Effective fluorination reaction with Et3N·3HF under microwave irradiation

Article abstract of DOI:10.1055/s-2003-39395

Fluorination reaction of epoxides and alkyl mesylates can be effectively achieved by reaction with Et₃N·3HF under microwave irradiation. The reaction time could be greatly reduced compared to the reaction under thermal conditions. The reactions

Full text of DOI:10.1055/s-2003-39395

SHORT PAPER
1157
Effective Fluorination Reaction with Et N·3HF Under Microwave Irradiation
3
M
T
icrowave-Ass
o
iste
d
Fluorin
m
ation Reaction
w
ith
o
Et
N
·
3HF take Inagaki, Tsuyoshi Fukuhara, Shoji Hara*
3
Division of Molecular Chemistry, Graduate School of Engineering, Hokkaido University, Sapporo 060-8628, Japan
Fax +81(11)7066556; E-mail: hara@org-mc.eng.hokudai.ac.jp
Received 14 February 2003; revised 12 March 2003
Abstract: Fluorination reaction of epoxides and alkyl mesylates
can be effectively achieved by reaction with Et N·3HF under micro-
3
wave irradiation. The reaction time could be greatly reduced com-
pared to the reaction under thermal conditions. The reactions were
completed in a few minutes and the use of large excess of reagents
could be avoided.
Key words: microwave irradiation, epoxides, fluorination, ring
Equation 1
opening, Et N·3HF
3
the fluorination was completed in 2 minutes and 4a was
Among HF reagents, Et N·3HF has been widely used as a obtained in 63% yield (Equation 2). Moreover, under the
3
fluorinating reagent because it is commercially available, microwave irradiation conditions, only 1.2 equivalents of
is close to neutral, has a high boiling point, and can be Et
N·3HF was necessary to 1 equivalent of the substrate,
while 10 equivalents of the reagent were used under the
3
1
used in glassware. However, the fluorination reactions
thermal conditions.
using Et N·3HF often require high temperature and long
3
reaction time due to its low reactivity. For instance, the re-
Et
3
N⋅3HF
action of Et N·3HF with cyclohexene oxide (1a) was car-
3
Ph
F
Ph
OMs
MW, 2 min
4a
ried out at 115 °C for 3.5 hours to give trans-2-
3
a
2
fluorocyclohexanol (2a) in 69% yield. In the reaction
Equation 2
with cyclooctene oxide (1b), it took 4 hours at 155 °C to
obtain 2-fluorocyclooctanol (2b) in 54% yield. Recently,
microwave irradiation has been used in many reactions to As Et N·3HF is close to neutral, the reaction can tolerate
3
reduce the reaction time and to avoid the use of a large ex- functional groups such as a double bond (1d) and an ester
3
cess of reagents. However, the fluorination reaction us- (3b) as shown in Table 1.
ing HF reagents under microwave irradiation has not so
4
far been well developed. We wish to report here that the
The melting points were measured with a Yanagimoto micro melt-
fluorination reaction using Et N·3HF is accelerated dra-
3
ing point apparatus and are uncorrected. The IR spectra were re-
1
matically by microwave irradiation to provide fluorinated corded using a Jasco FT/IR-410 spectrometer. The H NMR (400
products in a short time.
1
9
MHz) and F NMR (376 MHz) spectra were recorded in CDCl on
3
a Jeol JNM-A400II FT NMR and the chemical shifts are referred to
Under the microwave irradiation conditions, the fluorina-
tion reaction of 1a and 1b was completed in 2 and 10 min-
1
19
TMS ( H) and CFCl ( F), respectively. The EI-HRMS were mea-
3
sured on a Jeol JMS-700TZ spectrometer.
utes, respectively, and only 0.6 equivalent of Et N·3HF to
3
A commercially available Gold Star microwave oven (500 W, MW-
JIK96H5) was modified to accept a port for connecting a reactor to
1
equivalent of 1 was required to obtain the corresponding
fluoroalcohols 2a and 2b in 61 and 60% yields, respec-
tively (Equation 1). Various epoxides 1a–e could be con- ameter was drilled at the top of the oven and an 8 cm length of Te-
verted to the corresponding fluoroalcohols 2a–f in 2–10 flon PFA tube was snugly fitted into the hole. A reflux condenser
minutes under the irradiation of microwaves as shown in
6
a reflux condenser located outside the oven. A hole of 10 mm di-
TM
located outside was connected to the port tightly and another side of
the port in the oven was used to connect to a reactor which is a Te-
Table 1.
TM
flon PFA tube with a diameter of 10 cm and a length of 8 cm
Nucleophilic substitution reaction of a fluoride with or- sealed at one end. Et N·3HF was purchased from Aldrich Chemical
3
ganic halides and mesylates is also a versatile method to Co. Epoxides 1a–d were purchased from Tokyo Kasei Co. (1c was
obtain organofluorine compounds. However, the reaction a mixture of cis- and trans-isomer) and were used without further
purification. The epoxide 1e was prepared from dec-1-ene by
of alkyl mesylate 3a with Et N·3HF is reported to be slug-
gish under thermal conditions and the corresponding
3
7
oxidation and the mesylates 3a,b were prepared from the corre-
8
sponding alcohols.
fluoride 4a was formed in only 20% yield after 20 hours
5
at 80 °C. On the other hand, under microwave irradiation,
Fluorination Reactions with Et N·3HF; trans-2-Fluorocyclo-
3
hexan-1-ol (2a); Typical Procedure
Synthesis 2003, No. 8, Print: 05 06 2003.
Art Id.1437-210X,E;2003,0,08,1157,1159,ftx,en;F01103SS.pdf.
Cyclohexene oxide (1a; 98 mg, 1 mmol) and Et N·3HF (97 mg, 0.6
mmol) were introduced into a reactor consisting of a Teflon PFA
tube with a diameter of 10 mm sealed at one end. The open end of
3
TM
©
Georg Thieme Verlag Stuttgart · New York

1
158
T. Inagaki et al.
SHORT PAPER
Table 1 Fluorination Using Et N·3HF Under Microwave Irradia-
tion
trans-2-Fluorocyclooctan-1-ol (2b)
Yield: 60%; oil.
3
a
2
IR (film): 3410 cm–1 (OH).
1H NMR (400 MHz, CDCl3): = 4.52 (ddt, J = 48.8, 8.5, 2.4 Hz, 1
Substrate
React. Time Product
min)
Yield
(%)
b
(
H), 3.91–3.83 (m, 1 H), 2.44 (s, 1 H), 2.05–1.41 (m, 12 H).
19F NMR (376 MHz, CDCl3): = –172.03 to –172.24 (m, 1 F).
OH
F
2
61
60
O
trans-2-Fluorocyclododecan-1-ol (trans-2c)
Yield: 76% (cis/trans mixture); mp 65.5–67 °C (Lit. mp 64–
9
1
1
a
2
a
6
5 °C).
OH
1
0
IR (KBr): 3337 cm–1 (OH).
O
1
H NMR (400 MHz, CDCl ): = 4.55 (dm, J = 49.3 Hz, 1 H), 3.92–
.86 (m, 1 H), 2.49 (s, 1 H), 1.91–1.34 (m, 20 H).
F
3
3
b
2b
2c
2d
19F NMR (376 MHz, CDCl3): = –193.93 to –194.24 (m, 1 F).
OH
F
76d
O
10
cis-2-Fluorocyclododecan-1-ol (cis-2c)
Yield: 76% (cis/trans mixture); mp 87–88 °C (Lit. mp 84–86 °C).
IR (KBr): 3390 cm–1 (OH).
1
9
1
cc
H NMR (400 MHz, CDCl ): = 4.71(dm, J = 48.1 Hz, 1 H), 3.97–
O
OH
3
F
3
.89 (m, 1 H), 1.90 (s, 1 H), 1.80–1.18 (m, 20 H).
2
2
71e,f
19F NMR (376 MHz, CDCl3):
= –191.15 (br s, 1 F).
1
2-Fluorocyclododeca-4,8-dien-1-ol (2d) (a mixture of two re-
1
d
gioisomers)
Yield: 71%; oil.
IR (film): 3375 cm–1 (OH).
O
F
45
C10H21
OH
F
C10H21
2e
1
e
1H NMR (400 MHz, CDCl3): = 5.55–5.23 (m, 4 H), 4.81–4.58 (m,
H), 4.02–3.91 (m, 1 H), 2.32–1.43 (m, 13 H).
1
OH
19F NMR (376 MHz, CDCl3): = –185.88 (br s, 0.6 F), –192.68 (br
s, 0.4 F).
47
C10H21
2f
+
63g
HRMS (EI): m/z Calcd for C H FO (M ): 198.1420. Found:
1
1
2
19
Ph (CH2)3 OMs
2
1
Ph (CH2)3
F
98.1436.
3a
4a
77g
AcO (CH2)6 OMs
AcO (CH2)6 F
2-Fluorododecan-1-ol (2e)
Yield: 45%; oil.
IR (film): 3301 cm–1 (OH).
1
1
0
3
b
4b
a
Unless otherwise mentioned, 0.6 equiv of Et N·3HF to 1 equiv of
3
substrate was used.
H NMR (400 MHz, CDCl ): = 4.58 (dm, J = 50.3 Hz, 1 H), 3.78–
3
b
Isolated yields based on substrate used.
A mixture of two stereoisomers was used.
A mixture of two stereoisomers was obtained.
A mixture of two regioisomers was obtained.
.0 equiv of Et N·3HF was used.
1
3.61 (m, 2 H), 1.82 (s, 1 H), 1.76–1.26 (m, 12 H), 0.88 (t, J = 6.8
Hz, 3 H).
19F NMR (376 MHz, CDCl3): = –190.07 to –190.45 (m, 1 F).
c
d
e
f
1
3
g
1-Fluorododecan-2-ol (2f)
Yield: 47%; oil.
.2 equiv of Et N·3HF was used.
3
10
IR (film): 3376 cm–1 (OH).
the reactor was connected to the port in the oven and the port was
connected to a reflux condenser located outside the oven. Then, the
reaction mixture was submitted to microwave irradiation for 2 min.
After cooling, the reaction mixture was poured into aq NaHCO3
1H NMR (400 MHz, CDCl3): = 4.50–4.20 (m, 2 H), 3.94–3.82 (m,
1
H), 1.99 (s, 1 H), 1.46–1.26 (m, 12 H), 0.88 (t, J = 6.6 Hz, 3 H).
1
9
F NMR (376 MHz, CDCl ): = –228.85 (dt, J = 47.6, 17.7 Hz, 1
3
F).
soln. The product was extracted with Et O (3 ×) and the combined
2
ethereal layers were dried (MgSO ). Purification by column chro-
4
1
-Fluoro-3-phenylpropane (4a)
matography (silica gel, eluent: hexane–Et O) gave 2a in 61% yield;
2
3
,11
2
Yield: 63%; oil.
mp 22–23 °C (Lit. mp 23–24 °C).
–
1
IR (film): 3377 cm–1 (OH).
IR (film): 2963 cm .
1
1
H NMR (400 MHz, CDCl ): = 7.49–7.11 (m, 5 H), 4.46 (dt,
3
H NMR (400 MHz, CDCl ): = 4.26 (dm, J = 51.3 Hz, 1 H), 3.59–
3
J = 47.1, 6.1 Hz, 2 H), 2.75 (t, J = 7.8 Hz, 2 H), 2.08–1.95 (m, 2 H).
3
.68 (m, 1 H), 2.45 (br s, 1 H), 2.13–1.99 (m, 2 H), 1.77–1.69 (m, 2
1
9
H), 1.51–1.20 (m, 4 H).
19F NMR (376 MHz, CDCl3): = –182.59 (d, J = 51.3 Hz, 1 F).
F NMR (376 MHz, CDCl ): = –220.62 (tt, J = 47.1, 25.0 Hz, 1
3
3
F) (Lit. = –220.2).
Synthesis 2003, No. 8, 1157–1159 ISSN 1234-567-89 © Thieme Stuttgart · New York

SHORT PAPER
Microwave-Assisted Fluorination Reaction with Et N·3HF
1159
3
1
-Acetoxy-6-fluorohexane (4b)
(5) Giudicelli, M. B.; Picq, D.; Veyron, B. Tetrahedron Lett.
1990, 31, 6527.
12
Yield: 77%; oil.
IR (film): 1740 cm–1 (C=O).
(6) Michael, D.; Mingos, P.; Baghurst, D. R. Chem. Soc. Rev.
1991, 20, 1.
1
H NMR (400 MHz, CDCl ): = 4.45 (dt, J = 47.3, 6.1 Hz, 2 H),
3
(7) Paquette, L. A.; Barrett, J. H. Org. Synth., Coll. Vol. 5;
Wiley: New York, 1973, 467.
4
.07 (t, J = 6.6 Hz, 2 H), 2.05 (s, 3 H), 1.77–1.62 (m, 4 H), 1.49–
1
.37 (m, 4 H).
(
8) Photis, J. M.; Paquette, L. A. Org. Synth., Coll. Vol. 6;
Wiley: New York, 1988, 482.
19F NMR (376 MHz, CDCl3): = –218.95 (tt, J = 47.3, 25.0 Hz, 1
F).
(9) Michael, D.; Schlosser, M. Tetrahedron 2000, 56, 4253.
(
10) (a) Tamura, M.; Shibakami, M.; Arimura, T.; Kurosawa, S.;
Sekiya, A. J. Fluorine Chem. 1995, 70, 1. (b) Tamura, M.;
Shibakami, M.; Sekiya, A. J. Fluorine Chem. 1997, 85, 147.
References
(
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(
(
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1
(
(
2) Wölker, D.; Haufe, G. J. Org. Chem. 2002, 67, 3015.
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(
4) For the fluorination reaction using HF reagent under
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Synthesis 2003, No. 8, 1157–1159 ISSN 1234-567-89 © Thieme Stuttgart · New York