Selective introduction of fluorine atoms to the tert-carbons of functionalized adamantanes by BrF3

Article abstract of DOI:10.1016/j.jfluchem.2012.10.010

The direct fluorination reaction of the functionalized adamantanes was achieved by using BrF₃. In the reaction with methyl adamantane-1-caroxylate 1 and dimethyl adamantane-1,3-dicarboxylate 3, three and two fluorine atoms, respectively, were i

Full text of DOI:10.1016/j.jfluchem.2012.10.010

Journal of Fluorine Chemistry 145 (2013) 128–131
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Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Selective introduction of fluorine atoms to the tert-carbons of functionalized
adamantanes by BrF3
*
Toru Shishimi, 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:
The direct fluorination reaction of the functionalized adamantanes was achieved by using BrF3. In the
reaction with methyl adamantane-1-caroxylate 1 and dimethyl adamantane-1,3-dicarboxylate 3, three
and two fluorine atoms, respectively, were introduced selectively to their tert-carbons. On the other
hand, in the reactions with 1-acetoxymethyladamantane 5, and 2-adamantanone 9, not only the
expected fluorination of their tert-carbons, but also unexpected reactions such as fluorination of
carbonyl functionality occurred.
Received 26 September 2012
Received in revised form 18 October 2012
Accepted 18 October 2012
Available online 30 October 2012
Keywords:
ß 2012 Elsevier B.V. All rights reserved.
Poly-fluorination
Adamantane
Bromine trifluoride
1. Introduction
carboxylate. For the introduction of more fluorine atoms to
adamantane derivatives with low reactivity, a more reactive
Adamantane is a simple cage compound consisting of four tert-
carbons and six sec-carbon atoms. Bioactive derivatives of
adamantane are known, and 1-aminoadamantane (amantadine)
and 1-amino-3,5-dimethyladamantane (memantine) have medic-
inal uses [1]. Introduction of fluorine atoms in bioactive
compounds can enhance their activities and reduce undesirable
side-effects. Therefore, the synthesis of fluorinated adamantane
derivatives has received significant attention [2]. Recently, we
reported the direct fluorination of adamantanes by an electro-
chemical method [3]. One to three fluorine atoms can be
introduced selectively on the tert-carbons of the adamantanes
by controlling the conditions, and functional groups such as ester
or cyano groups could survive under the conditions. However, a
drawback is that special equipment is required for the electro-
chemical reaction. Therefore, we also studied the fluorination of
adamantanes by non-electrochemical methods, and succeeded in
the fluorination of adamantanes with IF5, without the special
equipment needed for electrolysis [4]. However, owing to the
inherent reactivity of IF5, only one or two fluorine atoms could be
introduced. Moreover, when electron-withdrawing groups were
attached on the substrate, fewer (or no) fluorine atoms could be
introduced. For example, 1-cyanoadamantane and dimethyl
adamantane-1,3-dicarboxylate were inert to IF5, and only one
fluorine atom could be introduced to methyl adamantane-1-
fluorination reagent than IF5 is required [5]. Herein, we report the
direct fluorination of adamantanes using BrF3 [6], which is more
reactive than IF5 [8].
2. Results and discussion
Initially, the reaction of methyl adamantane-1-carboxylate 1
with BrF3 was performed. The reaction proceeded even at À78 8C,
and three fluorine atoms were introduced to its tert-carbons (Entry
1 in Table 1). The best result was obtained by performing the
reaction using 4 eq. of BrF3 at 0 8C for 3 h, and methyl 3,5,7-
trifluoroadamantane-1-carboxylate 2 was obtained in 88% yield
(Entry 3). These results demonstrated the higher reactivity of BrF3
compared to IF5 in the direct fluorination reaction of the
adamantanes.
Next, we applied BrF3 to the fluorination of dimethyl
adamanatane-1,3-dicarboxylate 3, which was inert to IF5, and
obtained dimethyl 5,7-difluoroadamantane-1,3-dicarboxylate 4 in
86% yield (Entry 2 in Table 2). Unexpected reactions also occurred
during the fluorination reaction using BrF3. When 1-acetoxy-
methyladamantane 5 was reacted with BrF3 at À78 8C for 0.5 h,
two fluorine atoms were selectively introduced and 1-acetox-
ymethyl-3,5-difluoroadamantane 6 was obtained in 94% yield
(Entry 3). On the other hand, when the reaction was carried out at
0 8C for 6 h, three fluorine atoms were introduced and 1-
acetoxymethyl-3,5,7-trifluoroadamantane 7 was obtained in 62%
yield (Entry 4). However, unexpectedly, 1-((1,1-difluoroethoxy)-
methyl)-3,5,7-trifluoroadamantane 8 was also formed in 14% yield.
* Corresponding author.
E-mail address: shara@eng.hokudai.ac.jp (S. Hara).
0022-1139/$ – see front matter ß 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2012.10.010

T. Shishimi, S. Hara / Journal of Fluorine Chemistry 145 (2013) 128–131
129
Table 1
Reaction of methyl adamantane-1-carboxylate 1 with BrF3.
Entry
BrF3/1
Temperature (0 8C)
React time (h)
Yield of 2 (%)a
1
2
3
6
4
4
À78
0
1
2
3
72
(88)
0
88 (95)
a
Isolation yield based on 1, in parentheses, 19FNMR yield.
Table 2
Reaction of functionalized adamantanes with BrF3.a
Entry
Adamantane
Conditions
Product
Yield (%)b
1
0 8C, 2 h
88
2
0 8C, 6 h
86
3
À78 8C, 0.5 h
94
4
5
0 8C, 6 h
62c
5
0 8C, 6 h
67
a
If otherwise not mentioned, the reaction was carried out in CH2Cl2 using 4 eq. of BrF3.
Isolated yield based on 1 used. In parentheses, 19F NMR yield.
b
c
1-((1,1-Difluoroethoxy)methyl)-3,5,7-trifluoroadamantane 8 was also formed in 14% yield.

130
T. Shishimi, S. Hara / Journal of Fluorine Chemistry 145 (2013) 128–131
The mixture was extracted with CH2Cl2 (20 mL Â 3) and the
combined organic phase was washed with aq Na2S2O3 and dried
over MgSO4. After concentration under reduced pressure, 2 was
isolated by column chromatography (silica gel, hexane-ether) in
88% yield. mp 109–112 8C (sealed tube) (lit. [2] 108.5–110 8C); IR
(KBr) 2958, 1737, 1339, 1259, 1226, 964 cmÀ1; 1H NMR (400 MHz,
CDCl3)
CDCl3)
d
3.74 (s, 3H), 2.16–1.99 (m, 12H); 19F NMR (376 MHz,
d
À144.00 (s, 3F); 13C NMR (100 MHz, CDCl3)
d
173.4 (q, 4JC-
1
3
F = 3.4 Hz), 91.7 (dt, JC-F = 191.2, JC-F = 15.3 Hz, 3C), 52.6, 46.6–
46.0 (m, 3C), 43.2 (q, 3JC-F = 11.8 Hz), 42.1–41.7 (m, 3C); HRMS (EI)
calcd for C12H15O2F3 248.1024, found 248.1013.
4.2.2. Dimethyl 5,7-difluoroadamantane-1,3-dicarboxylate (4)
mp 87–89 8C (sealed tube); IR (KBr) 2960, 1738, 1435,
Scheme 1. Plausible mechanism for the formation of 10 and 11.
1275 cmÀ1 1H NMR (400 MHz, CDCl3)
; d 3.72 (s, 6H), 2.12 (t,
Under these conditions, the fluorination of the carbonyl group also
occurred [9]. In the reaction with 2-adamantanone 9, a mixture of
tetrafluorinated compounds 10 and 11 was obtained (Entry 5).
Rearrangement of the carbonyl group occurred in addition to the
fluorination of the carbonyl group and tert-carbons [11] (Scheme 1).
These unexpected reactions were due to the high reactivity of
BrF3, and were not observed in the case of IF5.
J = 5.3 Hz, 2H), 2.05–1.97 (m, 8H), 1.93 (brs, 2H); 19F NMR (376 MHz,
CDCl3)
d
À140.21 (s, 2F); 13C NMR (100 MHz, CDCl3)
d
173.9 (t, 4JC-
F = 2.6 Hz, 2C), 92.4 (dd, 1JC-F = 189.1, 3JC-F = 14.3 Hz, 2C), 52.4 (2C),
2
3
3
46.7 (t, JC-F = 19.3 Hz), 45.0 (t, JC-F = 11.0 Hz, 2C), 42.2 (t, JC-
F = 6.0 Hz, 2C), 42.0(t, 3JC-F = 5.9 Hz, 2C), 38.3(t, 4JC-F = 2.0 Hz);HRMS
(EI) calcd for C14H18O4F2, 288.1173, found 288.1183.
4.2.3. 1-(Acetoxymethyl)-3,5-difluoroadamantane (6)
3. Conclusion
IR (neat) 2949, 1741, 1243 cmÀ1 1H NMR (400 MHz, CDCl3)
; d
3.86 (s, 2H), 2.49 (brs, 1H), 2.10 (brs, 2H), 2.08 (s, 3H), 1.83–1.65 (m,
Various functionalized adamantanes were reacted with BrF3,
and two to three fluorine atoms were introduced selectively on
their tert-carbons. Even when less reactive substrates such as
methyl adamantane-1-carboxylate 1 or dimethyl adamantane-1,3-
dicarboxylate 3, were used, multiple fluorine atoms were
introduced to their tert-carbons. On the other hand, in the reaction
of 1-acetoxymethyladamantane 5 and 2-adamantanone 9, unex-
pected reactions occurred, such as the fluorination of carbonyl
group, and rearrangement.
8H), 1.43(brs, 2H); 19F NMR (376 MHz, CDCl3)
NMR (100 MHz, CDCl3)
d
À137.54 (s, 2F); 13
C
1
3
d
170.9, 93.0 (dd, JC-F = 188.1, JC-
4
2
F = 13.6 Hz, 2C), 71.1 (t, JC-F = 1.9 Hz), 47.5 (t, JC-F = 19.0 Hz),
43.3 (t, 4JC-F = 5.5 Hz), 43.1 (t, 4JC-F = 5.6 Hz), 40.8 (t, 4JC-F = 5.4 Hz),
40.6 (t, 4JC-F = 5.4 Hz), 39.2 (t, 3JC-F = 10.3 Hz), 36.6 (t, 4JC-F = 2.1 Hz),
3
30.4 (t, JC-F = 10.6 Hz), 20.7; HRMS (EI) calcd for C13H18O2F2
244.1275, found 244.1285.
4.2.4. 1-(Acetoxymethyl)-3,5,7-trifluoroadamantane (7)
mp 58–63 8C (sealed tube); IR (KBr) 2947, 1749, 1336, 1237,
4. Experimental
1217, 1024 cmÀ1 1H NMR (400 MHz, CDCl3)
; d 3.94 (s, 2H), 2.16–
2.08 (m, 6H), 2.10 (s, 3H), 1.69 (brs, 6H); 19F NMR (376 MHz, CDCl3)
4.1. General
d
À144.07 (s, 3F); 13C NMR (100 MHz, CDCl3)
d
170.7, 92.0 (dt, 1JC-
3
4
F = 190.5, JC-F = 15.0 Hz, 3C), 70.2 (q, JC-F = 2.1 Hz), 46.7–46.2 (m,
3C), 42.4–42.1 (m, 3C), 37.0 (q, JC-F = 11.4 Hz), 20.7; HRMS (EI)
3
The melting points were measured with a Yanagimoto micro
melting-point apparatus. The IR spectra were recorded using a
JASCO FT/IR-410. The 1H NMR (400 MHz) spectra, 19F NMR
(376 MHz) spectra, and 13C NMR (100 MHz) were recorded in
CDCl3 on a JEOL JNM-A400II FT NMR and the chemical shift,
referred to TMS (1H, 13C) and CFCl3 19F), respectively. BrF3 in a
cylinder was purchased from Galaxy Chemicals, LLC and used
without purification. BrF3 was transferred from cylinder to a
TeflonTM bottle through a TeflonTM tube using nitrogen pressure,
and a small quantity of BrF3 in a small Teflon bottle was kept in a
freezer [12]. It decomposes in air by humidity emitting HF fume
and was handled in a bench hood with rubber-gloved hands under
atmosphere of nitrogen. It is highly reactive and a special care is
required for its use. BrF3 is stable in glasswear but the reaction was
carried out in a centrifuge tube of TeflonTM FEP with a tight screw
cap because generation of HF occurs during the reaction.
calcd for C13H17O2F3 262.1181, found 262.1167.
4.2.5. 1-((1,1-Difluoroethoxy)methyl)-3,5,7-trifluoroadamantane (8)
d
, is
IR (neat) 2964, 1336, 1027 cmÀ1 1H NMR (400 MHz, CDCl3)
; d
(
3.67 (s, 2H), 2.15–2.04 (m, 6H), 1.75 (t, J = 13.3 Hz, 3H), 1.69 (brs,
6H); 19F NMR (376 MHz, CDCl3)
d
À69.92 (q, J = 13.3 Hz, 2F),
1
À144.07 (s, 3F); 13C NMR (100 MHz, CDCl3)
d 124.8 (t, JC-
1
3
F = 260.6 Hz), 92.1 (dt, JC-F = 191.6, JC-F = 3.2 Hz, 3C), 69.2–69.0
4
(m), 47.0–46.2 (m, 3C), 42.5–42.2 (m, 3C), 37.1 (t, JC-F = 11.5 Hz),
2
22.5 (t, JC-F = 32.6 Hz); HRMS (EI) calcd for C13H17F5O 284.11996,
found 284.11940.
4.2.6. 1,5,5,8-Tetrafluoro-4-oxatricyclo[4.3.1.13,8]undecane (10)
mp 102–104 8C, IR (KBr) 2965, 1389, 1116 cmÀ1 1H NMR
;
(400 MHz, CDCl3)
d 4.59 (s, 1H), 2.79 (brs, 1H), 2.31–2.25 (m, 4H),
2.18–2.04 (m, 2H), 2.03–2.00 (m, 2H), 1.91 (brs, 2H); 19F NMR
4.2. Fluorination of adamantane derivatives by BrF3
(376 MHz, CDCl3)
d
À57.71 (s, 2F) À135.66 (s, 2F); 13C NMR
1
1
(100 MHz, CDCl3)
d 128.2 (t, JC-F = 248.2 Hz), 93.0 (dd, JC-
3
3
4.2.1. Methyl 3,5,7-trifluoroadamantane-1-carboxylate (2)
F = 185.9 Hz, JC-F = 13.2 Hz, 2C), 71.6–71.2 (m), 47.1 (t, JC-
F = 18.8 Hz), 41.2–40.8 (m, 2C), 36.4–35.5 (m, 2C), 34.5–34.2
(m); HRMS (EI) calcd for C10H12F4O 224.08243, found 224.08195.
To a CH2Cl2 solution (1.5 mL) of BrF3 (378 mg, 2.76 mmol) in a
TeflonTM FEP reactor, methyl adamantane-1-carboxylate (134 mg,
0.69 mmol) in CH2Cl2 (0.8 mL) was added at À78 8C through a
TeflonTM cannula and the mixture was stirred at 0 8C for 2 h. Then
the mixture was cooled to À78 8C again, and 2 mL of Me3SiCl was
added slowly to decompose the excess of BrF3. The mixture was
brought up to room temperature and neutralized with aq NaHCO3.
4.2.7. 1,3,5,5-Tetrafluoro-4-oxatricyclo[4.3.1.13,8]undecane (11)
mp 85–87 8C, IR (KBr) 2961, 1371, 1111 cmÀ1
;
1H NMR
(400 MHz, CDCl3)
d 2.77 (brs, 1H), 2.59–2.50 (m, 2H), 2.37–2.21
(m, 3H), 2.10–2.02 (m, 2H), 1.96–1.89 (m, 3H), 1.72–1.68 (m, 1H);

T. Shishimi, S. Hara / Journal of Fluorine Chemistry 145 (2013) 128–131
131
19F NMR (376 MHz, CDCl3)
d
À59.87 (d, J = 166.3 Hz, 1F), À63.34 (d,
(c) A.A. Spasov, T.V. Khamidova, L.I. Bugaeva, I.S. Morozov, Pharmaceutical
Chemistry Journal 34 (2000) 1–7;
(d) W.J. Geldenhuys, S.F. Malan, J.R. Bloomquist, A.P. Marchand, C.J. Van der
Schyf, Medicinal Research Reviews 25 (2005) 21–48.
J = 166.3 Hz, 1F), À95.10 (d, J = 9.0 Hz, 1F), À135.99 (s, 1F); 13C
NMR (100 MHz, CDCl3) d
124.4 (dt, 3JC-F = 11.5 Hz, 1JC-F = 254.2 Hz),
114.3 (dt, 1JC-F = 217.0 Hz, 3JC-F = 15.3 Hz), 90.2 (dd, 1JC-F = 184.1 Hz,
[2] V.J. Jasys, F. Lombardo, T.A. Appleton, J. Bordner, M. Ziliox, R.A. Volkmann, Journal
of the American Chemical Society 122 (2000) 466–473.
[3] M. Aoyama, T. Fukuhara, S. Hara, Journal of Organic Chemistry 73 (2008) 4186–
4189.
4
3
3JC-F = 14.3 Hz), 46.6 (dt, JC-F = 2.9 Hz, JC-F = 23.8 Hz), 40.6–40.1
(m, 2C), 39.8 (dt, 3JC-F = 12.2 Hz, 2JC-F = 30.5 Hz), 35.3–35.0 (m), 28.8
(dd, 3JC-F = 12.4 Hz, 3JC-F = 10.5 Hz), 28.2 (brd, 4JC-F = 6.9 Hz); HRMS
(EI) calcd for C10H12F4O 224.08243, found 224.08157.
[4] S. Hara, M. Aoyama, Synthesis (2008) 2510–2512.
[5] S. Hara, in: K.K. Laali (Ed.), Advances in Organic Synthesis, Bentham Science
Publishers Ltd/, Hilversum, Netherlands, 2006, pp. 49–60.
[6] Previously, the reaction of 1-cyanoadamantane with BrF3 was reported to give
3,5-difluoroadamantane [7].
Acknowledgment
[7] S. Rozen, D. Rechavi, A. Hagooly, Journal of Fluorine Chemistry 111 (2001) 161–165.
[8] As for the reviews of the fluorination using BrF3, see:
(a) S. Rozen, Accounts of Chemical Research 38 (2005) 803–812;
(b) S. Rozen, Advanced Synthesis and Catalysis 352 (2010) 2691–2707.
We are grateful to Prof. Hermann-Josef Frohn (University of
Duisburg-Essen, Germany) for his kind advice on the handling of
BrF3.
[9] Conversion of an ester group to
a difluoromethylene ether was previously
reported by the reaction of a-cyano esters with BrF3 [7,10].
[10] A. Hagooly, S. Rozen, Journal of Organic Chemistry 69 (2004) 7241–7245.
[11] A similar fluorination reaction accompanying the rearrangement was reported in
the reaction of a trivalent bromine reagent with benzaldehyde, see: M. Ochiai, A.
Yoshimura, M.M. Hoque, T. Okubo, M. Saito, K. Miyamoto, Organic Letters, 13
(2011) 5568–5571.
References
[1] (a) J.W. Tilley, M.J. Kramer, in: G.P. Ellis, G.G. West (Eds.), Progress in Medicinal
Chemistry, Elsevier, Amsterdam, Netherlands, 1981, pp. 1–44;
(b) C.G. Parsons, W. Danysz, G. Quack, Neuropharmacology 38 (1999) 735–
767;
[12] BrF3 can be stored in a cylinder at room temperature under complete blocking of
humidity.