Selective fluorination of adamantanes by an electrochemical method

Article abstract of DOI:10.1021/jo8004759

(Chemical Equation Presented) Selective fluorination of adamantanes was achieved by the electrochemical fluorination method, using Et₃N-5HF as electrolyte and a fluorine source. Mono-, di-, tri-, and tetrafluoroadamantanes were selectively prepared from adamantanes by controlling the oxidation potential, and the fluorine atoms were introduced selectively at the tertiary carbons. Adamantanes that have functional groups such as ester, cyano, and acetoxymethyl were also fluorinated selectively.

Full text of DOI:10.1021/jo8004759

Selective Fluorination of Adamantanes by an Electrochemical
Method
Motoshi Aoyama, Tsuyoshi Fukuhara, and Shoji Hara*
Graduate School of Engineering, Hokkaido UniVersity, Sapporo 060-8628, Japan
shara@eng.hokudai.ac.jp
ReceiVed March 9, 2008
Selective fluorination of adamantanes was achieved by the electrochemical fluorination method, using
Et3N-5HF as electrolyte and a fluorine source. Mono-, di-, tri-, and tetrafluoroadamantanes were selectively
prepared from adamantanes by controlling the oxidation potential, and the fluorine atoms were introduced
selectively at the tertiary carbons. Adamantanes that have functional groups such as ester, cyano, and
acetoxymethyl were also fluorinated selectively.
Introduction
fluoroadamantanes because its starting materials are easily
available. However, for the direct fluorination of the adaman-
tanes, strong oxidizing reagents, such as F2, are generally
required, which are generally hazardous and require special skill
to use. Moreover, their high reactivity causes a low selectivity
of the reaction, which makes it difficult to introduce fluorine
atoms only at the desired positions by the direct method.6a,d,e,g,h
Therefore, the fluorinated analogues of the aminoadamantane
were synthesized via the deoxyfluorination reaction from the
corresponding hydroxy compounds,3b,c which is a more reliable
and safer way than the direct method, although it requires a
multistep process. Recently, an electrochemical fluorination
reaction with Et3N-5HF as a fluorine source and an electrolyte
has been developed as a useful method for the partial fluorination
of organic compounds.7 There are three advantages of using
the electrochemical fluorination method with Et3N-5HF. (1)
The oxidation potential can be controlled precisely by using
Adamantane (C10H16) is a simple tricyclic cage compound
consisting of only two kinds of carbons: four tertiary carbons
and six secondary carbons. Adamantane derivatives such as
aminoadamantanes are known to have interesting biological
properties,1 and 1-aminoadamantane (amantadine) and 3,5-
dimethyl-1-aminoadamantane (memantine) are used as medi-
cines for treating influenza, Parkinson’s disease, and Alzheimer’s
disease. As the introduction of fluorine atoms into bioactive
compounds can enhance or modify their activities,2 preparation
of fluorine derivatives has attracted the attention of organic and
medicinal chemists.3 Fluorination of adamantanes has been
carried out through the deoxyfluorination of adamantanols,4
halogen exchange reaction from other haloadamantanes,5 or
direct fluorination of the adamantane itself.6 Among them, the
direct fluorination method is preferable for the synthesis of the
(1) Wishnok, J. S. J. Chem. Educ. 1973, 50, 780.
(2) Welch, J. T. Tetrahedron 1987, 43, 3123.
(5) (a) Bhandari, K. S.; Pincock, R. E. Synthesis 1974, 655. (b) Rozen, S.;
Brand, M. J. Org. Chem. 1981, 46, 733. (c) Olah, G. A.; Shih, J. G.; Singh,
B. P.; Gupta, B. G. B. Synthesis 1983, 713. (d) Olah, G. A.; Shih, J. G.;
Krishnamurthy, V. V.; Singh, B. P. J. Am. Chem. Soc. 1984, 106, 4492. (e)
Della, E. W.; Head, N. J. J. Org. Chem. 1992, 57, 2850. (f) Della, E. W.; Head,
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47, 4975.
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Chem. 1979, 44, 3872. (c) Adcock, W.; Kok, G. B. J. Org. Chem. 1987, 52,
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4186 J. Org. Chem. 2008, 73, 4186–4189
10.1021/jo8004759 CCC: $40.75 2008 American Chemical Society
Published on Web 05/07/2008

SelectiVe Fluorination of Adamantanes
TABLE 1. Electrochemical Fluorination of Adamantanea
yield of products (%)b
applied potential
solvent
(Et3N-5HF:CH2Cl2)
entry
(V vs Ag/Ag+)
electricity (F/mol)
temp (°C)
2
3
4
5
1c
2
2.30
2.30
2.50
2.70
2.70
3.00
2.2
2.5
4.4
11.0
14.0
60.0
35
35
35
35
45
35
2:1
2:1
1:1
5:1
1:0
1:0
74
67
(2)
(2)
15
79
(6)
(6)
3
(1)
49
61
4d
5e
6f
(2)
41
a If otherwise not mentioned, the reaction was carried out with 1 mmol of substrate in 12 mL of solvent. b Isolated yield based on substrate used. In
parentheses, GC yield. c 4% of 1 remained. d Chlorinated product was also formed (5%). e The reaction was carried out with a solution of 0.5 mmol of 1
in 12 mL of Et3N-5HF. f 4 was used as the starting material.
electrochemistry, and only the desired reaction occurs selec-
tively. (2) Et3N-5HF is less acidic than HF, and many organic
compounds are soluble in it. Therefore, the method can be used
for the fluorination of various organic compounds. (3)
Et3N-5HF is stable under oxidation conditions up to ∼2.8 V
and the method can be used for the fluorination of substrates
that are difficult to oxidize.7d Therefore, we used the electro-
chemical fluorination with Et3N-5HF for the direct fluorination
of various adamantanes.
Results and Discussion
Oxidation Potential of Adamantane. The oxidation poten-
tials of the adamantane (1) and 1-fluoroadamantane (2) were
reported to be 2.35 and 2.50 V, respectively, vs Ag/Ag+ in
CH3CN,8 and the oxidation occurs selectively at the tertiary
carbons. When the oxidation potential of the adamantane (1)
was measured by cyclic voltammetry with a Pt wire electrode
FIGURE 1. Cyclic voltammograms for the oxidation of adamantane
in Et3N-5HF, three peaks appeared at 2.30, 2.50, and 2.70 V
(0.04 M) in Et3N-5HF: working, 1 mm × 10 mm Pt, counter, 20 mm
× 20 mm Pt; scan rate 50 mv/s.
vs Ag/Ag+ as shown in Figure 1. Two of them correspond to
the reported potential values of 1 and 2, and therefore, mono-
and difluorination of 1 must occur at 2.30 and 2.50 V in
Et3N-5HF, respectively. Trifluorination of 1 can be expected
to occur at 2.70 V from the observed oxidation potential value.
On the other hand, a distinct peak corresponding to the
tetrafluorination of 1 did not appear in the cyclic voltammetry,
which indicates that a higher potential than 2.80 V will be
required for the tetrafluorination.
Et3N-5HF and CH2Cl2 (0.08 M) at 35 °C. When the electrolysis
of 1 was carried out at 2.30 V until 2.2 F/mol of electricity had
passed, monofluorination occurred selectively at the tertiary
carbon to form 1-fluoroadamantane (2) in 74% yield with 2%
of 1,3-difluoroadamantane (3) (entry 1 in Table 1). Under these
conditions, 4% of 1 remained unchanged. However, when the
electrolysis was continued until the complete consumption of
1 (2.5 F/mol), the yield of 2 decreased to 67%, and the yield of
3 increased to 15% (entry 2). Difluorinated product 3 could be
prepared selectively by carrying out the electrolysis at 2.50 V
until 4.4 F/mol of electricity had passed. Under these conditions,
3 could be obtained in 79% yield with 2% of 2, which is
separable from 3 by silica gel column chromatography. When
the electrolysis of 1 was carried out at 2.70 V to obtain 1,3,5-
trifluoroadamantane (4), a large excess of electricity was
required to complete the reaction (11.0 F/mol), and 4 was
obtained in a moderate yield (entry 4). At this potential, a
chlorinated byproduct was formed by the chloride ion generated
from CH2Cl2. Therefore, in the preparation of 4, CH2Cl2 could
not be used as the cosolvent, and the reaction was carried out
in neat Et3N-5HF. To dissolve 1 in neat Et3N-5HF, the
reaction was carried out at a higher temperature (45 °C) in a
lower concentration (0.04 M). Under these conditions, the yield
of 4 increased to 61%, although a large excess of electricity
was still required (14.0 F/mol) (entry 5). Under the same
Anodic Fluorination of the Adamantane. As 1 is only
slightly soluble in neat Et3N-5HF at room temperature, the
fluorination reaction of 1 was carried out in a 2:1 mixture of
(7) (a) Yoneda, N.; Chen, S.-Q.; Hatakeyama, T.; Hara, S.; Fukuhara, T.
Chem. Lett. 1994, 849. (b) Hara, S.; Chen, S.-Q.; Hatakeyama, T.; Fukuhara,
T.; Sekiguchi, M.; Yoneda, N. Tetrahedron Lett. 1995, 36, 6511. (c) Hara, S.;
Chen, S.-Q.; Hoshio, T.; Fukuhara, T.; Yoneda, N. Tetrahedron Lett. 1996, 37,
8511. (d) Chen, S.-Q.; Hatakeyama, T.; Fukuhara, T.; Hara, S.; Yoneda, N.
Electrochim. Acta 1997, 42, 1951. (e) Hara, S.; Hatakeyama, T.; Chen, S.-Q.;
Ishi-i, K.; Yoshida, M.; Sawaguchi, M.; Fukuhara, T.; Yoneda, N. J. Fluorine
Chem. 1998, 87, 189. (f) Hou, Y.; Fuchigami, T. Tetrahedron Lett. 1999, 40,
7819. (g) Kobayashi, S.; Sawaguchi, M.; Ayuba, S.; Fukuhara, T.; Hara, S. Synlett
2001, 1938. (h) Hasegawa, M.; Ishii, H.; Fuchigami, T. Tetrahedron Lett. 2002,
43, 1503. (i) Tajima, T.; Fuchigami, T. Synthesis 2002, 2597. (j) Fukuhara, T.;
Akiyama, Y.; Yoneda, N.; Tada, T.; Hara, S. Tetrahedron Lett. 2002, 43, 6583.
(k) Hasegawa, M.; Ishii, H.; Fuchigami, T. Green Chem. 2003, 5, 512. (l) Tajima,
T.; Nakajima, A.; Fuchigami, T. J. Org. Chem. 2006, 71, 1436. As for the
reviews, see: (m) Noel, M.; Suryanarayanan, V.; Chellammal, S. J. Fluorine
Chem. 1997, 83, 31. (n) Dawood, K. M. Tetrahedron 2004, 60, 1435. (o)
Fuchigami, T.; Tajima, T. J. Fluorine Chem. 2005, 126, 181. (p) Fuchigami, T.
J. Fluorine Chem. 2007, 128, 311.
(8) Koch, V. R.; Miller, L. L. Tetrahedron Lett. 1973, 9, 693.
J. Org. Chem. Vol. 73, No. 11, 2008 4187

Aoyama et al.
TABLE 2. Electrochemical Fluorination of Functionalized Adamantanesa
a The reaction was carried out with 1 mmol of substrate in 12 mL of Et3N-5HF at room temperature. b Isolated yield based on substrate used. In
parenthese, GC yield.
conditions, the oxidation of Et3N-5HF also occurred competi-
tively, causing the low current efficiency of the reaction. The
preparation of 1,3,5,7-tetrafluoroadamantane (5) is more difficult
because the reaction must be carried out at a higher potential.
When the electrolysis of 1 was carried out at 3.0 V, the reaction
mixture turned dark brown, and 5 was obtained only in low
yield with the formation of insoluble solid materials. Therefore,
we adopted trifluoroadamantane 4 as the starting material for
5, which is more soluble than 1 in neat Et3N-5HF. Then, the
reaction could be carried out at a lower temperature (35 °C).
Under these conditions, 5 could be obtained in 41% yield,
although a large excess of electricity was required (60 F/mol)
(entry 6).
Fluorination of Functionalized Adamantanes. The elec-
trochemical fluorination of functionalized adamantanes, methyl
adamantane-1-carboxylate (6), dimethyl adamantane-1,3-dicar-
boxylate (10), 1-(acetoxymethyl)adamantane (13), and adaman-
tane-1-carbonitrile (17), was attempted. They are more soluble
in Et3N-5HF than 1, and the reactions could be carried out in
neat Et3N-5HF at room temperature. Methyl adamantane-1-
carboxylate 6 exhibited three anodic peaks at 2.45, 2.60, and
2.90 V vs Ag/Ag+in its cyclic voltammogram.9 When the
electrolysis of 6 was carried out at 2.45 V until 2.8 F/mol of
electricity had passed, the monofluorination of 6 occurred
selectively to produce methyl 3-fluoroadamantane-1-carboxylate
(7) in 84% yield (entry 1 in Table 2). A difluorinated product,
methyl 3,5-difluoroadamantan-1-carboxylate (8), was obtained
in 72% yield with 6% of a trifluorinated product (9) by carrying
out the electrolysis at 2.60 V (6.6 F/mol of electricity) (entry
2). For the selective preparation of the trifluorinated product 9,
although the reaction was carried out at a high oxidation
potential (2.90 V), 9 could be selectively obtained in 92% yield
(entry 3). The trifluorinated product 9 was prepared previously
from methyl 3-hydroxyadamantane-1-carboxylate in nine steps
in low overall yield and used for the synthesis of 3,5,7-trifluoro-
1-aminoadamantane (trifluoroamantadine) as a key inter-
mediate.3b In our method, 9 can be directly prepared from 6 in
high yield. Similarly, from dimethyl adamantane-1,3-dicarboxy-
late 10, a monofluorinated product (11) and a difluorinated
product (12) were obtained selectively in 76% and 86% yield,
respectively, by carrying out the reaction at 2.53 and 2.80 V
(entries 4 and 5). The monofluorination of 1-(acetoxymethyl)-
adamantane 13 occurred at 2.45 V to produce 1-(acetoxym-
ethyl)-3-fluoroadamantane (14) in 86% yield (entry 6). The
difluorination of 13 occurred at 2.70 V, and a difluorinated
product (15) was obtained in 80% yield with 6% of 14 and 5%
of a trifluorinated product (16) (entry 7). The fluorination of
(9) Koch, V. R.; Miller, L. L. J. Am. Chem. Soc. 1973, 95, 8631.
4188 J. Org. Chem. Vol. 73, No. 11, 2008

SelectiVe Fluorination of Adamantanes
were washed with aq NaHCO3 and dried over MgSO4. GC analysis
showed the adamantane 1, 1-fluoroadamantane (2), and 1,3-
difluoroadamantane (3) were present in a ratio of 5:92.5:2.5 in the
reaction mixture.10 Purification by column chromatography (silica
gel/hexane-ether) gave 2 (114 mg, 0.74 mmol) in 74% yield: mp
200-204 °C (sealed tube) (lit.5a mp 210-212 °C); IR (KBr) 2910,
2855, 1353, 1071 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.23 (br s,
3H), 1.90-1.88 (m, 6H), 1.66-1.56 (m, 6H); 19F NMR (376 MHz,
CDCl3) δ -129.02 to -129.07 (m, 1F) {lit.4e -128.95 to -129.01
(m)}; 13C NMR (100 MHz, CDCl3) δ 92.5 (d, 1JC-F ) 182.6 Hz),
42.7 (d, 2JC-F ) 17.3 Hz, 3C), 35.8 (d, 4JC-F ) 2.7 Hz, 3C), 31.5
(d, 3JC-F ) 9.3 Hz, 3C); HRMS (EI) calcd for C10H15F 154.1158,
found 154.1159.
adamantane-1-carbonitrile 17 was carried out at 2.70 V to
produce a monofluorinated product (18) in 80% yield with 7%
of a difluorinated product (19) (entry 8). Thus, the electrochemi-
cal fluorination of the adamantanes possessing the functional
groups such as ester, cyano, and acetoxymethyl groups pro-
ceeded selectively without influencing the functional groups.
On the other hand, the fluorination of the heteroatom-substituted
adamantanes, such as 1-adamantanol, 1-aminoadamantane,
1-(acetoxyamino)adamantane, and 1-bromoadamantane, was
unsuccessful, and the carbon-heteroatom bond was cleaved to
produce the 1-fluoroadamantane 2 instead of the expected
functionalized fluoroadamantanes.9
Preparation of Methyl 3-Fluoroadamantane-1-carboxylate
(7). The reaction was carried out as in the case of 4 except that the
electrolysis was carried out with 6 (194 mg, 1 mmol) at room
temperature in Et3N-5HF (12 mL) at 2.45 V (vs Ag/Ag+)7d until
2.8 F/mol of electricity had passed. Methyl 3-fluoroadamantane-
1-carboxylate (7) was obtained in 84% yield (purification by column
chromatography; silica gel/hexane-CH2Cl2): IR (neat) 2918, 2864,
Summary
We succeeded in the selective fluorination of adamantanes
by use of the electrochemical fluorination method with
Et3N-5HF as an electrolyte and a fluorine source. The selective
introduction of 1-3 fluorine atoms into the adamantanes was
achieved by carrying out the reaction under the control of the
oxidation potential, and the fluorine atoms were introduced
selectively into the tertiary carbons of adamantanes. Functional
groups, such as ester, cyano, and acetoxy, can tolerate the
reaction conditions, and 1-3 fluorine atoms could be selectively
introduced into the functionalized adamantanes.
1
1731, 1254, 1230 cm-1; H NMR (400 MHz, CDCl3) δ 3.68 (s,
3H), 2.34 (br s, 2H), 2.03 (d, J ) 5.7 Hz, 2H), 1.88-1.77 (m, 8H),
1.61-1.58 (m, 2H); 19F NMR (376 MHz, CDCl3) δ -132.97 (s,
4
1F); 13C NMR (100 MHz, CDCl3) δ 176.2 (d, JC-F ) 2.3 Hz),
1
3
92.1 (d, JC-F ) 183.8 Hz), 51.8, 44.8 (d, JC-F ) 10.2 Hz), 43.6
(d, 2JC-F ) 19.8 Hz), 41.8 (d, 2JC-F ) 17.7 Hz, 2C), 37.5 (d, 4JC-F
) 1.9 Hz, 2C), 34.7 (d, 4JC-F ) 2.2 Hz), 30.8 (d, 3JC-F ) 10.0 Hz,
2C); HRMS (EI) calcd for C12H17O2F 212.1213, found 212.1199.
Experimental Section
Supporting Information Available: General methods and
1
procedures for the preparation of fluoroadamantanes; H and
Preparation of 1-Fluoroadamantane (2). Adamantane (136 mg,
1 mmol) was dissolved in a mixture of Et3N-5HF (8 mL) and
CH2Cl2 (4 mL) and introduced into an undivided cell made of
Teflon PFA (20 mL). The electrolysis was carried out at 35 °C
with use of two smooth Pt sheets (20 mm × 20 mm) for the anode
and cathode at 2.30 V (vs Ag/Ag+)7d until 2.2 F/mol of electricity
had passed. Then, the reaction mixture was poured into water and
extracted with CH2Cl2 three times. The combined organic layers
13C NMR spectra of all fluoroadamantane products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO8004759
(10) A capillary column (25 m × 0.20 mm) of 100% polydimethylsiloxane
was used.
J. Org. Chem. Vol. 73, No. 11, 2008 4189