Practical synthesis of gem-difluorides from cyclohexanone: Synthesis of gem-bistrifluoroacetates and their reactions with fluoride nucleophiles

Article abstract of DOI:10.1016/j.jfluchem.2009.09.017

Formation of ketone acylals bearing trihaloacetoxy groups and their nucleophilic geminal disubstitution by fluoride ions were investigated. Cyclohexanone reacted with trifluoroacetic anhydride without catalyst to give gem-bistrifluoroacetates via a concerted bimolecular reaction. Treatment with hydrogen fluoride under mild conditions efficiently yielded the corresponding gem-difluorides. In this reaction process, trifluoroacetic acid was recovered and converted to trifluoroacetic anhydride using P₂O₅. Since gem-difluorides were derived from ketones, HF and P₂O₅, this constitutes a practical synthesis of gem-difluorides.

Full text of DOI:10.1016/j.jfluchem.2009.09.017

Journal of Fluorine Chemistry 131 (2010) 29–35
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Practical synthesis of gem-difluorides from cyclohexanone: Synthesis of
gem-bistrifluoroacetates and their reactions with fluoride nucleophiles
c
a
Masahiro Tojo a,b, , Shinsuke Fukuoka , Hiroshi Tsukube
*
a Department of Chemistry, Graduate School of Science, Osaka City University, Sugimoto, Sumiyoshi-ku, Osaka 558-8585, Japan
b Chemistry and Chemical Process Laboratory, Asahi KASEI Chemicals Corporation, 2767-11 Niihama, Kojima-Shionasu, Kurashiki, Okayama 711-8510, Japan
c New Business Development, Asahi KASEI Corporation, 1-105 Kanda Jinbocho, Chiyoda-ku, Tokyo 101-8101 Japan
A R T I C L E I N F O
A B S T R A C T
Article history:
Formation of ketone acylals bearing trihaloacetoxy groups and their nucleophilic geminal disubstitution
by fluoride ions were investigated. Cyclohexanone reacted with trifluoroacetic anhydride without
catalyst to give gem-bistrifluoroacetates via a concerted bimolecular reaction. Treatment with hydrogen
fluoride under mild conditions efficiently yielded the corresponding gem-difluorides. In this reaction
process, trifluoroacetic acid was recovered and converted to trifluoroacetic anhydride using P2O5. Since
gem-difluorides were derived from ketones, HF and P2O5, this constitutes a practical synthesis of gem-
difluorides.
Received 5 September 2009
Received in revised form 22 September 2009
Accepted 24 September 2009
Available online 30 September 2009
Keywords:
Fluorination
gem-Difluorides
Acylals
ß 2009 Elsevier B.V. All rights reserved.
Bistrifluoroacetates
1. Introduction
thiocarbonyl derivatives with electrophilic halonium species were
also developed [16]. Since the employed fluorinating agents and
Aldehyde acylals are readily synthesized from aldehydes and
acid anhydrides with the aid of various catalysts [1,2]. They are
successfully used as protecting groups of aldehydes [3] and
substrates for nucleophilic substitution [1,4]. On the other hand,
only a limited number of ketones react with substituted acid
anhydrides having electron withdrawing groups such as trichlor-
oacetic anhydride [5] and trifluoroacetic anhydride to give ketone
acylals [6]. Since it was found that some ketone acylals are subject
to hydrolysis [2d] and elimination of carboxylic acids [7], their
derivatives bearing two acyloxy groups on the same carbon atom
can serve as reactive intermediates for nucleophilic geminal
disubstitution to give gem-difluorides.
gem-Difluorides have been synthesized as potential pharma-
ceuticals [8] and functional organic materials [9] by various
methods [10]. Direct fluorination of carbonyl compounds was
reported using SF4, diethylaminosulfur trifluoride (DAST) [11],
carbonyl fluoride [12], fluoroalkylamino reagent (FAR) [13], and
2,2-difluoro-1,3-dimethylimidazolidine (DFI) [14]. Indirect fluor-
ination of carbonyl compounds with IF or BrF3 [15] and oxidative
desulfurization-fluorination of ortho-thioesters, dithiolanes, and
oxidizing agents were not re-used easily, these methods were not
applicable in industrial processes. Furthermore, sophisticated
reactions were required in which hydrogen fluoride and metal
fluorides worked as nucleophilic fluorinating agents. We have
previously reported the synthesis of gem-bistrifluoroacetoxy
derivatives from ketones and trifluoroacetic anhydride. The
obtained ketone acylals efficiently reacted with fluoride anion to
give gem-difluorides [6]. Herein, we report the chemical reactivity
and reaction mechanism of ketone acylals, the formation of gem-
bistrifluoroacetates, and their subsequent reaction with several
fluorides to give gem-difluorides. Cyclohexanone was demon-
strated to react with trifluoroacetic anhydride to give gem-
bistrifluoroacetates via a concerted bimolecular reaction even in
the absence of catalyst. Further treatment with hydrogen fluoride
or pyridinium poly(hydrogen fluoride) yielded gem-difluorides
under mild conditions with the aid of catalyst. We successfully
recovered the trifluoroacetic acid from the reaction mixture and
converted it to trifluoroacetic anhydride using P2O5. Therefore, the
present method provides a practical synthesis of gem-difluorides.
2. Results and discussion
2.1. Formation of ketone acylals
* Corresponding author at: Chemistry and Chemical Process Laboratory, Asahi
KASEI Chemicals Corporation, 2767-11 Niihama, Kojima-Shionasu, Kurashiki,
Okayama 711-8510, Japan. Tel.: +81 86 458 6601; fax: +81 86 458 3335.
E-mail address: tojo.mb@om.asahi-kasei.co.jp (M. Tojo).
We first compared the reactivity of acid anhydrides 2a–2c in the
formation of ketone acylals 3a–3c. In order to characterize the
0022-1139/$ – see front matter ß 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2009.09.017

30
M. Tojo et al. / Journal of Fluorine Chemistry 131 (2010) 29–35
Table 1
Reaction of cyclohexanone 1 with acid anhydrides 2.
.
Entry
(RCO)2O (equiv.)
BF3-OEt2 (mol%)
Time (h)
Yielda
Initial rateb (% hꢀ1
)
Kc (L molꢀ1
)
3 (%)
4 (%)
6 (%)
1
2
3
2a (1)
2a (1)
2a (3)
0.8
0
4
36
73
1
4
3
6
9.0
8.8
8.0
72
9.8
8.4
6.6
5
44
76
2
4
0
0
43
0
4
32
92
0.5
2
0
0
72
4
5d
6
2b (3)
2b (3)
2c (3)
2c (3)
0
72
4
1
17
0
0
5
0
9
0
22
0
0
0
72
4
7
0.8
12
3
a
Determined by gas-liquid chromatography.
Initial formation rate: yield (3, %)/time(h).
K = [3a]/[1][2a].
b
c
d
Carried out at 100 8C.
reaction profiles, three kinds of acid anhydrides having –CF3, –CCl3,
and –CH3 groups were compared. Cyclohexanone 1 was reacted
with acid anhydrides 2 at room temperature. Reaction conditions
and selected results are summarized in Table 1. When trifluor-
oacetic acid anhydride 2a was employed (Entries 1–3), 1,1-
bistrifluoroacetoxycyclohexane 3a was formed as the major
product.
the distillation was conducted at higher pressure (bp 107–110 8C/
70 mmHg), acylal 3a decomposed gradually to starting materials
2a and 1. This indicates that the acylal formation reaction occurred
reversibly. Since acylal 3a was successfully isolated by distillation,
a practical synthetic process was developed.
2.2. Mechanism for ketone acylal formation
When the reaction was carried out without catalyst at room
temperature for 72 h, gem-diacyloxycyclohexane 3 was obtained
in 92% yield with 2a (Entry 3), 1% with 2b (Entry 4) and 0% with 2c
(Entry 6). Since 2a was the most reactive acid anhydride, the
trifluoromethyl group with its smaller bulkiness and higher
electron-withdrawing ability was suggested to be more effective
than trichloromethyl and methyl groups. In addition to the main
product 3, a small amount of cyclohexenyl acylate 4 was detected
as a by-product, which was derived from 3 by elimination of
carboxylic acid 5. Addition of BF3-OEt2 slightly influenced the
initial rate of 3a (9.0 [% hꢀ1] with BF3-OEt2 and 8.8 [% hꢀ1] without
catalyst), indicating that it did not catalyze the main reaction but
did catalyze the condensation of 1 to form by-product 6 [17]. Acylal
3b was obtained in 17% yield at 100 8C as reported earlier [5],
though considerable amounts of 4b and 6 were formed (Entry 5).
BF3-OEt2 seemed to work in the case of 2c and promoted the
formation of 4c and 6 (Entry 7).
The product/reactant ratios (K = [3a]/[1][2a]) were calculated
after equilibrium was reached (Entries 1–3 in Table 1). They ranged
from 6.6 to 9.8 [L molꢀ1] depending on the concentrations of 2a
and BF3-OEt2. The yield of acylal 3a reached 92% with three
equivalents of 2a, while the formation of by-product 4a decreased
(Entry 3). These observations indicate that the equilibrium
between 1 and 3a was far to the right at room temperature.
The unreacted 2a was first distilled from the reaction mixture of
Entry 3 under reduced pressure (20 mmHg), and then acylal 3a was
distilled under reduced pressure (bp 84–86 8C/19 mmHg). When
There are several mechanisms which can explain the non-
catalytic reaction of ketone (or aldehyde) and trihaloacetic
anhydride 2 (Scheme 1). Route A involves nucleophilic attack by
the ketone carbonyl group on 2 to form a carbocation and a
trihaloacetate anion [18]. Routes B and C involve dipolar concerted
reactions via intermolecular rearrangement through 6-centered
transition states [5,18]. Route B comprises a one-step addition of 2
to the carbonyl compound via bimolecular reaction, while Route C
comprises a two-step addition of 2 to the carbonyl compound via
trimolecular reaction [5]. Route D involves the participation of two
anhydride molecules in the acid-catalyzed aldehyde acylal
formation [19,1b].
We characterized kinetic profiles of the reaction between
ketone 1 and acid anhydrides 2 to elucidate the mechanism (Fig. 1).
The addition reaction occurred reversibly, but the reverse reaction
could be disregarded during the initial reaction period (<10 h). If
the reaction follows second-order kinetics in 1 and 2, integral
representations of the reaction rates are:
1
1
ꢀ
¼ k2t ðwhen ½1ꢁ0 ¼ ½2ꢁ0Þ
(1)
(2)
½1ꢁ ½1ꢁ0
ꢀ
ꢁ
½2ꢁ ½1ꢁ
½1ꢁ00½2ꢁ
ln
¼ k2t ðwhen ½1ꢁ0 ¼ ½2ꢁ0Þ
where [1]0 and [2]0 are the initial concentrations of 1 and 2.

M. Tojo et al. / Journal of Fluorine Chemistry 131 (2010) 29–35
31
Scheme 1. Possible mechanism of acylal formation.
If the reaction follows first-order kinetics in 1, integral
representation of the reaction rate is:
shown in Fig. 1 (right). Different k1 values were obtained (Entry 1:
0.28 hꢀ1; Entry 3: 0.17 hꢀ1), indicating that first-order kinetics are
inapplicable to the present reaction system. Thus, the addition
reaction of 1 with 2a was demonstrated to occur via a bimolecular
reaction. BF3-OEt2 catalyst was reported to promote the formation
of the aldehyde acylal [2a,4b,4d] and ketone acylal from 2c [2b],
but did not influence the reactions of 2a and 2b [5,17]. Our studies
suggest that the formation of the acylal bearing trihaloacetoxy
groups involves a dipolar concerted reaction via intermolecular
rearrangement through a 6-centered bimolecular transition state
as illustrated in Route B of Scheme 1.
ln½1ꢁ ꢀ ln½1ꢁ0 ¼ k1t
(3)
Second-order plots (left) and first-order plots (right) of Entries 1
and 3 are shown in Fig. 1. To disregard the reverse reaction, the
data were taken at <10 h. As plotted in Fig. 1 (left), the calculated
(1/[1] ꢀ 1/[1]0) of Eq. (1) and the calculated {ln([2a]0[1]/[1]0[2a])}
of Eq. (2) were found to have linear relationships with time. The
second-order rate constants k2 were calculated from the slopes of
the linear plots to be 0.034 L molꢀ1 hꢀ1 for Entry 1, and
0.035 L molꢀ1 hꢀ1 for Entry 3. Since the two obtained k2 values
are almost identical, second-order kinetics are applicable to the
present reaction system. For comparison, first-order rate constants
k1 for the different initial concentration conditions were calculated
based on a linear relationship between (ln[1] ꢀ ln[1]0) and time as
2.3. Reaction of ketone acylals with fluoride ion
The nucleophilic fluorination of the isolated acylals 3 was
carried out next (Table 2). When acylal 3a was treated with HF-
pyridine (HF-Py) without catalyst at ꢀ60 8C to room temperature
for 2 h, a precipitate appeared and the reaction did not proceed
(Entry 1). Addition of trifluoroacetic acid 5a initiated the reaction,
and 1,1-difluorocyclohexane 8 was obtained in 94% yield (Entry 2).
The yield of 8 depended on the amount of HF-pyridine (Entries 2
and 3), though a possible intermediate 1-fluoro-1-trifluoroacetox-
ycyclohexane 7 was not observed in the reaction. Other ketone
acylals 3b and 3c reacted with HF-pyridine in the presence of 5a to
give 8 in 26% yield from 3b and 0.5% yield from 3c (Entries 4 and 5),
showing that 3a was the most reactive acylal. Anhydrous hydrogen
fluoride (AHF) also worked as a fluorinating agent (Entry 7)
without 5a (Entry 8). Metal fluorides were also examined as
nucleophilic fluorinating agents, but KF and CsF did not promote
the reaction (Entries 9 and 10).
Since addition of an acid catalyst initiated the reaction, the
reaction may begin with protonation of the carbonyl group of
substrate 3 (Scheme 2). The trihaloacetoxy group itself did not
work as a good leaving group, but came off when the protonation
occurred via a SN2cA or SN1cA mechanism. This enhanced the
reactivity of the ketone acylal enough for it to be attacked by a
weak nucleophile such as a fluoride ion even at low temperature.
Fig. 1. Kinetic profiles of the reaction between ketone 1 and acid anhydride 2a.
Second-order plots of 1/[1] ꢀ 1/[1]0 vs time for Entry 1, and ln([2a]0[1]/[1]0[2a]) vs
time for Entry 3 (left); first-order plots of ln[1] ꢀ ln[1]0 vs time for Entries 1 and 3
(right). Conditions: see Table 1.

32
M. Tojo et al. / Journal of Fluorine Chemistry 131 (2010) 29–35
Table 2
Formation of gem-difluorides from gem-bistrifluoroacetates.
.
Entry
3a
3a
Fluoride (equiv.)
5a (mol%)
Solvent (wt%)
Temperature
Time (h)
Isolated yield of 8 (%b)
1
2
HF-Py (39)
HF-Py (39)
HF-Py (23)
HF-Py (39)
HF-Py (39)
HF-Py (39)
AHF (23)
AHF (23)
KF (20)
0
7
None
ꢀ60 8C to rtd
ꢀ60 8C to rt
ꢀ30 8C to rt
ꢀ30 8C to rt
ꢀ30 8C to rt
ꢀ30 8C to rt
ꢀ30 8C to rt
ꢀ30 8C to rt
80–90 8C
2
2
0
94
83
26
0.5
99
88
81
0
3a
3a
3b
3c
3ac
3a
3a
3a
3a
None
3
7
None
2
4
7
None
5
5
7
None
5
6
5
None
5
7
7
None
12
12
8
8
0
None
9
200
7
Sulfolan (63)
Sulfolan (58)
10
CsF (10)
80–90 8C
10
0
a
Distilled 3 (99.5% purity) was used.
Yield is based on 3.
b
c
A mixture containing 3a (93%) and 4a (3%) was prepared from the reaction mixture of Entry 3 in Table 1.
When the acylal was added to the HF-pyridine solution at ꢀ60 8C, a precipitate appeared.
d
Scheme 2. Possible mechanism for gem-difluoride formation from acylal: nuclephilic substitution.
A mixturecontaining 3a (93%)and 4a (3%) was prepared from the
2.4. Recovery of trifluoroacetic acid anhydride 2a for recycling
reaction mixture of Entry 3 in Table 1. This gave 8 in 99% yield under
the employed conditions (Entry 6 in Table 2). Since contaminant 4a
was not detected in the reaction mixture, 4a was converted to
possibleintermediate7aenrouteto8. Thismeans that4aisnot aby-
product but one of the intermediates for 8 via an elimination-
additionmechanism. The isolated9aalsoreactedwithHFtoafford8,
indicating that the addition of HF to 4a and 9a occurred. However,
the conversion of 3a to 4a occurred very slowly with or without acid
catalyst (Entries 1 and 2 in Table 1), suggesting that the elimination
of 5a from trifluoroacetates 3a and 7a occurred slowly (Scheme 3).
Thus, fluorine disubstitution proceeded mainly via nucleophilic
substitution as shown in Scheme 2.
synthesis of gem-difluorides
Two recycle synthesis systems of gem-difluoride 8 were
compared in Scheme 4. In the HF-Py process, trifluoroacetic acid
5a was recovered via calcium trifluoroacetate in order to
separate it from HF-Py. In the AHF process, 5a was recovered
by distillation. The recovered 5a was dehydrated to 2a using
P2O5 in both processes. Both HF-Py and AHF fluorinated the
ketone acylals, but AHF is a more favorable reagent from an
industrial perspective because AHF does not yield by-product
except H3PO4, and HF is easily recovered by distillation when
AHF is used.
Scheme 3. Possible mechanism for gem-difluoride formation from acylal: elimination–addition.

M. Tojo et al. / Journal of Fluorine Chemistry 131 (2010) 29–35
33
Scheme 4. Recycling synthesis systems of gem-difluoride 4.
3. Conclusions
4.1.3. 1,1-Diacetoxycyclohexane 3c [2c,2d,7b]
Colorless liquid, bp 98–100 8C/5 mmHg. MS (EI): m/z 200 (M+,
5%). 1H NMR (CDCl3):
1.35–1.5 (m, 6H), 1.7–1.8 (m, 4H), 2.1 (s, 6H).
We described the formation and nucleophilic geminal disub-
stitution of ketone acylals 3. Acylals having trihaloacetoxy groups 3
easily reacted with HF to give gem-difluorides 4 in good yields
under mild conditions without any active fluorinating agents and
oxidizing agents. This two-step gem-difluorination procedure was
applicable to a variety of ketones and aldehydes [6d]. Since the
formed 5a was recycled to 2a using P2O5 as a dehydrating agent,
d
4.1.4. 1-Trifluoroacetoxycyclohexene 4a [20]
MS (EI): m/z 194 (M+, 25%). 1H NMR (CDCl3):
2.0–2.4 (m, 4H), 5.5 (m, 1H).
d
1.6–2.0 (m, 4H),
4.1.5. 1-Trichloroacetoxycyclohexene 4b [5]
the present method provides
difluorides from ketones, HF and P2O5.
a
practical synthesis of gem-
Colorless liquid, bp 50–52 8C/0.09 mmHg (Ref. [5] 53–56 8C/
0.11 mmHg). MS (EI): m/z 226 (M+, 10%). 1H NMR (CDCl3):
d1.6–1.8
(m, 4H), 2.1–2.3 (m, 4H), 5.4–5.6 (m, 1H).
4. Experimental
4.1.6. 1-Acetoxycyclohexene 4c [21]
4.1. Synthetic procedure of ketone acylals 3 (Table 1)
Colorless liquid, bp 84–85 8C/25 mmHg (Ref. [21b] 74–76 8C/
17 mmHg). MS (EI): m/z 98 (M+ ꢀ42, 100%). 1H NMR (CDCl3):
d 1.4–
To the magnetically stirred solution of carboxylic anhydride 2
(0.1–1.35 mol) and BF3-etherate (0.8 mmol), cyclohexanone 1
(0.1–0.45 mol) was added slowly at room temperature under
nitrogen atmosphere, and the mixture was stirred for up to 72 h.
Only trichloroacetic anhydride 2b was reacted at 100 8C for 4 h. All
the reaction mixtures were analyzed using gas-liquid chromato-
graphy every 2–10 h. After the unreacted carboxylic anhydride was
evaporated under reduced pressure, the crude product was
distilled under reduced pressure to give 3. Products 4a, 4b, 4c
and 6 were also separated by gas-liquid chromatography and
characterized spectroscopically.
2.4 (m, 8H), 2.1 (s, 3H), 5.2–5.4 (m, 1H).
4.1.7. 2-(1-Cyclohexenyl)cyclohexanone 6 [17]
MS (EI): m/z 178 (M+, 57%). 1H NMR (CCl4):
d 0.7–3.0 (m, 17H),
5.4–5.5 (m, 1H).
4.2. Synthetic procedure of 1,1-difluorocyclohexane 4 (Table 2, Entries
1–6)
4.2.1. 1,1-Difluorocyclohexane 8 [22]
70% HF-Pyridine1 (60 g, 2.1 mol) and 5a (1.9 mmol or 1.4 mmol)
were mixed in a 1-L polyethylene bottle and cooled to ꢀ60 or
ꢀ30 8C.2 1,1-Diacyloxycyclohexane 3 (27 mmol) was added slowly
at ꢀ30 8C with stirring, and the mixture was further stirred for 2 h
while warming to room temperature. The resulting mixture was
4.1.1. 1,1-Bis(trifluoroacetoxy)cyclohexane 3a [6a]
Colorless liquid, bp 84–86 8C/19 mmHg, 107–110 8C/70 mmHg
(slightly decomposed). MS (EI): m/z 308 (M+, 1%), 195 (27), 194
(38), 81 (100), 80 (83). 1H NMR (CDCl3):
(m, 4H).
d 1.2–1.8 (m, 6H), 2.1–2.7
1
Caution: HF-pyridine is corrosive and should be handled in a well ventilated
hood with protection.
4.1.2. 1,1-Bis(trichloroacetoxy)cyclohexane 3b [5]
Colorless liquid, bp 105–107 8C/0.04 mmHg (Ref. [5] 110–
112 8C/0.05 mmHg). MS (EI): m/z 245 (M+ –OCOCCl3, 20%). 1H NMR
2
When the acylal was added to the HF-pyridine solution at ꢀ 60 8C, a solid
material precipitated. As they were both soluble at ꢀ 30 8C, addition of the residual
acylal rarely gave precipitation, suggesting that the solid materials were the
unsolubilized acylal.
(CDCl3):
d 1.2–1.8 (m, 6H), 2.0–2.8 (m, 4H).

34
M. Tojo et al. / Journal of Fluorine Chemistry 131 (2010) 29–35
extracted with diethyl ether (20 mL ꢂ 5). The extract was washed
with water (20 mL ꢂ 2), saturated aq. NaHCO3 (20 mL ꢂ 3), and
water (20 mL ꢂ 2). The combined organic layers were dried over
MgSO4, and the solvent was evaporated. The residue was distilled
under atmospheric pressure to give 1,1-difluorocyclohexane 8
[22]: colorless liquid, bp 99–101 8C/760 mmHg (Ref. [22b] 99–
was extracted with diethyl ether and analyzed by gas–liquid
chromatography.
Acknowledgment
The authors thank Prof. Katagiri at Okayama University for
fruitful discussions about the organic fluorine chemistry.
100 8C/760 mmHg). 1H NMR (CDCl3):
d 1.9–2.3 (m, 10H). MS (EI):
m/z 120 (M+, 9%), 100 (63), 80 (12), 57 (98), 41 (100). Fluoride anion
and trifluoroacetate anion were detected by ion chromatographic
analysis of the combined aqueous layer.
References
[1] (a) L.K. Sydnes, M. Sandberg, Proc. Ind. Nat. Sci. Acad.: Part A 68 (2002) 141–174;
(b) S.M. Lukyanov, A.V. Koblik, Russ. Chem. Rev. 65 (1996) 1–25;
Usp. Khim. 65 (1996) 3–28.
[2] (a) M.B. Smith, J. March, Advanced Organic Chemistry, 6th ed., John Wiley & Sons,
Inc., Hoboken, NJ, 2007, p. 1273;
4.2.2. Synthetic procedure of authentic sample 8
1-Fluorocyclohexene 9 was synthesized according to literature
procedures [23]. 1-Fluorocyclohexene 9 [22c,24]: MS (EI): m/z 100
(M+, 47%). 1H NMR (CCl4):
d 1.7–2.0 (m, 4H), 2.1–2.4 (m, 4H), 5.1 (d,
1H). Authentic sample 8 was derived from 9 [25]. HF-Pyridine
(71 g, HF 2.5 mol) was added in a polyethylene bottle and cooled to
ꢀ30 8C. 9 (200 mmol) was added slowly at ꢀ30 8C with stirring,
and the mixture was further stirred for 2 h while warming to room
temperature. The resulting mixture was worked up as described
above to give 8: yield 15.1 g (63%). The obtained 8 showed identical
1H NMR spectra to the reported one [22c,23].
(b) M. Curini, F. Epifano, M.C. Marcotullio, O. Rosati, M. Nocchetti, Tetrahedron
Lett. 43 (2002) 2709–2711;
(c) W. Su, J. Can, J. Chem. Res. (2005) 88–90;
(d) P. Sun, Z. Hu, J. Chem. Res. (2005) 659–660.
[3] T.W. Greene, P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd ed., Wiley,
New York, 1999, pp. 306–307.
[4] (a) Y.K. Ku, R. Patel, D. Sawick, Tetrahedron Lett. 34 (1993) 8037–8040;
(b) L.K. Sydnes, M. Sandberg, Tetrahedron 53 (1997) 12679–12690;
(c) M. Sanberg, L.K. Sydnes, Tetrahedron Lett. 39 (1998) 6361–6364;
(d) M. Sandberg, L.K. Sydnes, Org. Lett. 2 (2000) 687–689;
(e) B.M. Trost, C.B. Lee, J. Am. Chem. Soc. 123 (2001) 12191–12201;
(f) L.K. Sydnes, G.S. Pedersen, B. Holmelid, M. Sandberg, Synthesis (2007) 3692–
3696.
4.2.3. Conversion of 5a to 2a
[5] J. Libman, M. Sprecher, Y. Mazur, Tetrahedron 25 (1969) 1679–1698.
[6] (a) M. Tojo, S. Fukuoka, Jpn. Kokai Tokkyo Koho (1988), JP 63-041443;
Chem. Abstr. 109 (1988) 230380;
2a was typically recovered from the aqueous extracts and
washings of the reaction mixture in Entry 6 in Table 2. One half
of the aqueous mixture (105 g) containing trifluoroacetate anion
(28 mmol) was added to a 500-mL polyethylene bottle and
cooled to 0 8C. Ca(OH)2 (45 g, 0.61 mol) was added slowly at 0 8C
with vigorous stirring, and the mixture was further stirred for
2 h while warming to room temperature. After the formed CaF2
and excess of Ca(OH)2 were filtered off, the filtrate was distilled
at atmospheric pressure to recover pyridine and diethyl ether as
azeotropic mixtures with water, and then passed through a
polystyrenesulfonic acid type cation-exchange column
(exchange capacity: 1.2 equiv./L, 100 mL) to convert calcium
trifluoroacetate to its acid solution. The column was washed by
water (100 mL), and the washing was added to the acid solution.
The concentrated 5a solution (5a: 64 wt%, 27 mmol) was
obtained after adding distilled water. Phosphorus pentoxide
(5.7 g, 40 mmol) was added with cooling to the concentrated 5a
solution, and the mixture was stirred at room temperature for
8 h [26]. Distillation under reduced pressure yielded a mixture
of 2a and 5a (2.8 g, 2a: 88 wt%, 12 mmol), which means that 89%
of 2a was recovered.
(b) M. Tojo, S. Fukuoka, Jpn. Kokai Tokkyo Koho (1988), JP 63-044536;
Chem. Abstr. 109 (1988) 230381;
(c) M. Tojo, S. Fukuoka, Jpn. Kokai Tokkyo Koho (1988), JP 63-054331;
Chem. Abstr. 110 (1989) 74914;
(d) S. Fukuoka, M. Tojo, Jpn. Kokai Tokkyo Koho (1989), JP 1-199922;
Chem. Abstr. 112 (1990) 97726.
[7] (a) R. Dalpozzo, A. De Nino, L. Maiuolo, M. Nardi, A. Procopio, B. Russo, A. Tagarelli,
ARKIVOC (Gainesville, FL, United States) (2006) 181–189;
(b) I.V. Machinskaya, J. Gen. Chem. USSR 22 (1952) 1205–1207;
Zh. Obshch. Khim. 22 (1952) 1159–1163.
[8] (a) S. Purser, P.R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 37 (2008)
320–330;
(b) K. Mueller, C. Faeh, F. Diederich, Science 317 (2007) 1881–1886;
(c) K. Uneyama, Fluorine in Drug Designs. Organofluorine Chemistry, Blackwell,
Oxford, 2006, pp. 206–222;
(d) T. Itoh, in: I. Ojima (Ed.), Fluorine in Medicinal Chemistry and Chemical
Biology, Wiley–Blackwell, London, 2009, pp. 313–315;
(e) T. Itoh, in: V.A. Soloshonok, K. Mikami, T. Yamazaki, J.T. Welch, J.F. Hoenk
(Eds.), Current Fluoroorganic Chemistry: New Synthetic Directions, Technologies,
Materials, and Biological Applications, ACS Symp. Ser. 949, American Chemical
Society, Washington, DC, 2007, pp. 352–362.
[9] (a) S. Singh, Liquid Crystals: Fundamentals, World Scientific Publications, 2002;
(b) T. Itoh, M. Kanbara, M. Ohashi, S. Hayase, M. Kawatsura, T. Kato, K. Miyazawa,
Y. Takagi, H. Uno, J. Fluorine Chem. 129 (2007) 1112–1120.
[10] (a) K. Uneyama, Transformation of Carbonyl group to –CF2–. Organofluorine
Chemistry, Blackwell, Oxford, 2006, pp. 263–266;
(b) P. Kirsch, Modern Fluoroorganic Chemistry. Synthesis, Reactivity
Applications, Wiley–VCH, Weinheim, Germany, 2004;
(c) R.D. Chambers, Fluorine in Organic Chemistry, Blackwell, Oxford, 2004;
(d) B.E. Smart, K.E. Laali (Eds.), Advances in Organic Synthesis, vol. 2, 2006, pp. 3–
592 (Chap. 1–16);
4.2.4. Synthetic procedure of 8 (Table 2, Entry 7) and recovery of 2a
The reaction was carried out in a Hastelloy C reactor equipped
with a distillation column, a thermometer, a pressure gauge and a
safety valve. 3a (15.4 g, 0.05 mol) and 5a (7 mol%, 3.5 mmol) were
introduced in the reactor, followed by AHF (46 g, 2.3 mol) in vacuo
after cooling down the reactor (ꢀ76 8C). The reaction mixture was
fractionated under atmospheric pressure without further work-up,
and separated into a first fraction boiling up to 30 8C (45 g, HF:
99 wt%, 5a: 0.9 wt%), a second fraction boiling up to 101 8C (12 g,
5a: 96 wt%, 8: 4 wt%) and a final fraction with a boiling point in the
range of 102 to 104 8C (5.3 g, 8: 99.9%, yield: 88%). To the second
fraction described above, phosphorus pentoxide (4.3 g, 30 mmol)
was added with cooling, and the mixture was stirred at room
temperature for 8 h. Distillation under reduced pressure yielded a
mixture of 2a, 8, and 5a (11 g, 2a: 89 wt%, 47 mmol). This shows
that 94% of 2a was recovered.
(e) T. Itoh, N. Ishida, K. Mitsukura, K. Uneyama, J. Fluorine Chem. 112 (2001) 63–
68;
(f) Y. Guo, K. Fujiwara, H. Amii, K. Uneyama, J. Org. Chem. 72 (2007) 8253–8256.
[11] (a) V. Prakash Reddy, M. Perambuduru, R. Alleti, Adv. Org. Synth. 2 (2006) 327–
351;
(b) S. Das, S. Chandrasekhar, J.S. Yadav, R. Gree, Tetrahedron Lett. 48 (2007)
5305–5307;
(c) R.P. Singh, D.T. Meshri, J.M. Shreeve, Adv. Org. Synth. 2 (2006) 291–326.
[12] F.S. Fawcett, C.W. Tullock, D.D. Coffman, J. Am. Chem. Soc. 84 (1962) 4275–4285.
[13] V.A. Petrov, Adv. Org. Synth. 2 (2006) 269–290.
[14] (a) H. Sonoda, K. Okada, K. Fukumura, K. Goto, J. Naruse, H. Hayashi, T. Nagata, A.
Takahashi, EP 895991, 1999.
(b) H. Hayashi, H. Sonoda, K. Fukumura, T. Nagata, Chem. Commun. (2002) 1618–
1619.
[15] (a) D.F. Shellhamer, V.L. Heasley, Adv. Org. Synth. 2 (2006) 43–48;
(b) S. Rozen, Acc. Chem. Res. 38 (2005) 803–812.
[16] (a) M. Kuroboshi, K. Kanie, T. Hiyama, Adv. Synth. Catal. 343 (2001) 235–250;
(b) M. Shimizu, T. Hiyama, Ang. Chem. Int. Ed. 44 (2005) 214–231.
[17] T. Hiyama, H. Taguchi, S. Fujita, H. Nozaki, Bull. Chem. Soc. Jpn. 45 (1972) 1863–
1866.
4.2.5. Synthesis of 4 (Table 2, Entries 9 and 10)
Metal fluoride (KF: 20 equivalent; CsF: 10 equivalent) was used
in place of HF-Pyridine in sulfolan solution. The reaction mixture
[18] A.L. Ternay, D. Deavenport, G. Bledsoe, J. Org. Chem. 22 (1974) 3268–3271.

M. Tojo et al. / Journal of Fluorine Chemistry 131 (2010) 29–35
35
[19] K.S. Kochhar, B.S. Bal, R.P. Deshpande, S.N. Rajadhyaksha, J. Org. Chem. 48 (1983)
(b) D.R. Strobach, G.A. Boswell Jr., J. Org. Chem. 36 (1971) 818–820;
(c) C. Hu, F. Qing, C.J. Shen, Chem. Soc. Perkin Trans. 1 (1993) 335–338.
[23] G. Wittig, U. Mayer, Chem. Ber. 96 (1963) 329–341.
[24] T. Ando, T. Ishihara, E. Ohtani, H.J. Sawada, J. Org. Chem. 46 (1981) 4446–4450.
[25] G.N. Valkanas, H. Hopff, U.S. Patent 3,093,692, 1963.
Chem. Abstr. 59 (1963) 61712.
1765–1767.
[20] (a) T.R. Forbus Jr., J.C. Martin, J. Org. Chem. 44 (1979) 313–314;
(b) P. Strazzolini, G. Verardo, A.G. Giumanini, J. Org. Chem. 53 (1988) 3321–3325.
[21] (a) L.W. Rotherham, J.E. Semple, J. Org. Chem. 63 (1998) 6667–6672;
(b) P.Z. Bedoukian, J. Am. Chem. Soc. 67 (1945) 1430–1431.
[22] (a) W.R. Hasek, W.C. Smith, V.A. Engelhardt, J. Am. Chem. Soc. 82 (1960) 543–
551;
[26] T.P. Smyth, B.W. Corby, Org. Process Res. Dev. 1 (1997) 264–267.