Fluorocyclization of unsaturated alcohols and carboxylic acids by iodotoluene difluoride and amine-HF complexes

Article abstract of DOI:10.1016/S0022-1139(00)00241-4

In the presence of amine-HF complexes, iodotoluene difluoride reacted with unsaturated alcohols and carboxylic acids to give cyclic fluoroethers and fluorolactones, respectively.

Full text of DOI:10.1016/S0022-1139(00)00241-4

Journal of Fluorine Chemistry 104 (2000) 277±280
Fluorocyclization of unsaturated alcohols and carboxylic acids
by iodotoluene di¯uoride and amine-HF complexes
Masanori Sawaguchi, Shoji Hara*, Tsuyoshi Fukuhara, Norihiko Yoneda1
Division of Molecular Chemistry, Graduate School of Engineering, Hokkaido University, Sapporo 060-8628, Japan
Received 15 October 1999; received in revised form 11 January 2000; accepted 16 February 2000
Abstract
In the presence of amine-HF complexes, iodotoluene di¯uoride reacted with unsaturated alcohols and carboxylic acids to give cyclic
¯uoroethers and ¯uorolactones, respectively. # 2000 Elsevier Science S.A. All rights reserved.
Keywords: Iodotoluene di¯uoride; Cyclic ¯uoroethers; Fluorolactones; Amine-HF complexes
1. Introduction
hand, when a strongly acidic complex such as Et3N-7HF or
pyridine-9HF was used, 2a was consumed even at 458C in
1 h, but a complex mixture was formed. Consequently, a
slightly acidic reagent such as Et3N-5HF and pyridine-6HF
was found to be suitable for the reaction and especially, in
the presence of pyridine-6HF, the reaction was completed at
458C in 3 h to give the desired ¯uorinated tetrahydrofuran
derivative 3a in 60% yield as a mixture of two stereoi-
somers2 (Entry 1 in Table 1).
Under the same reaction conditions, 1-cyclohexyl-3-
buten-1-ol (2b) and 1-decen-5-ol (4) gave the ¯uorinated
tetrahydrofuran derivative (3b) and tetrahydropyran deriva-
tive (5), respectively, in moderate yields (Entries 2, 4). From
1-allylcyclohexanol (2c), which has an acid-sensitive tert-
alcohol function, the expected spiro compound (3c) was
obtained in lower yield (Entry 3). Consequently, the unsa-
turated alcohols (2a-4) gave endo-cyclized products in 40±
60% yields. The ¯uorocyclization of unsaturated carboxylic
acids (6, 8) was more sluggish and was carried out at room
temperature. In the reaction of 3-butenoic acid, the endo-
cyclization product, g-¯uoro-g-butyrolactone (7), was
obtained. During the isolation, 7 partially changed to an
unsaturated lactone by the loss of HF which caused a
decrease in the yield (Entry 5). From the 4-pentenoic acids
(8), unexpected exo-cyclization products, g-¯uoromethyl-g-
butyrolactones (9), were obtained instead of the expected d-
valerolactone derivatives (Entries 6, 7).
Fluorinated carbohydrates have been of great interest
because of their signi®cant biological activity and useful-
ness in proving biochemical mechanisms [1±14]. Fluorocy-
clization reaction of unsaturated alcohols and carboxylic
acids by electrophilic ¯uorinating reagents seems to be
effective for the synthesis of ¯uorinated carbohydrates.
However, such methodology for transformation has not been
developed because the electrophilic ¯uorinating reagents are
generally too reactive to control the ¯uorination±cyclization
sequences. Recently, we found that iodotoluene di¯uoride
(1) reacts with alkenes to give vic-di¯uorides as the electro-
philic ¯uorinating reagents [15], and in an extension of that
work, we applied 1 to the ¯uorocyclization reaction of
unsaturated alcohols and carboxylic acids (Scheme 1).
2. Results and discussion
At ®rst, the ¯uorocyclization reaction of 1-nonen-4-ol
(2a) was examined. The reaction of 2a with 1 was carried out
in CH2Cl2 using various kinds of HF-amine complexes
which are necessary for the activation of 1 [15]. Recently,
Et3N-3HF has been used as a mild and less-corrosive
¯uorinating reagent [16,17]. However, Et3N-3HF did not
effectively activate 1 and the starting 2a remained
unchanged after 24 h at room temperature. On the other
These results can be explained as follows: lodotoluene
di¯uoride 1 activated by amine-HF adds to the double bond
* Corresponding author. Tel.: ‡81-11-706-6556; fax: ‡81-11-706-6556.
E-mail address: hara@org-mc.eng.hokudai.ac.jp (S. Hara)
1 Co-corresponding author.
2 The separation of the stereoisomers was possible by column
chromatograhy but the determination of their structures were difficult.
0022-1139/00/$ ± see front matter # 2000 Elsevier Science S.A. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 0 ) 0 0 2 4 1 - 4

278
M. Sawaguchi et al. / Journal of Fluorine Chemistry 104 (2000) 277±280
Scheme 1.
to give the intermediate (10). In the case of nˆ1, the attack
of a ¯uoride on the C3 of 10 is faster than the formation of a
four membered ring by the intramolecular attack of a
hydroxy group. The resulting iodonium intermediate (11)
cyclized to give the ¯uorinated tetrahydrofuran derivatives
(3a±c) or g-lactone (7) (Scheme 2).
In the case of nˆ2, the formation of the ®ve-membered
intermediate (12) by the intramolecular attack of the
hydroxy group on C4 of 10 is faster than the intermolecular
¯uoride attack. When the unsaturated alcohol (4) was used,
the elimination of the p-Tol-I-F part was assisted by the lone
pair electron on ethereal oxygen to give the bicyclic oxo-
nium intermediate (13) [18], which was then converted to
Scheme 2.
the ¯uorinated tetrahydropyran derivative (5) by the attack
of a ¯uoride on C4. Therefore, from the unsaturated alcohols
and 3-butenoic acid 6, the formally endo-cyclized products
were obtained (Scheme 3).
In the reaction of the 4-pentenoic acids, the oxygen
attached to the carbonyl group is not so nucleophilic as
to form an oxonium intermediate such as 13, and the simple
displacement of the p-Tol-I-F group of 12 by a ¯uoride took
Table 1
Fluorocyclization of unsaturated alcohols and carboxylic acidsa
Entry
Substrate
Reaction conditions
Product
Yield (%)b
60 (1:1)
1
458C, 3 h
2
3
4
5
6
7
458C, 2 h
458C, 3.5 h
458C, 4 h
r.t., 3 h
55 (1:1)
40
50 (4:3)
40
r.t., 3 h
40
r.t., 3 h
50 (2:1)
a The reaction was carried out as shown in an experimental part.
b Isolated yields based on substrates used. The ratio of stereoisomers is shown in parentheses.

M. Sawaguchi et al. / Journal of Fluorine Chemistry 104 (2000) 277±280
279
[22]. Into a 300 ml three-necked round ¯ask equipped with a
dry ice condenser, a mechanical stirrer, and an inlet tube for
the introduction of Cl2, were placed iodotoluene (21.8 g,
100 mmol) and CH2Cl2 (75 ml). The Cl2, generated from
MnO2 (30.5 g, 350 mmol) and conc. HCl (80 ml), was
introduced to the reaction mixture under stirring. After
the introduction of Cl2, the mixture was stirred for 1 h at
room temperature and then cooled to 788C. The generated
solid was separated by ®ltration, washed with a small
amount of CHCl3 and dried in air on ®lter paper to give
iodotoluene dichloride (a yellow solid, 24.5 g) which was
used for the next step.
Scheme 3.
Into a 500 ml vessel made of ¯uororesin, iodotoluene
dichloride (24.5 g), HgO (23.8 g, 110 mmol) and CH2Cl2
(200 ml) were introduced and the mixture was vigorously
stirred at room temperature. Then 46% hydro¯uoric acid
(60 ml) was added and the mixture was stirred vigorously
again. After 10 min, a white solid (HgCl2) was removed by
®ltration using an apparatus made of ¯uororesin, and the
®ltrate was extracted three times with CH2Cl2. The organic
layer was dried over MgO and concentrated under reduced
pressure to give a pale yellow solid of iodotoluene di¯uoride
Scheme 4.
place to provide the g-¯uoromethyl-g-lactones (9a, 9b)
(Scheme 4).
1
3. Conclusion
(21.3 g, 83 mmol). mp. 140±1428C. H NMR d: 2.47 (s,
3H), 7.56 (d, 2H, Jˆ8.4 Hz), 7.84 (d, 2H, Jˆ8.4 Hz) ppm.
19F NMR d: 147.30 (s, 2F) ppm.
The ¯uorocyclization reaction of unsaturated alcohols
and carboxylic acids was carried out using iodotoluene
di¯uoride 1 and pyridine-6HF. From the 1-alken-4-ols
and 1-alken-5-ol, the formal endo-cyclization products,
the 3-¯uorotetrahydrofuran derivatives and 3-¯uorotetrahy-
dropyran derivative, were selectively obtained, respectively.
On the other hand, the ¯uorinated g-lactone derivatives were
obtained from 3-butenoic acid and the 4-pentenoic acids.
4.2. Fluorocyclization reaction of unsaturated alcohols
2a±c, 4
To a CH2Cl2 solution (5 ml) of an unsaturated alcohol
(1 mmol) in a vessel made of ¯uororesin was added at
458C, a pyridine-6HF solution (5 ml) of iodotoluene
di¯uoride (332 mg, 1.3 mmol). The reaction was monitored
by TLC and continued until the consumption of the starting
material was con®rmed. The mixture was then poured into
water, and the product was extracted with CH2Cl2. The com-
bined organic layers were dried over MgSO4. After con-
centration under reduced pressure, the product was isolated
by column chromatography (silica gel/hexane-ether).
2-Pentyl-4-¯uorotetrahydrofuran (3a, one isomer): IR:
4. Experimental details
IR spectra were recorded using a JASCO FT/IR-410. The
1H NMR (400 MHz) and 19F NMR (376 MHz) spectra were
recorded in CDCl3 on a JEOL JNM-A400II FT NMR.
Chemical shifts, d, are referred to TMS (1H) and CFCl3
(19F), respectively. EI-low and high-resolution mass spectra
were measured on a JEOL JMS-DX303. The pyridine-HF
and Et3N-HF complexes were prepared from freshly dis-
tilled pyridine or Et3N and anhydrous HF [19]. The unsa-
turated alcohols 2a, 2b and 2c were prepared by the reaction
of allylmagnesium bromide with heptanal, cyclohexanecar-
boaldehyde, and cyclohexanone, respectively. Similarly, 4
was prepared from 3-butenylmagnesium bromide and hex-
anal. The unsaturated carboxylic acid 8b was prepared by
the reaction of the phenylacetic acid dianion with allyl
bromide [20].
1
1101, 1079, 962 cm . 1H NMR d: 0.89 (t, 3H, Jˆ6.8 Hz),
1.31±1.66 (m, 9H), 2.21±2.31 (m, 1H), 3.90±4.12 (m, 3H),
5.18±5.33 (m, 1H) ppm. 19F NMR d: 174.37 to 173.89
(m, 1F) ppm. HRMS (EI) calc. for C9H17FO 160.1263 found
160.1253.
1
(3a, another isomer): IR: 1134, 1096, 962 cm . 1H NMR
d: 0.89 (t, 3H, Jˆ6.8 Hz), 1.30±1.88 (m, 9H), 2.25±2.39 (m,
1H), 3.59±3.71 (m, 3H), 3.81±3.88 (m, 1H), 4.10±4.18 (m,
1H), 5.1±5.30 (m, 1H) ppm. 19F NMR d: 171.57 to
171.10 (m, 1F) ppm. HRMS (EI) calc. for C9H17FO
160.1263 found 160.1276.
2-Cyclohexyl-4-¯uorotetrahydrofuran (3b, one isomer):
1
IR: 1450, 1080, 962 cm . 1H NMR d: 0.95±1.76 (m, 11H),
4.1. Preparation of iodotoluene difluoride 1
1.92±1.96 (m, 1H), 2.15±2.25 (m, 1H), , 5.17±5.33 (m, 1H)
ppm. 19F NMR d: 174.57 to 174.09 (m, 1F) ppm. HRMS
(EI) calc. for C10H17FO 172.1263 found 172.1269.
Iodotoluene di¯uoride was prepared from iodotoluene
dichloride [21] by a modi®cation of the reported procedure

280
M. Sawaguchi et al. / Journal of Fluorine Chemistry 104 (2000) 277±280
1
(3a, another isomer): IR: 1450, 1082, 963 cm . 1H NMR
4.48 (m, 3H), 4.46±4.61 (m, 3H), 7.26±7.40 (m, 5H)
ppm. 19F NMR: d: 233.90 to 233.50 (m, 1F) ppm.
HRMS calc. for C11H11FO2 194.0743 found 194.0760.
d: 0.88±2.00 (m, 12H), 2.18±2.33 (m, 1H), 3.48±3.68 (m,
2H), 4.08±4.17 (m, 1H), 5.14±5.30 (m, 1H) ppm. 19F NMR
d: 171,70 to 171.24 (m, 1F) ppm. HRMS (EI) calc. for
C10H17FO 172.1263 found 172.1248.
(9b, minor stereoisomer): IR: 1764, 1498, 1458,
1
1172 cm
.
1H NMR: d: 2.31±2.40 (m, 1H), 2.69±2.76
3-Fluoro-1-oxaspiro[4.5]decane (3c): IR: 1447, 1088,
(m, 1H), 3.91±3.97 (m, 1H), 4.44±4.60 (m, 1H), 4.65±
4.81 (m, 2H), 7.26±7.40 (m, 5H) ppm. 19F NMR: d:
233.90 to 233.50 (m, 1F) ppm. HRMS calc for
C11H11FO2 194.0743 found 194.0735.
1
1
965 cm . H NMR d: 1.40±1.94 (m, 1H), 2.05±2.14 (m,
1H), 3.87±4.13 (m, 2H) 5.15±5.31 (m, 1H) ppm. 19F NMR
d: 172.43 to 171.96 (m, 1F) ppm. HRMS (EI) calc. for
C9H15FO 158.1107 found 158.1110.
5-Fluoro-2-pentyltetrahydropyran (5, major isomer): IR:
1
1
1101, 1039 cm . H NMR: d: 0.88 (t, Jˆ 6.7 Hz, 3H),
1.21±1.82 (m, 11H), 2.18±2.24 (m, 1H), 3.19±3.30 (m, 1H),
4.42±4.62 (m, 1H) ppm. 19F NMR: d: 188.00 to 187.805
(m, 1F) ppm. HRMS calc. for C10H19FO 174.1420 found
174.1418.
Acknowledgements
This work was ®nancially supported by a Grant-in-Aid
for Scienti®c Research (B) from the Japanese Ministry of
Education, Science, Sports and Culture.
1
(5, minor stereoisomer): IR: 1118, 1061 cm . 1H NMR:
d: 0.89 (t, Jˆ6.83 Hz, 3H), 1.24±1.80 (m, 11H), 2.09±2.18
(m, 1H), 3.26±3.30 (m, 1H), 3.47±3.60 (m, 1H), 4.07±4.15
(m, 1H), 4.51±4.64 (m, 1H) ppm. 19F NMR: d: 189.40 to
188.00 (m, 1F) ppm. HRMS calc. for C10H19FO 174.1420
found 174.1423.
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1
1
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(m, 1H), 5.36±5.43 (m, 1H); 19F NMR: d: 176.96 to
176.50 (1F, m) ppm. HRMS calc. for C9H17FO
104.0274 found 104.0274.
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1
1187 cm
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(m, 1H), 2.50±2.68 (m, 2H), 4.39±4.77 (m, 3H) ppm. 19F
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1
.
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