An expeditious preparation of E-2-amino-5-hydroxyadamantane and its Z-isomer

Article abstract of DOI:10.1016/j.tetlet.2006.09.056

Reductive amination of 5-hydroxy-2-adamantanone with S-α-methylbenzylamine using 5% Rh-C as the catalyst in the presence of Al(iOPr)₃ gave a 3:1 mixture of the E- and Z-5-hydroxy-adamantane-1-phenethylamines. Choice of catalyst, concentration,

Full text of DOI:10.1016/j.tetlet.2006.09.056

Tetrahedron Letters 47 (2006) 8063–8067
An expeditious preparation of
E-2-amino-5-hydroxyadamantane and its Z-isomer
Libuse Jaroskova, Louis Van der Veken, Paul de Belser, Gaston Diels,
Alex de Groot and Joannes T. M. Linders*
Department of Medicinal Chemistry, Johnson and Johnson Pharmaceutical Research and Development,
a Division of Janssen Pharmaceutica, Turnhoutseweg 30, B-2340 Beerse, Belgium
Received 29 August 2006; revised 8 September 2006; accepted 12 September 2006
Available online 2 October 2006
´
´
Dedicated to Professor Alajos Kalman on the occasion of his 70th birthday
Abstract—Reductive amination of 5-hydroxy-2-adamantanone with S-a-methylbenzylamine using 5% Rh–C as the catalyst in the
presence of Al(iOPr)3 gave a 3:1 mixture of the E- and Z-5-hydroxy-adamantane-1-phenethylamines. Choice of catalyst, concentra-
tion, solvent and the presence of the hydroxyl group on the adamantane influenced the stereoselectivity of the amination reaction.
The desired E-isomer could be isolated by fractional crystallization from diisopropyl ether. Debenzylation gave the elusive E-2-
amino-5-hydroxyadamantane in a 45% overall yield.
ꢀ 2006 Elsevier Ltd. All rights reserved.
There is a growing number of biologically active com-
pounds containing an adamantane moiety. 1-Amino-
adamantane (amantadine) and its 3,5-dimethyl analogue
memantine are NMDA antagonists with efficacy in pre-
clinical animal models for Parkinson’s and Alzheimer’s
disease. Memantine has been approved for the treatment
of Alzheimer’s patients.1 In addition, amantadine,
memantine and related aminoadamantanes have a
strong activity against influenza A.2 Adamantane
structures are also found in RXR antagonists such as
adipalene,3 squalene synthetase inhibitors,4 and kinase
inhibitors such as adaphostin5 and P2X7 receptor anta-
gonists.6 Recently, Novartis and BMS progressed their
DPPIV inhibitors vildagliptin7 and saxagliptin,8 which
contain a 3-hydroxyadamantane moiety, to advanced
clinical trials. The 3-hydroxyl group was introduced in
the starting adamantane by a simple oxidation of the
1-substituted adamantanes with potassium permanga-
nate8 or nitric acid.9
literature did not reveal any practical procedure for
the preparation of 1 in preparative useful yields
(Fig. 1). It even appeared that neither 1 nor its Z-isomer
2 had been obtained in a pure form. Gonzalez-Nunez
et al.11,12 reported the oxidation of 2-aminoadamantane
and derivatives with methyl(trifluoromethyl) dioxirane
to give a 1:1 mixtures of 1 and 2, but they were unable
to separate the isomers, even as the trifluoroacetamides.
Nitration of 2-aminoadamantane gave a mixture of 1
and 2 in a low yield, after hydrolysis of the nitrate
esters.13 Geluk and Schlattmann14 reported the LiAlH4
reduction of the oxime of commercially available 5-hy-
droxy-2-adamantanone (which can be prepared by the
oxidation of 2-adamantanone with nitric acid15 or
chromic acid16) to give a 1:1 ratio of 1 and 2, which
could not be separated at this stage. Similarly, we found
that hydrogenation of the oxime or methoxime of 5-hy-
droxy-2-adamantanone over Raney-nickel also gave a
We needed a quick access to E-2-amino-5-hydroxyad-
amantane 1,10 but an exhaustive review of the existing
3
3
2
2
H2N
H2N
4
5
4
5
10
10
1
1
OH
OH
9
6
9
6
7
7
8
8
Keywords: Reductive amination; Stereoselective; Heterogeneous cata-
lysis; Adamantane; Stereoisomers.
1 E-2-amino-5-hydroxyadamantane 2 Z-2-amino-5-hydroxyadamantane
*
Corresponding author. Tel.: +32 14602117; fax: +32 14605344;
e-mail: jlinders@prdbe.jnj.com
Figure 1.
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.056

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L. Jaroskova et al. / Tetrahedron Letters 47 (2006) 8063–8067
1:1 mixture of 1 and 2.17 Lavrova et al. reported the
Leuckart reaction of 5-hydroxy-2-adamantanone with
formamide and formic acid to give the same 1:1 mixture
of 1 and 2.18 Some years ago, Johnson et al.19 described
the biooxidation of N-benzoyl-2-aminoadamantane to
afford the elusive E-isomer in a 78% yield as a crystalline
substance. According to our knowledge, this is the only
method to prepare 1 albeit as its N-benzoyl protected
form.
We here report the preparation of 1 and 2 in the pure
form for the first time.
LeNoble20,21 and others22 have shown that stereoselec-
tive reactions on 5-substituted adamantan-2-ones are
possible with different degrees of E/Z-selectivity depend-
ing on the 5-substituent. We reasoned that hydrogena-
tion of the imines of 5-hydroxy-2-adamantanone and
benzylamines under carefully controlled conditions
might lead to an improved ratio of the E- and Z-iso-
mers, whereby the hydroxyl group would direct the
stereoselectivity of the reduction, either through com-
plexation with the catalyst surface or by its hyperconju-
gation effect.20–22 Furthermore, the presence of the N-
benzyl substituent would offer the possibility for an easy
HPLC separation, after which it could be removed by a
simple hydrogenation.
O
NH
HN
H
H
iii
+
OH
OH
OH
Indeed, hydrogenation of imine 4 of 5-hydroxy-2-ada-
mantanone and L-S-a-methylbenzylamine over Pt–C
gave a mixture of the E- and Z-isomers in a 3.5:1 ratio
in a quantitative yield (Scheme 1, Table 1). Separation
by preparative HPLC23 or over silicagel gave the pure
isomers 5 and 6, which were debenzylated under stan-
dard conditions to give 1 and 2 in a quantitative yield.
Isomers 5 and 6 were identified as E and Z, respectively,
based upon the different NOE correlations of the C2-
proton with the neighbouring protons of 4 and 9 for 5
and of 8 and 10 in the case of 6. The 2D assigned carbon
spectra24 were consistent with the extensive available
data on 13C NMR spectra of 2,5-disubstituted adaman-
3
5
6
i
ii
iv
iv
N
H
NH2
OH
H2N
H
OH
OH
4
1 E-isomer
2 Z-isomer
1
tanes.11,25 In the H NMR spectra of 5 and 6, the posi-
tion of the C2-proton (2.59 ppm E-isomer, 2.45 ppm
Z-isomer) can be used as an easy diagnostic for the
identification of the E- and Z-isomers.
Scheme 1. Reagents and conditions: (i) S-a-methylbenzylamine,
EtOH, reflux; (ii) H2, 5% Rh–C, toluene, 50 ꢁC; (iii) S-a-methylbenz-
ylamine, H2, 5% Rh–C, toluene, 50 ꢁC; (iv) H2, 10% Pd–C, MeOH.
Table 1. Reduction of preformed imines
R
R
R
N
Reducing agent
Conditions
NH
HN
H
H
+
OH
OH
OH
Z
E
Entry
R
Red. agent
Solvent
Scale/concn (mmol/M)
Ratio E/Za
1
2
3
4
5
6
7
8
9
S-a-Methyl
S-a-Methyl
S-a-Methyl
S-a-Methyl
R-a-Hydroxymethyl
H
S-a-Methyl
S-a-Methyl
S-a-Methyl
R-a-Hydroxymethyl
H2/5% Pt–C
H2/5% Pt–C
H2/RaNi
H2/5% Rh–C
H2/5% Pt–C
H2/5% Pt–C
BH3
NaBH4/HOAc
NaBH4/HOAc
NaBH4/HOAc
THF
THF
MeOH
THF
THF
THF
THF
THF
THF
THF
1/0.025
56/0.15
1/0.025
14/0.28
7/0.14
10/0.25
1/0.025
1/0.025
1/0.025
1/0.025
3.5:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
10
a Calculated from the integration of the signals for H-2.

L. Jaroskova et al. / Tetrahedron Letters 47 (2006) 8063–8067
8065
Table 2. Reductive amination of 5-hydroxy-2-adamantanone with
different benzylamines using H2/5% Rh–C (1.6 mol %) and Al(iOPr)3.
(16 h, 50 ꢁC)
cantly less selective (entries 7 and 8). Apparently, the
presence of sterically demanding groups is determining
for the E/Z selectivity of the reduction. With tert-butyl-
amine a 3.2/1 mixture of E and Z was obtained (entry
9), but dimethylphenylamine (cumylamine) did not form
the imine, even after heating for extended periods of
time.
R
R
O
amine
NH
HN
H
H
+
Conditions
Toluene is clearly superior to ethereal or polar solvents,
which may complex with the catalyst surface, thereby
decreasing the selectivity (entries 11–14). Also, increas-
ing the concentration lowered the selectivity (entry 2),
but increasing the amount of catalyst to 5 mol %
increased the selectivity for the E-isomer to 4:1 (entry
5). Increasing the amount of amine to 1.8 or 3 equiv also
improved the selectivity to about 4:1 (data not shown).
The importance of the hydroxyl group in directing the
course of hydrogenation is clearly seen in entries 15–
17. Replacement of the hydroxyl group with bromine,
fluorine or benzyloxy essentially removed the stereo-
selectivity of hydrogenation.26
OH
OH
OH
3
E
Z
Entry Amine
Solvent Scale/concn Ratio
(mmol/M)
E/Za
1
2
3
4
5
6
7
8
9
S-a-Methylbenzyl
Toluene 10/0.2
3:1
2:1
3.3:1
3.3:1
4:1b
3.3:1
2.3:1
2.7:1
3.2:1
No
reaction
2.2:1
1.3:1
1:1
1:1c
1.1:1
1.4:1
1:1
S-a-Methylbenzyl
S-a-Methylbenzyl
R-a-Methylbenzyl
S-a-Methylbenzyl
R/S-a-Methylbenzyl
1-Methylnaphthyl
Benzyl
Toluene 90/0.6
Toluene 3/0.075
Toluene 3/0.075
Toluene 10/0.2
Toluene 3/0.075
Toluene 3/0.075
Toluene 3/0.075
Toluene 3/0.075
Toluene 3/0.075
t-Butyl
Dimethylbenzyl
Upon scaling up to 0.2 mol, under the optimized condi-
tions, reaction of 5-hydroxyadamantan-2-one with S-a-
methylbenzylamine in the presence of Al(OiPr)3 gave a
3:1 mixture of the adamantyl benzylamines 5 and 6.
Crystallization from diisopropyl ether gave pure benzyl-
amine 5 in a 48% yield. After debenzylation, the desired
E-2-amino-5-hydroxy-adamantane 1 was obtained in a
45% yield from 5-hydroxy-2-adamantanone 3.27 The
mother liquor obtained after crystallization of 5 con-
sisted of an approximately 1:1 mixture of 5 and 6. De-
10
11
12
13
14
15
16
17
S-a-Methylbenzyl
S-a-Methylbenzyl
S-a-Methylbenzyl
S-a-Methylbenzyl
S-a-Methylbenzyl/5-Br Toluene 3/0.075
S-a-Methylbenzyl/5-F Toluene 3/0.075
DIPE
THF
iPrOH
MeOH
3/0.075
3/0.075
3/0.075
3/0.075
S-a-Methylbenzyl/
5-OBn
Toluene 3/0.075
a Calculated from the integration of the signals at H-2.
b 5 mol % of catalyst.
c Complete conversion after 5 days.
benzylation gave the mixture of amines 1 and 2, which
28,29
was oxidized with KMnO4
to give 5-hydroxy-2-
adamantanone.30
In conclusion, 5-hydroxy-2-adamantanone 3 can be
reductively aminated with good stereoselectivity, giving
access to the elusive E- and Z-2-amino-5-hydroxyada-
mantanes 1 and 2.
Besides experiencing the problem of overreducing the
phenyl ring, it proved to be impossible to increase the
scale and concentration without losing selectivity com-
pletely (entry 2). Hydrogenation of 4 over Raney-Ni
or rhodium–C gave a 1:1 mixture of 1 and 2 (entries 3
and 4). Also, hydrogenation of the imines derived from
hydroxymethyl benzylamine and benzylamine gave a
complete loss of selectivity (entries 5 and 6). Reduction
of the imines using borane or sodium borohydride/
acetic acid in THF afforded a 1:1 mixture of both
isomers (entries 7–10).
Acknowledgement
We would like to thank Jef Proost, Center of Excellence
Separations, for performing the large scale HPLC sepa-
ration of 5 and 6.
It proved to be more convenient to perform the prepara-
tion of 5 and 6 via reductive amination of 3 (Scheme 1),
thereby circumventing the preparation and isolation of
imine 4. In this case of rhodium on carbon proved to
be the catalyst of choice, yielding 5 and 6 in a similar
yield and selectivity as observed in the hydrogenation
of 4 (Table 2, entry 1). With this method in hand, we
studied different alkylarylamines (Table 2). a-Methyl-
benzylamines proved to give the highest ratios (entries
3, 4 and 6). We did not observe any influence of chirality
on the selectivity of the reaction. Substitution on the a-
carbon proved to be advantageous for high selectivity,
benzyl amine or naphthyl methylamine being signifi-
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.09.056.
References and notes
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heptane 50/50.
24. 13C NMR:
#C
5
6
1
2
1
2
3
4
5
6
7
8
34.91a
57.83
33.09a
44.82b
68.05
45.56
30.01
29.85c
44.57b
30.05c
55.03
24.96
35.81d
57.31
34.04d
39.46e
67.92
45.51
30.14
35.97e
39.20f
35.71f
54.69
24.97
36.80
54.32
36.80
44.78
67.56
45.60
30.27
29.25
44.78
29.25
—
37.71
53.75
37.71
38.66
67.79
45.46
29.55
35.98
38.66
35.98
—
9
10
CH
Me
Aromatic-q
-ortho
-meta
-para
—
—
—
—
—
—
—
—
146.38
126.51
128.31
126.68
146.39
126.51
128.31
126.65
—
—
a–f
These signals may be mutually interchanged.
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dry toluene was added, 40 mL of a 5% solution of
thiophene in toluene, Al(OiPr)3 (40.0 g, 0.2 mol) and 5%
Rh–C (20 g). With stirring, the mixture was hydrogenated
for 16 h at 50 ꢁC. After cooling to room temperature, the
catalyst was filtered off, and the filtrate was evaporated till
dryness. The residue was taken up in dichloromethane
(500 mL), and washed with water (2 · 150 mL). After
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´
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L. Jaroskova et al. / Tetrahedron Letters 47 (2006) 8063–8067
8067
HCl (60 mL). NaOH (3 M, 40 mL) was added, followed
by a mixture of MgSO4 (19.2 g) in 40 mL of water. To this
mixture was added dropwise over a period of 1 h, a
solution of KMnO4 (22.3 g) in water (350 mL). After
stirring for 3 h, solid NaHSO3 was added until a clear
solution was obtained. Extraction with dichloromethane
(3 · 100 mL), the organic layers were washed with 1 M
HCl, satd NaHCO3 (2 · 50 mL), dried over MgSO4 and
evaporated to give 4.5 g of 5-hydroxy-2-adamantanone 3
(27 mmol, 51%), identical to authentic material.