 274.126561 (obs. 274.125985).
cis-6-Fluoro-1-pyridin-3-ylmethyl-1,2,3,4-tetrahydro-naphthalen-2-yla-
mine (1, R156-F, R253-pyridyl). 6-Fluoro-b-tetralone (4.14 g, 25.2 mmol)
was dissolved in 100 mL benzene with stirring. Pyridine-3-carboxalde-
hyde (2.2 mL, 23.3 mmol) and catalytic piperidine (0.062 mL,
0.63 mmol) was added and, the solution was heated under Dean-Starke
conditions under a nitrogen atmosphere for 21 h. The solvent was eva-
porated in vacuo and the residue was purified by chromatography on
silica gel using a gradient of hexanes to ethyl acetate/Et3N(200/1 to
yield the product, 5 (R156-F, R253-pyridyl) as a 4:1 mixture of Z:E
isomers 4.74 g (74%) as a yellow–orange waxy solid. Z isomer (faster
running): NMR (CDCl3): ꢀ 8.62 (d, 1H), 8.51 (dd, 1H), 7.69 (d, 1H),
7.61 (s, 1H), 7.29–7.16 (m, 2H), 7.02 (dd, 1H), 6.76 (dt, 1H), 3.07 (t,
2H), and 2.67 (t, 2H). MS: m/z 254.5 (MHþ). E isomer (slower running):

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cis-a-Substituted-b-aminotetralins
2225
NMR (CDCl3): ꢀ 8.74 (d, 1H), 8.55 (dd, 1H), 8.16 (d, 1H), 7.53 (dd, 1H),
7.32 (dd, 1H), 7.10–6.94 (m, 3H), 3.07 (t, 2H), and 2.70 (t, 2H). MS: m/z
254.5 (MHþ).
The product from the previous reaction, 5 (R156-F, R253-pyridyl),
(4.61 g, 18.2 mmol) was dissolved in 150 mL methanol with stirring.
Ammonium acetate (21.09 g, 273.6 mmol) and sodium cyanoborohydride
(5.97 g, 95.0 mmol) was added to the methanol solution and the mixture
was heated to reflux under nitrogen for 1.5 h. The reaction was evaporated
in vacuo to yield a residue, that was suspended in 300 mL water and then
made basic by the addition of 200 mL 1 N NaOH. This aqueous mixture
was extracted three times with 200 mL methylene chloride. The combined
organics were washed twice with 200 mL brine then extracted four times
with 100 mL 1 N HCl. These acidic extracts were made basic with 500 mL
1 N NaOH solution and then extracted six times with 100 mL methylene
chloride. The combined organics were dried over MgSO4, to yield the
crude aminotetralin. This crude material was subjected to silica gel chro-
matography eluted with a gradient of DCM to DCM/MeOH/NH4OH
(86/14/1.4) to yield the product as its free base as a green oil. The oil
was dissolved in methanol and an excess of ethereal HCl was added.
Evaporation of the solvents yielded a solid, which was dried in vacuo to
yield the product bis HCl salt as a light yellow powder 3.83 g (64%). NMR
(DMSO-d6): 8.83 (d, 2H), 8.73 (br s, 3H), 8.32 (d, 1H), 7.97 (t, 1H), 7.05
(dd, 1H), 6.68 (dt, 1H), 6.11 (dd, 1H), 3.62 (m, 1H), 3.52–3.33 (m, 2H),
3.14–3.02 (m, 1H), 3.01–2.85 (m, 1H), 2.84–2.67 (m, 1H), and 2.18–1.96
(m, 2H). MS: m/z 257.2 (MHþ). HPLC (220 nm): 83% cis, 17% trans.
HRMS; C16H18FN2 Calcd. for 257.145402 (obs. 257.145652).
cis-1-Cyclopropylmethyl-6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-
ylamine (1, R156-OMe, R25c-C3H5). A solution of 6-methoxy tetralone
(2.70 g, 15.3 mmol), cyclopropanecarboxaldehyde (1.03 mL, 13.8 mmol)
and piperidine (38 mL, 0.38 mmol) in benzene (75 mL) was heated to
reflux under Dean-Stark conditions for 17 h. Solvent was evaporated in
vacuo, and the product was preabsorbed onto silica gel, and purified by
flash chromatography using ethyl acetate in hexanes (0–20%) to give the
products, 7 (R1 5 6-OMe, R2 5 c-C3H5) a mixture of E and Z isomers,
2.91 g (92%). MS: m/z 229 (MHþ).
A solution of the tetralone 7 (R1 5 6-OMe, R2 5 c-C3H5) (2.91 g,
12.7 mmol), ammonium acetate (14.7 g, 0.191 mol), and sodium cyano-
borohydride (4.0 g, 63.7 mmol) in methanol (600 mL) was heated at reflux
for 21 h. The reaction mixture was concentrated in vacuo, and DCM
(400 mL) was added. Aqueous sodium hydroxide (1 N) was added with
stirring, until the aqueous layer remained basic. The organic layer was
separated, washed successively with aqueous sodium hydroxide (1 N),

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2226
Youngman et al.
and water, and dried over sodium sulfate. The solvent was evaporated in
vacuo. The product was dissolved in diethyl ether and treated with an
excess of ethereal hydrochloric acid (1 N). The aminotetralin 1 (R156-
OMe, R25c-C3H5) crystallized on standing to give 1.75 g (52%) of a
colorless solid, a single peak by analytical HPLC. NMR(DMSO-d6):
ꢀ ꢁ0.06–0.02 (m, 1H), 0.17–0.28 (m, 1H), 0.42–0.53 (m, 2H), 0.65–0.78
(m, 1H), 1.27–1.55 (m, 2H), 1.88–2.00 (m, 2H), 2.75–3.10 (m, 3H), 3.48
(br m, 1H), 3.70 (s, 3H), 6.67 (s, 1H), 6.70 (d, 1H), 7.13 (d, 1H), and 8.20
(br s, 3H). MS: m/z 232.2 (MHþ). HRMS; C15H22NO Calcd. for
232.171218 (obs. 232.171218).
bis-(1-benzyl-6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-amine (6,
R1-OMe, R25Ph). 6-Methoxy-a-benzyl-b-tetralone (3.64 g, 13.7 mmol)
was dissolved in 700 mL methanol with stirring. Ammonium acetate
(10.67 g, 138 mmol) and sodium cyanoborohydride (4.29 g, 68.3 mmol)
was added to the methanol solution and the mixture was heated at
reflux under nitrogen for 21 h. At this point the ratio of the desired
aminotetralin to the bis-alkylated contaminant based on HPLC analysis
of the crude reaction mixture at 220 nm was 79:21. The solvent was
evaporated in vacuo to yield a residue which was suspended in 600 mL
diethyl ether and washed twice with 225 mL 0.1 N NaOH. The combined
aqueous washes were back-extracted three times with 100 mL diethyl
ether. The combined organics were dried over MgSO4 to yield the
crude aminotetralin. This crude material was dissolved in ethyl ether
and an excess of ethereal HCl was added. Evaporation of this mixture
yielded a solid that was stirred with 25 mL hot ethyl acetate, cooled, and
filtered. The filtrate was found to contain a large portion of the bis-
alkylated contaminant. Treatment of the filtrate with additional ethereal
HCl and MeOH followed by partial evaporation yielded a solid that was
filtered off, dried, and found to be the bis-alkylated HCl salt (0.034 g).
NMR (DMSO-d6): ꢀ 9.16 (br s, 2H), 7.24 (m, 6H), 7.12 (d, 4H), 6.70 (d,
2H), 6.33 (dd, 2H), 5.89 (d, 2H), 3.78 (br, 2H), 3.66 (s, 6H), 3.48 (br d,
2H), 3.30 (m, 2H), 3.17–2.88 (m, 4H), 2.58 (m, 2H), and 2.32 (br, 4H).
MS: m/z 518.9 (MHþ).
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©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
cis-a-Substituted-b-aminotetralins
2227
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Received in the USA November 8, 2002

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