Synthesis of functionalized adamantanes from fluoroadamantanes

Article abstract of DOI:10.1016/j.tet.2009.02.059

Selective introduction of functional groups on the tert-carbon of adamantane was performed by substitution with fluorides. A methyl, phenacyl, aryl, cyclohexyl, alkoxy, or azido group was introduced into the adamantane skeleton without influencing the oth

Full text of DOI:10.1016/j.tet.2009.02.059

Tetrahedron 65 (2009) 3682–3687
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Synthesis of functionalized adamantanes from fluoroadamantanes
*
Motoshi Aoyama, Shoji Hara
Graduate School of Engineering, Hokkaido University, Sapporo 060-8628, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Selective introduction of functional groups on the tert-carbon of adamantane was performed by sub-
stitution with fluorides. A methyl, phenacyl, aryl, cyclohexyl, alkoxy, or azido group was introduced into
the adamantane skeleton without influencing the other functional groups present. Various
functionalized adamantanes were synthesized using this scheme. A fluorinated analog of memantine
(3-fluoro-5,7-dimethyl-1-adamantylammonium acetate 25) was synthesized from methyl 3,5-dimethyl-
adamantane-1-carboxylate 6.
Received 3 February 2009
Received in revised form 24 February 2009
Accepted 24 February 2009
Available online 3 March 2009
Keywords:
Ó 2009 Elsevier Ltd. All rights reserved.
Fluoroadamantane
Functionalization
Substitution
Fluoromemantine
1. Introduction
an effective method for the synthesis of functionalized ada-
mantanes using the fluoroadamantanes as a starting material.
Adamantane consists of four tert-carbons and six sec-carbons
bonded together to form a simple cage compound. Adamantane
derivatives, such as aminoadamantanes, are known to have in-
teresting biological properties, 1-aminoadamantane (amantadine)
and 3,5-dimethyl-1-aminoadamantane (memantine) are used
medically to treat influenza, Parkinson disease, and Alzheimer
disease.1 Furthermore, because incorporation of an adamantane
unit into polymers can enhance their thermal stability and improve
their physical properties,2 adamantane compounds are attracting
a great deal of attention as functional materials. Functional groups
can be introduced on the tert-carbons of adamantanes by several
methods, including oxidation reactions,3 radical reactions,4 Frie-
del–Crafts reactions,5 and cross-coupling reactions.6 However,
most of these reactions have been applied to the unsubstituted
substrates, and few have been used for the synthesis of poly-
functionalized adamantanes.3f,3d,5 Recently, we reported a selective
introduction of fluorine atoms on the tert-carbons of adamantanes
by an electrochemical method7 or by reaction with IF5.8 One to four
fluorine atoms can be introduced selectively on substituted ada-
mantanes without influencing other functional groups such as the
ester and the cyano group. Recently, alkyl fluorides have been used
as substrates for alkylation or introduction of functional groups by
substitution of a fluorine atom.9 Therefore, we planned to develop
Me
Me
NH2
amantadine
NH2
memantine
2. Results and discussion
We used Me3Al for the methylation of 1-fluoroadamantane (1)7,8
analogous to the method for the methylation of tert-alkyl fluorides
by Me3Al reported by Maruoka et al.9a We found that the reaction
proceeds under mild conditions to give 1-methyladamantane (4) in
high yield (Table 1). The reaction of methyl 3-fluoroadamantane-1-
carboxylate (2)7,8 with Me3Al proceeded without affecting the ester
group to give methyl 3-methyladamantane-1-carboxylate (5) in
high yield. However, the reaction of methyl 3,5-difluoroadaman-
tane-1-carboxylate with Me3Al was sluggish, and methyl 3,5-
dimethyladamantane-1-carboxylate (6) was obtained only in poor
yield. On the other hand, 6 can be prepared in high yield from
methyl 3-fluoro-5-methyladamantane-1-carboxylate (3) by re-
action with Me3Al.10 Attempts to use other alkylaluminium re-
agents, such as Et3Al or i-Bu3Al, for reaction with
1 were
unsuccessful. During the reaction, fluoride reduction occurred
competitively, and significant amount of unsubstituted ada-
mantane as well as the expected 1-alkyladamantanes was formed.9a
* Corresponding author. Tel./fax: þ81 11 706 6556.
E-mail address: shara@eng.hokudai.ac.jp (S. Hara).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.02.059

M. Aoyama, S. Hara / Tetrahedron 65 (2009) 3682–3687
3683
Table 1
influencing the ester group giving an isomeric mixture of methyl
3-(cyclohexen-1-yl)adamantane-1-carboxylate and methyl 3-
(cyclohexen-3-yl)adamantane-1-carboxylate. Their double bonds
in these compounds were hydrogenated without purification, and
methyl 3-cyclohexyladamantane-1-carboxylate (11) was isolated in
high yield (entry 3). Friedel–Crafts reaction of thiophene with 8 or
that of anisole with 116 gave isomeric mixtures of thienylada-
mantanes (12) or (methoxyphenyl)adamantanes (13), re-
spectively17 (entries 4 and 5).
Methylation of fluoroadamantanes with Me3Ala
Substrate
Product
Yieldb (%)
94
Me
F
1
4
Me
Me
F
2
F
98
92
COOMe
COOMe
COOMe
An ethoxy group18 or an azido group22 can be introduced into
the adamantane 1 by reaction with ethoxytrimethylsilane or azi-
dotrimethylsilane in the presence of a Lewis acid, giving high
yields of 1-ethoxyadamantane (15) or 1-azidoadamantane (16)
(entries 1 and 2 in Table 3). The functional groups, such as an
acetoxy group (entry 3) and an ester group (entries 4, 5, and 7),
can tolerate the reaction conditions and the corresponding func-
tionalized ethers (17, 18, and 20) and an azide (19) were obtained
in high yields. An electron-withdrawing substituents on ada-
mantane decreases the reactivity toward the electrophiles, and
a higher temperature was required for introduction of an ethoxy
group to the substrate having two ester groups (14) (entry 4). The
reaction of ethoxytrimethylsilane with 1,3-difluoroadamantane 7
5
Me
Me
COOMe
3
6
a
1.1 equiv of Me3Al to substrate was used.
Isolated yield based on substrate.
b
Next, we examined the Friedel–Crafts-type reactions for alkyl-
ation of the adamantanes. Maruoka also reported that tert-alkyl
groups can be introduced into an -position of the esters by the
Me3Al-catalyzed reaction of ketene silyl acetals with tert-alkyl
fluorides.9a The reaction of 1 with an
-(trimethylsiloxy)styrene
proceeded smoothly in the presence of a Lewis acid to give 1-
phenacyladamantane (9) in high yield (entry 1 in Table 2). BF3
etherate or Al(OTf)3,12 used as Lewis acid, is effective for this
reaction, and AlCl3 or TiCl4 is not suitable because they cause the
undesired competitive chlorination of the adamantanes. The re-
a
also required
a higher temperature to obtain 1,3-diethoxy-
a
adamantane (20) (entry 6). Introduction of a (1R)-menthoxy
group is possible by using a (1R)-menthoxytrimethylsilane, and
the corresponding (1R)-menthyl ether (21) was obtained in high
yield (entry 7).
Introduction of a fluorine atom into bioactive compounds can
enhance or modify their activity, and therefore the fluorinated
analogs of bioactive compounds have attracted much attention.23
Memantine, 1-amino-3,5-dimethyladamantane, is used to treat
Parkinson disease and Alzheimer disease, and therefore its fluo-
rinated analog should be evaluated. We attempted to synthesize
1-amino-3-fluoro-5,7-dimethyladamantane, a fluorinated analog
action of a-(trimethylsiloxy)styrene with difluoroadamantane (7)
was sluggish, and required higher temperature. Under a high
temperature condition, 1,3-diphenacyladamantane (10) was
obtained in moderate yield (entry 2).13 The Lewis acid-catalyzed
reaction of
2 with cyclohexene proceeded slowly without
Table 2
Friedel–Crafts-type alkylation of adamantanes
Entry
1
Substrate
Reagent
Reaction conditions
rt, 4 h
vProduct
Yielda (%)
97
Me3SiO
1
, BF3$Et2O
CH2COPh
Ph
9
CH2COPh
F
Me3SiO
Ph
2
3
, Al(OTf)3
40 ꢀC, 15 h
60
CH2COPh
10
F
7
2
, Al(OTf)3
83 ꢀC, 20 h
91b
COOMe
11
F
S
4
, Al(OTf)3
40 ꢀC, 15 h
75
94
CH2OAc
S
CH2OAc
8
(2-:3- = 7:3)
12
OMe
MeO
5
1
, Al(OTf)3
rt, 12 h
(o-: p-: 2:3)
13
a
Isolation yield based on substrate used.
Product was isolated after hydrogenation.
b

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M. Aoyama, S. Hara / Tetrahedron 65 (2009) 3682–3687
Table 3
Alkoxylation and azidation of adamantanes
Entry
1
Substrate
Reagent
Reaction conditions
Product
Yielda (%)
97
OEt
1
EtOSiMe3, BF3$Et2O
N3SiMe3, BF3$Et2O
rt, 24 h
rt, 5 h
15
N3
2
3
1
8
97
80
16
EtO
EtOSiMe3, Al(OTf)3
EtOSiMe3, Al(OTf)3
rt, 20 h
CH2OAc
17
COOMe
COOMe
4
84 ꢀC, 8 h
98
COOMe
COOMe
EtO
F
14
18
N3
5
6
3
N3SiMe3, Al(OTf)3
EtOSiMe3, Al(OTf)3
rt, 24 h
95
82
Me
COOMe
OEt
19
EtO
7
3
30 ꢀC, 8 h
20
O
7
, Al(OTf)3
40 ꢀC, 24 h
96
Me3SiO
Me
COOMe
21
a
Isolation yield based on substrate used.
of memantine, from methyl 3,5-dimethyladamantane-1-carbox-
After the hydrolysis of ester group, the resulting 3-fluoro-5,7-
dimethyladamantane-1-carboxylic acid (23) was treated with
diphenylphosphoryl azide (DPPA) to give the N-benzylcarbonate
of the 1-amino-3-fluoro-5,7-dimethyladamantane (24). Depro-
tection of the amino group in acetic acid gave 3-fluoro-5,7-di-
methyl-1-adamantylammonium acetate (25) (Scheme 1).
ylate 6.24 Fluorine atom was electrochemically introduced on
a
tert-carbon of 6 to give methyl 7-fluoro-3,5-dimethylada-
mantane-1-carboxylate (22) in 78% yield.7 Conversion of the ester
group of 6 to amine was performed using a published procedure.24
Me
Me
3. Conclusion
Electrolysis
Et3N-5HF
Me
COOMe
Me
COOMe
Selective alkylation or introduction of functional groups on the
tert-carbon of adamantane was performed by substitution with
fluorides. The reaction proceeds under mild conditions, and various
functionalized adamantanes were synthesized. We also performed
the synthesis of 3-fluoro-5,7-dimethyl-1-adamantylammonium
acetate 25, which is a fluorinated analog of memantine.
F
6
78%
22
Me
Me
F
DPPA, Et3N
BnOH
NaOH
COOH
MeOH
74%
23
88%
4. Experimental
4.1. General
Me
Me
Me
F
H2, Pd/C
AcOH
The IR spectra were recorded using a JASCO FT/IR-410. The 1H
NMR (400 MHz), 19F NMR (376 MHz), and 13C NMR (100 MHz)
spectra were recorded in CDCl3 on a JEOL JNM-A400II FT NMR and
the chemical shift,
respectively. The EI low- and high-resolution mass spectra were
Me
NH3
AcO
NHCOOBn
F
24
88%
25
d
, were referred to TMS (1H, 13C) and CFCl3 (19F),
Scheme 1. Fluoromemantine synthesis.

M. Aoyama, S. Hara / Tetrahedron 65 (2009) 3682–3687
3685
measured on a JEOL JMS-700TZ, JMS-FABmate or JMS-HX110.
(12H, m). 13C NMR
d
199.99 (2C), 138.64 (2C), 132.77 (2C), 128.46
Me3Al in hexane and Et3N-5HF were purchased from Tokyo Kasei
Co., Ltd. Al(OTf)3 was purchased from Aldrich and used after drying
under reduced pressure. Fluoroadamantanes 1, 2, 3, 7, 8, 14 were
prepared by the previously reported methods.7,8
(4C), 128.29 (4C), 50.59 (2C), 48.36, 41.89 (4C), 35.75, 34.59 (2C),
28.56 (2C). HRMS (EI) calcd for C26H28O2 372.2089, found 372.2089.
4.7. Methyl 3-cyclohexyladamantane-1-carboxylate (11)
4.2. 1-Methyladamantane (4)
A mixture of 27,8 (106 mg, 0.5 mmol) and Al(OTf)3 (47 mg,
0.1 mmol) in cyclohexene (20 mL) was stirred under reflux for 20 h.
Then, the mixture was poured to water (30 mL) and extracted with
CH2Cl2 (20 mLꢁ3). The combined organic layer was dried over
MgSO4 and concentrated under reduced pressure. Purification by
column chromatography (silica gel, hexane/AcOEt¼20:1) gave 11
(116 mg) in 91% yield; clear oil. IR (neat): 2926, 1731 (C]O),
To a CH2Cl2 solution (8 mL) of 1-fluoroadamantane 17,8 (77 mg,
0.5 mmol) was added at room temperature under N2 atmosphere,
a 1.4 M hexane solution of Me3Al (0.4 mL, 0.55 mmol), and the
mixture was stirred for 30 min. Then, the mixture was poured into
water (30 mL) and extracted with CH2Cl2 (20 mLꢁ3). The combined
organic layer was dried over MgSO4 and concentrated under re-
duced pressure. Purification by column chromatography (silica gel,
hexane/ether¼10:1) gave 4 (71 mg) in 94% yield; white solid: mp
1241 cmꢂ1. 1H NMR
m), 1.51–1.43 (4H, m), 1.25–1.06 (4H, m), 0.98–0.83 (3H, m). 13C
NMR 178.37, 51.53, 48.30, 41.57, 41.03, 38.67 (2C), 38.59 (2C),
d 3.65 (3H, s), 1.84–1.74 (8H, m), 1.65–1.57 (6H,
d
101 ꢀC (lit.11c 100–101 ꢀC). IR (KBr): 2900, 1454 cmꢂ1. 1H NMR
d
1.92
(3H, br s), 1.75–1.54 (6H, m), 1.44 (6H, br s), 0.76 (3H, s). 13C NMR
44.61 (3C), 36.91 (3C), 31.44 (3C), 29.79, 28.85.
36.28, 34.73, 28.48 (2C), 27.15 (2C), 26.82, 26.05 (2C). HRMS (EI)
calcd for C18H28O2 276.2089, found 276.2095.
d
4.3. Methyl 3-methyladamantane-1-carboxylate (5)
4.8. 1-Acetoxymethyl-3-thienyladamantane (12)
The reaction was carried out as described above using methyl 3-
fluoroadamantane-1-carboxylate 27,8 (106 mg, 0.5 mmol). Purifi-
cation by column chromatography (silica gel, hexane/ether¼5:1)
gave 5 (101 mg) in 98% yield; clear oil. IR (neat): 2903, 1730 (C]O),
The reaction was carried out as described above using 87,8
(113 mg, 0.5 mmol) and Al(OTf)3 (24 mg, 0.05 mmol) in thiophene
(2 mL) at 40 ꢀC under N2 atmosphere for 15 h. Purification by col-
umn chromatography (silica gel, hexane/ether¼5:1) gave 12
(109 mg) in 75% yield as a mixture of isomers (thien-2-yl/thien-3-
yl¼7:3); pale yellow oil. IR (neat): 2905, 1742 (C]O), 1245 cmꢂ1. 1H
1233 cmꢂ1. 1H NMR
d
3.65 (3H, s), 2.06 (2H, br s), 1.84–1.75 (4H, m),
1.62–1.56 (4H, m), 1.43 (4H, br s), 0.83 (3H, s). 13C NMR
d
178.11,
51.53, 45.51, 43.43 (2C), 41.59, 38.14 (2C), 35.66, 30.78, 30.01, 28.49
(2C). HRMS (EI) calcd for C13H20O2 208.14633, found 208.14615.
NMR
d
7.28–7.26 (0.3H, m), 7.14 (0.7H, dd, J¼5.0, 1.3 Hz), 7.09 (0.3H,
dd, J¼5.0, 1.3 Hz), 6.96–6.93 (1H, m), 6.83 (0.7 Hz, dd, J¼3.6, 1.3 Hz),
3.75 (2H, s), 2.18 (2H, br s), 2.07 (3H, s), 1.98–1.82 (4H, m), 1.75–1.68
4.4. Methyl 3,5-dimethyladamantane-1-carboxylate (6)
(4H, m), 1.57 (4H, br s). 13C NMR (thien-2-yl isomer):
d
171.29,
157.12, 126.31, 122.08, 120.38, 73.43, 46.54, 44.25 (2C), 38.28 (2C),
36.34, 35.87, 34.21, 28.60 (2C), 20.85; (thien-3-yl isomer): 171.27,
The reaction was carried out as described above using 38
(113 mg, 0.5 mmol). Purification by column chromatography (silica
gel, hexane/ether¼10:1) gave 6 (102 mg) in 92% yield; clear oil. IR
d
152.73, 125.35, 125.07, 117.59, 73.61, 45.13, 42.84 (2C), 38.43 (2C),
36.03, 35.49, 34.01, 28.50 (2C), 20.85. HRMS (EI) calcd for C17H22O2S
290.13405, found 290.13436.
(neat): 2900, 1732 (C]O), 1455, 1263 cmꢂ1. 1H NMR
d 3.65 (3H, s),
2.11–2.09 (1H, m), 1.71 (2H, br s), 1.56–1.47 (4H, m), 1.38–1.30 (4H,
m), 1.15 (2H, br s), 0.84 (6H, s). 13C NMR
(2C), 42.72 (2C), 42.52, 37.51, 30.85 (2C), 30.41 (2C), 29.12. HRMS
(EI) calcd for C14H22O2 222.1620, found 222.1616.
d
178.07, 51.58, 50.61, 44.93
4.9. 1-Methoxyphenyladamantane (13)
The reactionwas carried out as described above using 17,8 (77 mg,
0.5 mmol) and Al(OTf)3 (47 mg, 0.1 mmol) in anisole (2 mL) at room
temperature under N2 atmosphere for 12 h. Purification by column
chromatography (silica gel, hexane/AcOEt¼20:1) gave 1-(o-
methoxyphenyl)adamantane (46 mg) and 1-(p-methoxyphenyl)-
adamantane (68 mg) in 94% total yield. o-Isomer: white solid: mp
4.5. 2-(1-Adamantyl)-1-phenylethanone (9)
A mixture of 17,8 (77 mg, 0.5 mmol),
a-(trimethylsiloxy)styrene
(192 mg, 1.0 mmol), and BF3 etherate (10 mg, 0.07 mmol) in CH2Cl2
(8 mL) was stirred at room temperature for 4 h. Then, the mixture
was poured to water (30 mL) and extracted with CH2Cl2 (20 mLꢁ3).
The combined organic layer was dried over MgSO4 and concen-
trated under reduced pressure. Purification by column chroma-
tography (silica gel, hexane/ether¼5:1) gave 9 (123 mg) in 97%
yield; white solid: mp 66–67 ꢀC (lit.25 mp 64–65 ꢀC). IR (KBr): 2907,
100–102 ꢀC (lit.26 mp 100–102 ꢀC). 1H NMR
6.94–6.87 (2H, m), 3.83 (3H, s), 2.10–2.06 (9H, m), 1.77 (6H, br s). 13C
NMR 158.78, 138.46, 126.75, 126.42, 120.43, 111.62, 54.89, 40.51
(3C), 37.12 (3C), 36.92, 29.08 (3C). p-Isomer: white solid, mp 79–
80 ꢀC (lit.26 mp 80–83 ꢀC). 1H NMR
7.28 (2H, d, J¼8.9 Hz), 6.84 (2H,
d, J¼8.9 Hz), 3.79 (3H, s), 2.08 (3H, br s),1.89 (6H, br s),1.80–1.71 (6H,
m). 13C NMR
157.28, 143.65, 125.74 (2C), 113.33 (2C), 55.13, 43.34
d 7.26–7.16 (2H, m),
d
d
1665 (C]O), 1257 cmꢂ1. 1H NMR
m), 7.47–7.43 (2H, m), 2.72 (2H, s), 1.94 (3H, br s), 1.70–1.61 (12H,
m). 13C NMR
200.27, 138.81, 132.67, 128.40 (2C), 128.34 (2C), 51.16,
d 7.96–7.94 (2H, m), 7.57–7.53 (1H,
d
(3C), 36.76 (3C), 35.48, 28.95 (3C).
d
42.92 (3C), 36.69 (3C), 33.89, 28.64 (3C).
4.10. 1-Ethoxyadamantane (15)27
4.6. 1,3-Diphenacyladamantane (10)
The reaction was carried out as described above using 17,8
(77 mg, 0.5 mmol), Me3SiOEt (118 mg, 1.0 mmol), and BF3 etherate
(10 mg, 0.07 mmol) in CH2Cl2 (8 mL) at room temperature for 24 h.
Purification by column chromatography (silica gel, hexane/
ether¼5:1) gave 15 (87 mg) in 97% yield; clear oil. IR (neat): 2907,
The reaction was carried out as described above using 77,8
(88 mg, 0.5 mmol), a-(trimethylsiloxy)styrene (288 mg, 1.5 mmol),
and Al(OTf)3 (237 mg, 0.5 mmol) in CH2Cl2 (8 mL) under reflux for
15 h. Purification by column chromatography (silica gel, hexane/
ether¼5:1) gave 10 (108 mg) in 60% yield; pale yellow oil. IR (neat):
1117 cmꢂ1. 1H NMR
d
3.47 (2H, q, J¼6.9 Hz), 2.91 (3H, br s), 1.75 (6H,
2894, 1672 (C]O), 1254 cmꢂ1. 1H NMR
d
7.93–7.90 (4H, m), 7.56–
s), 1.66–1.58 (6H, m), 1.16 (3H, t, J¼7.0 Hz). 13C NMR
d 71.78, 54.87,
7.52 (2H, m), 7.49–7.41 (4H, m), 2.75 (4H, s), 2.02 (2H, br s),1.65–1.56
41.58 (3C), 36.48 (3C), 30.46 (3C), 16.35.

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M. Aoyama, S. Hara / Tetrahedron 65 (2009) 3682–3687
4.11. 1-Azidoadamantane (16)28
4.16. Methyl 3-(1R)-menthoxy-5-methyladamantane-1-
carboxylate (21)
The reaction was carried out as described above using 17,8
(77 mg, 0.5 mmol), Me3SiN3 (115 mg, 1.0 mmol), and BF3
etherate (10 mg, 0.07 mmol) in CH2Cl2 (8 mL) at room tem-
perature for 5 h. Purification by column chromatography (silica
gel, hexane/ether¼10:1) gave 16 (86 mg) in 97% yield; clear oil.
The reaction was carried out as described above using 38
(113 mg, 0.5 mmol), (1R)-MenOSiMe3 (148 mg, 0.65 mmol), and
Al(OTf)3 (119 mg, 0.25 mmol) in CH2Cl2 (10 mL) at room temper-
ature for 24 h. Purification by column chromatography (silica gel,
hexane/AcOEt¼10:1) gave 21 (174 mg) in 96% yield; clear oil. IR
IR (neat): 2917, 2086 (N3), 1253 cmꢂ1
.
1H NMR
d
2.15 (3H, br s),
1.81 (6H, s), 1.71–1.62 (6H, m). 13C NMR
35.88 (3C), 29.77 (3C).
d
59.00, 41.49 (3C),
(neat): 2949, 1730, 1455 cmꢂ1 1H NMR
. d 3.66 (3H, s), 3.37–3.31
(1H, dt, J¼4.3, 10.4 Hz), 2.28–2.21 (2H, m), 1.93–1.35 (16H, m),
1.13–0.80 (13H, m), 0.72 (3H, d, J¼6.9 Hz). 13C NMR
d 177.09, 73.34,
70.10, 51.74, 49.33 (0.5), 49.30 (0.5), 49.06, 45.72, 44.75 (0.5),
44.72 (0.5), 44.38 (0.5), 44.35 (0.5), 43.66 (0.5), 43.63 (0.5), 42.39,
41.57 (0.5), 41.50 (0.5), 37.29 (0.5), 37.24 (0.5), 34.48, 33.18 (0.5),
33.15 (0.5), 31.77, 30.36, 30.06, 24.66, 23.17, 22.43, 21.61, 16.14.29
HRMS (EI) calcd for C23H38O3 362.28210, found 362.28225.
4.12. 1-Acetoxymethyl-3-ethoxyadamantane (17)
The reaction was carried out as described above using 87,8
(113 mg, 0.5 mmol), Me3SiOEt (118 mg, 1 mmol), and Al(OTf)3
(119 mg, 0.25 mmol) in CH2Cl2 (2 mL) at room temperature under
N2 atmosphere for 20 h. Purification by column chromatography
(silica gel, hexane/ether¼2:1) gave 17 (101 mg) in 80% yield; yellow
4.17. Methyl 3-fluoro-5,7-dimethyladamantane-1-
carboxylate (22)
oil. IR (neat): 2907, 1744 (C]O), 1243 cmꢂ1. 1H NMR
d 3.74 (2H, s),
3.47 (2H, q, J¼7.0 Hz), 2.24–2.22 (2H, m), 2.06 (3H, s), 1.77–1.68 (4H,
Electrochemical fluorination was performed as reported before.7
A Et3N-5HF solution (12 mL) of 6 (223 mg, 1 mmol) was introduced
into an undivided cellmade of Teflon PFA. The electrolysis was carried
out at room temperature using two smooth Pt sheets
(20 mmꢁ20 mm) for the anode and cathode at 2.55 V (vs Ag/Agþ)
until 3.0 F/mol of electricity had passed. Then, the reaction mixture
was poured into water and extracted with CH2Cl2 (20 mLꢁ3). The
combined organic layers was washed with aqueous NaHCO3 and
dried over MgSO4. Purification by column chromatography (silica gel,
hexane/AcOEt¼10:1) gave 22 (187 mg) in 78% yield; clear oil. IR
m), 1.58–1.55 (4H, m), 1.45 (4H, br s), 1.16 (3H, t, J¼7.0 Hz). 13C NMR
d
171.16, 73.00, 72.10, 55.10, 43.15, 40.84 (2C), 38.23 (2C), 36.35,
35.75, 29.87 (2C), 20.78, 16.19. HRMS (EI) calcd for C15H24O3
252.17255, found 252.17273.
4.13. Dimethyl 5-ethoxyadamantane-1,3-dicarboxylate (18)
The reaction was carried out as described above using 147
(135 mg, 0.5 mmol), Me3SiOEt (118 mg, 1 mmol), and Al(OTf)3
(119 mg, 0.25 mmol) in CH2Cl2 (2 mL) under reflux for 8 h. Puri-
fication by column chromatography (silica gel, hexane/AcOEt¼2:1)
gave 18 (145 mg) in 98% yield; pale yellow oil. IR (neat): 2949,
(neat): 2951, 1732, 1269 cmꢂ1 1H NMR
. d 3.68 (3H, s), 1.91 (2H, d,
J¼5.3 Hz), 1.60–1.38 (8H, m), 1.16–1.12 (2H, m), 0.96 (6H, s). 19F NMR
d
ꢂ137.62 (s,1F).13C NMR
176.16 (d, J¼2.4 Hz), 93.49 (d, J¼184.0 Hz),
d
1731 (C]O), 1223 cmꢂ1
.
1H NMR
d
3.68 (6H, s), 3.49 (2H, q,
51.90, 49.32 (d, J¼1.9 Hz), 47.76 (2C, d, J¼16.8 Hz), 45.48 (d,
J¼10.8 Hz), 43.90 (2C), 42.38 (d, J¼20.1 Hz), 34.63 (2C, d, J¼11.1 Hz),
29.18 (2C). HRMS (EI) calcd for C14H21O2F 240.1526, found 240.1526.
J¼7.0 Hz), 2.39–2.37 (1H, m), 1.96 (2H, br s), 1.88 (4H, br s), 1.77
(4H, br s), 1.73 (2H, br s), 1.16 (3H, t, J¼7.0 Hz). 13C NMR
d 175.88
(2C), 71.70 (2C), 55.17, 51.51 (2C), 43.26, 41.58 (2C), 39.61, 38.89,
36.81 (2C), 29.30, 15.74. HRMS (EI) calcd for C16H24O5 296.16238,
found 296.16173.
4.18. 3-Fluoro-5,7-dimethyladamantane-1-carboxylic
acid (23)
A mixture of 22 (390 mg, 1.6 mmol), 1 M aqueous NaOH
(3.2 mL), MeOH (1.2 mL), and THF (0.8 mL) was stirred at room
temperature for 15 h. The mixture was extracted with CH2Cl2
(20 mL) and organic layer was washed with 1 M aqueous NaOH
(10 mL). The combined aqueous layer was acidified with 1 M HCl
and extracted with CH2Cl2 (20 mLꢁ3). The combined organic layer
was dried over MgSO4 and concentrated under reduced pressure to
give 23 (268 mg) in 74% yield; white solid: mp 118–120 ꢀC. IR (KBr):
4.14. Methyl 3-azido-5-methyladamantane-1-carboxylate (19)
The reaction was carried out as described above using 38
(113 mg, 0.5 mmol), Me3SiN3 (104 mg, 0.9 mmol), and Al(OTf)3
(95 mg, 0.2 mmol) in CH2Cl2 (2 mL) at room temperature for
24 h. Purification by column chromatography (silica gel, hex-
ane/ether¼8:1) gave 19 (118 mg) in 95% yield; clear oil. IR
(neat): 2924, 2360, 2090 (N3), 1731 (C]O), 1261 cmꢂ1 1H NMR
.
3403, 2926, 1697 cmꢂ1 1H NMR
. d 11.50 (1H, s), 1.93 (2H, d,
d
3.68 (3H, s), 2.31–2.29 (1H, m), 1.93–1.83 (2H, m), 1.78–1.69
(4H, m), 1.66–1.47 (4H, m), 1.41 (2H, br s), 0.94 (3H, s). 13C NMR
176.35, 59.46, 51.56, 47.22, 44.35, 43.60, 41.95, 41.90, 39.82,
J¼5.5 Hz),1.58–1.43 (8H, m), 1.21–1.13 (2H, m), 0.97 (6H, s). 19F NMR
d
ꢂ137.89 (s, 1F). 13C NMR
d
182.28 (d, J¼2.2 Hz), 93.36 (d,
d
J¼184.0 Hz), 49.26 (d, J¼1.9 Hz), 47.70 (2C, d, J¼16.8 Hz), 45.33 (d,
J¼11.0 Hz,), 43.60 (2C, d, J¼1.9 Hz), 42.05 (d, J¼20.6 Hz), 34.63 (2C,
d, J¼10.1 Hz), 29.16 (2C, d, J¼1.4 Hz). HRMS (EI) calcd for C13H19O2F
226.13691, found 226.13676.
36.86, 32.59, 29.69, 29.67. HRMS (EI) calcd for C13H19O2N3
249.1477, found 249.1476.
4.15. 1,3-Diethoxyadamantane (20)
4.19. 1-(Benzyloxycarbonylamino)-3-fluoro-5,7-
dimethyladamantane (24)
The reaction was carried out as described above using 77,8
(88 mg, 0.5 mmol), Me3SiOEt (173 mg, 1.5 mmol), and Al(OTf)3
(237 mg, 0.5 mmol) in CH2Cl2 (8 mL) at 30 ꢀC for 8 h. Purification by
column chromatography (silica gel, hexane/ether¼3:1) gave 20
(92 mg) in 82% yield; clear oil. IR (neat): 2927, 1079 cmꢂ1. 1H NMR
A mixture of 23 (280 mg, 1.2 mmol), Et3N (170 mg, 1.7 mmol),
diphenylphosphoryl azide (413 mg, 1.5 mmol) in benzene (10 mL)
was stirred under reflux for 45 min. After cooling to room temper-
ature, benzyl alcohol (260 mg, 2.4 mmol) was added and the mixture
was stirred under reflux for 3 days. After cooling to room tempera-
ture, a volatile part was removed under reduced pressure. Purifica-
tion by column chromatography (silica gel, hexane/AcOEt¼4:1) gave
d
3.47 (4H, q, J¼7.0 Hz), 2.30 (2H, br s), 1.78 (2H, s), 1.71–1.65 (8H,
m), 1.17 (6H, t, J¼7.0 Hz). 13C NMR
d 74.16 (2C), 55.48 (2C), 45.45,
40.69 (4C), 35.45, 30.76 (2C), 16.27 (2C). HRMS (EI) calcd for
C14H24O2 224.1776, found 224.1770.

M. Aoyama, S. Hara / Tetrahedron 65 (2009) 3682–3687
3687
Tetrahedron Lett. 2004, 45, 2555; (c) Begum, S. A.; Terao, J.; Kambe, N. Chem.
Lett. 2007, 196; (d) Terao, J.; Begum, S. A.; Shinohara, Y.; Tomita, M.; Naitoh, Y.;
Kambe, N. Chem. Commun. 2007, 855; (e) Terao, J.; Todo, H.; Watabe, H.; Ikumi,
A.; Shinohara, Y.; Kambe, N. Pure Appl. Chem. 2008, 80, 941.
24 (350 mg) in 88% yield; clear oil. IR (neat): 3328, 2950, 2137, 1714,
1523, 1215 cmꢂ1. 1H NMR
7.39–7.32 (5H, m), 5.04 (2H, s), 4.72 (1H,
d
br s), 2.00 (2H, d, J¼5.6 Hz), 1.64–1.52 (8H, m), 1.13 (2H, s), 0.96 (s,
6H). 19F NMR
d
ꢂ138.16 (s, 1F). 13C NMR
d 154.26, 136.46, 128.52 (3C),
10. Methylation at tert-carbon of the adamantane was previously performed by the
reaction of MeMgX with Cl-, Br-, or I-adamantane at higher temperature (40–
85 ꢀC).11 But methylation of the adamantanes having functional group was not
reported.
11. (a) Osawa, E.; Majerski, Z.; Schleyer, P. R. J. Org. Chem. 1971, 36, 205; (b) Molle,
G.; Dubois, J. E.; Bauer, P. Can. J. Chem. 1987, 65, 2428; (c) Ohno, M.; Shimizu, K.;
Ishizaki, K.; Sasaki, T.; Eguchi, S. J. Org. Chem. 1988, 53, 729; (d) Kira, M.;
Akiyama, M.; Ichinose, M.; Sakurai, H. J. Am. Chem. Soc. 1989, 111, 8256.
12. Olah, G. A.; Farooq, O.; Morteza, S.; Farnia, F.; Olah, J. A. J. Am. Chem. Soc. 1988,
110, 2560.
13. Compound 5 was previously prepared by photochemical reaction of aceto-
phenone enolate with 1-iodoadamantane in moderate yield.14 However,
application of that method for the synthesis of 10 was unsuccessful.15
14. Borosky, G. L.; Pierini, A. B.; Rossi, R. A. J. Org. Chem. 1990, 55, 3705.
15. Lee, G. S.; Bashara, J. N.; Sabih, G.; Oganesyan, A.; Godjoian, G.; Duong, H. M.;
Marinez, E. R.; Gutie´rrez, C. G. Org. Lett. 2004, 6, 1705.
16. Friedel–Crafts adamantylation of aromatic compounds using 1-fluo-
roadamantane was previously studied by Olah et al., see: Olah, G. A.; Farooq, O.;
Morteza, S.; Farnia, F.; Wu, A. J. Org. Chem. 1990, 55, 1516.
17. As for the Friedel–Crafts adamantylation of arenes using bromo- or chloro-
adamantanes, see: (a) Perkins, R.; Bennett, S.; Bowering, E.; Burke, J.; Reid, K.;
Wall, D. Chem. Ind. 1980, 790; (b) Handa, I.; Bauer, L. J. Chem. Eng. Data 1984, 29,
223; (c) Hachiya, I.; Moriwaki, M.; Kobayashi, S. Bull. Chem. Soc. Jpn. 1995, 68,
2053.
18. 1-Alkoxyadamantanes were previously prepared by oxidation–solvation of 1-
iodoadamantane,19 solvolysis of 1-adamantanyl chloroformate,20 or photo-in-
duced substitution reaction of haloadamantane.21 However, those methods are
not practical for the synthesis of alkoxyadamantanes because significant
amount of by-products was formed19,20 or chemical yields of the products were
not shown.21
128.10 (2C), 93.36 (d, J¼184.4 Hz), 66.14, 54.40 (d, J¼12.9 Hz), 49.20
(d, J¼1.9 Hz), 47.62 (2C, d, J¼16.8 Hz), 46.53 (2C), 45.23 (d, J¼19.0 Hz),
34.61 (2C, d, J¼10.3 Hz), 28.86 (2C, d, J¼1.4 Hz). HRMS (EI) calcd for
C20H26NO2F 331.19475, found 331.19439.
4.20. 3-Fluoro-5,7-dimethyl-1-adamantylammonium
acetate (25)
A hydrogenolysis operation was performed in an autoclave. A
mixture of acetic acid (2 mL), 10% Pd–C (0.2 g), and 24 (166 mg,
0.5 mmol) was stirred at room temperature under H2 atmosphere
(4 atm) for 24 h. The catalyst was removed by filtration and washed
with ether. The filtrate was concentrated under reduced pressure to
give a solid material. Recrystallization from hexane/CH2Cl2 gave
a pure 25 (106 mg) in 88% yield; a white solid: mp 132–133 ꢀC. IR
(KBr): 3430, 2951, 1559 cmꢂ1. 1H NMR
d 6.15 (3H, br s), 2.01 (3H, s),
1.82 (2H, d, J¼5.3 Hz),1.59–1.35 (8H, m),1.26–1.17 (2H, m), 0.98 (6H,
s).19F NMR
d
ꢂ138.98 (s,1F).13C NMR
d
178.23, 92.78 (d, J¼185.9 Hz),
53.56 (d, J¼12.0 Hz), 48.81, 47.24 (2C, d, J¼17.0 Hz), 46.36 (2C), 45.22
(d, J¼20.1 Hz), 34.74 (2C, d, J¼10.3 Hz), 28.69 (2C), 24.92. HRMS (EI)
calcd for C12H20NF (free amine) 197.1580, found 197.1582.
19. Davidson, R. I.; Kropp, P. J. J. Org. Chem. 1982, 47, 1904.
20. Moss, R. A.; Tian, J.; Sauers, R. R. Org. Lett. 2004, 6, 4293.
References and notes
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K.; Mismash, B.; Bolz, J. T. J. Am. Chem. Soc. 1996, 118, 5192; (b) Papeo, G.;
Posteri, H.; Vianello, P.; Varasi, M. Synthesis 2004, 2886; (c) Iranpoor, N.; Fir-
ouzabadi, H.; Akhlaghinia, B.; Nowrouzi, N. Tetrahedron Lett. 2004, 45, 3291; (d)
Rad, M. N. S.; Behrouz, S.; Khalafi-Nezhad, A. Tetrahedron Lett. 2007, 48, 3445.
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York, NY, 1991; (b) Welch, J. T. Tetrahedron 1987, 43, 3123.
24. Fluorinated analogs of amantadine were previously prepared, see: Jasys, V. J.;
Lombardo, F.; Appleton, T. A.; Bordner, J.; Ziliox, M.; Volkmann, R. A. J. Am.
Chem. Soc. 2000, 122, 466.
25. Lewis, F. D.; Johnson, R. W.; Kory, D. R. J. Am. Chem. Soc. 1974, 96, 6100.
26. Ng, S. Aust. J. Chem. 1973, 26, 2303.
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28. Nyfeler, E.; Renaud, P. Org. Lett. 2008, 10, 985.
29. As four tert-carbons of the adamantane skeleton were substituted by different
atoms, the compounds 3 is optically active (racemic)24 and compounds 21 is
a mixture of two diastereomers.30 Therefore, in 13C NMR of 21, the signals of
two diastereomers appeared separately.
1. (a) Wishnok, J. S. J. Chem. Educ. 1973, 50, 780; (b) Spasov, A. A.; Khamidova, T. V.;
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