Synthetic utilization of 2-chloro-1,1,1,2-tetrafluoroethane

Article abstract of DOI:10.1002/chem.201100900

β-Substituted α-fluoro-α,β-unsaturated carboxylic acids have been successfully synthesized, usually in a (Z)-stereospecific manner by way of a stepwise or a one-pot three-step procedure starting from 2-chloro-1,1,1,2-tetrafluoroethane (HCFC-124), one of the major byproducts of the industrial process for tetrafluoroethene formation from chlorofluoromethane (HCFC-22). Get some Z's! β-Substituted α-fluoro-α,β- unsaturated carboxylic acids have been successfully synthesized from 2-chloro-1,1,1,2-tetrafluoroethane, one of the major byproducts of tetrafluoroethene formation from chlorofluoromethane. The products are usually obtained with Z stereoselectivity, by either a stepwise or a one-pot three-step procedure (see scheme).

Full text of DOI:10.1002/chem.201100900

DOI: 10.1002/chem.201100900
Synthetic Utilization of 2-Chloro-1,1,1,2-tetrafluoroethane
Keiji Notsu, Yasuyuki Zushi, Shin Ota, Tomoko Kawasaki-Takasuka, and
Takashi Yamazaki*[a]
Abstract: b-Substituted a-fluoro-a,b-unsaturated carboxylic acids have been suc-
Keywords: allylic alcohols · carbox-
ylic acids · fluorine · hydrochloro-
cessfully synthesized, usually in a (Z)-stereospecific manner by way of a stepwise
or a one-pot three-step procedure starting from 2-chloro-1,1,1,2-tetrafluoroethane
(HCFC-124), one of the major byproducts of the industrial process for tetrafluor-
oethene formation from chlorofluoromethane (HCFC-22).
fluorocarbons (HCFCs)
tropic rearrangement
· sigma-
Introduction
Results and Discussion
The hydrochlorofluorocarbon (HCFC) 2-chloro-1,1,1,2-tet-
rafluoroethane (HCFC-134/1c) is produced as one of the
side products of the industrial process for the formation of
tetrafluoroethylene from chlorodifluoromethane (HCFC-
22). Taking limited amounts of fluorine sources, ozone layer
depletion, and the global warming characteristics of 1c into
account, it is quite important to consider its efficient con-
sumption from a synthetic point of view. However, to our
surprise, almost all articles[1] and patents[2] thus far have con-
centrated on its conversion to the corresponding hydrofluor-
ocarbons (HFCs) 1,1,2,2-tetrafluoroethane (HFC-134) and
pentafluoroethane (HFC-125), or fluorinated C2-alkene de-
rivatives. This prompted us to develop new and efficient
transformations into synthetically useful intermediates.
Among a variety of materials, our attention was focused on
b-substituted a-fluoro-a,b-unsaturated carboxylic acids 8[3,4]
because of their utility as constituents of biologically active
substances.[5] However, their preparation has sometimes suf-
fered from stereoisomer contamination.[3] In this article, we
disclose detailed reactions of the anion of 1c with a variety
of carbonyl compounds and transformation of the resultant
fluorinated alcohols 5 into the respective fluorinated acids 8,
mostly in a Z-stereospecific manner. This process was per-
formed not only in successive fashion, but also in a one-pot
three-step sequence. The last step offers a better chance to
decrease the amount of solvent and base required.
Theoretical comparison of HCFC-124 (1c) with HFC-134a
(1a) and HCFC-133a (1b): A literature search based on the
related HCFC or HFC families indicated that proper gener-
ation of anions is possible from CF3CHXY, in which both X
and Y are halogens, by the action of a typical strong base,
such as nBuLi. Conversely, the subsequent ready elimination
of a fluorine atom from the CF3 group is usually observed
when X=H and Y=halogen. For clarification of this dis-
crepancy, theoretical calculations were performed[6] for 1c
and the structurally related compounds, CF3CH2F (1a) and
CF3CH2Cl (1b). The results are summarized in Table 1. We
have calculated the thermodynamic stability of substrates 1,
lithiated intermediates 2 (after proton abstraction from 1 by
monomeric MeLi as the simplified model base), terminally
difluorinated ethenes 3 (obtained by b-elimination of fluo-
ride from 2), and carbenes 4 (obtained by a-elimination of
chloride from 2). Initial lithiation (Table 1, step 1) seemed
to proceed smoothly due to an energetic preference (DE=
15 to 30 kcalmolꢀ1) for the combination of species 2 and
methane when compared with the substrate pair 1 and
MeLi. A considerably high energy barrier was estimated for
the formation of 4 (Table 1, step 3) because of the signifi-
cant instability of 4 with respect to 2. On the other hand, b-
elimination from 2 (Table 1, step 2) was expected to furnish
the thermodynamically more favorable ethenes 3, which
bear two fluorine atoms at the terminal carbon atom, with
low activation energies of up to only 7 kcalmolꢀ1. Deproto-
nation of 1a by nBuLi constructed 3a, in accordance with
the computational result. The vinylic proton of 3a was fur-
ther abstracted and the resultant anion could be eventually
trapped with appropriate carbonyl compounds to give fluori-
nated allylic alcohols.[4,7] Intramolecular interaction of Li···F
(206.0 pm) in 2a seemed to be one of the major promoters
for conversion to 3a, which, as a result, would effect a
[a] K. Notsu, Dr. Y. Zushi, S. Ota, Dr. T. Kawasaki-Takasuka,
Dr. T. Yamazaki
Division of Applied Chemistry, Institute of Engineering
Tokyo University of Agriculture and Technology
2-24-16 Nakamachi
Koganei 184-8588 (Japan)
Fax : (+81)42-388-7038
ꢀ
9.4 pm elongation of the C F···Li bond. Although 1b ener-
getically preferred transformation to lithiated 2b rather
than 3b (by 4 kcalmolꢀ1 on the basis of the present calcula-
tion, either in Et2O or THF), 2b is in fact known to follow
E-mail: tyamazak@cc.tuat.ac.jp
9200
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Chem. Eur. J. 2011, 17, 9200 – 9208

FULL PAPER
Table 1. Computational results for compounds 1a–c.[a]
Compound
X
H
Y
F
Solvent
DE [kcalmolꢀ1
CF3CLiXY (2)
]
Charge on 2[b]
TSstep2
F2C=XY (3)
CF3CX(4)
C1
C2
X
Y
1a
none
Et2O
THF
none
Et2O
THF
none
Et2O
THF
ꢀ21.652
ꢀ15.002
ꢀ14.151
ꢀ25.920
ꢀ22.179
ꢀ22.239
ꢀ28.289
ꢀ26.620
ꢀ26.948
2.671
1.186
0.869
1.104
5.365
6.051
7.186
4.980
4.798
ꢀ9.354
ꢀ23.130
ꢀ24.015
ꢀ7.550
ꢀ18.346
ꢀ18.300
ꢀ1.715
ꢀ9.055
ꢀ8.590
57.349
47.632
47.234
57.995
46.082
45.117
34.704
25.168
25.091
0.971
ꢀ0.413
0.178
ꢀ0.495
1b
1c
H
F
Cl
Cl
0.995
0.947
ꢀ0.779
ꢀ0.145
0.205
ꢀ0.200
ꢀ0.284
ꢀ0.383
[a] Calculations were carried out by Gaussian 03W at the B3LYP/6–31+G* level of theory. Solvent effect was estimated by the single point calculation
for the fully optimized conformers by using the SCI-PCM (self-consistent isodensity polarized continuum model) method. [b] Charges were obtained by
natural bond orbital analysis.
the same b-elimination as 2a by treatment with nBuLi.[8]
This experimental fact is a reflection of the higher negative
charge localized on C2, which might render anion 2b less
stable and promote the irreversible elimination of LiF. A
Table 2. Investigation of the reaction conditions.
ꢀ
weak Li···F contact (264.7 pm) and elongated C F···Li bond
(4.4 pm) were also observed for 2b. However, in the case of
1c, in addition to the substantial energetic stability of lithiat-
Base
Solvent
T [8C]
Yield[a] [%]
76 (73)[b]
ed 2c relative to 3c and 4c, a much lower level of negative
charge was accumulated on C2; a result of effective electron
delocalization over two electronegative elements attached
to the same carbon atom. These computational results led to
a strong expectation that the anion from 1c would be uti-
lized experimentally in a successful manner.[9]
1
2
3
4
5
6
7
8
9
nBuLi
sBuLi
MeLi
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
THF
ꢀ80 to 0
ꢀ80 to 0
ꢀ80 to 0
ꢀ80 to 0
ꢀ80 to 0
ꢀ80 to 0
ꢀ80
64
22
64
LDA
[c]
EtMgBr
tBuOK
nBuLi
nBuLi
nBuLi
–
39
trace
10
Et2O/hex[d]
Et2O
ꢀ80
Formation of fluorinated alcohols 5 by the reaction of 1c
with carbonyl compounds: With these computational results
in hand, the efficiency of proton abstraction from 1c was
first investigated by use of a variety of bases. The results,
compared after trapping the generated anion with 1-naph-
thaldehyde, are collected in Table 2. A similar yield of the
desired alcohol 5a was obtained after treatment with nBuLi,
sBuLi, or lithium diisopropylamine (LDA) (Table 2, en-
tries 1, 2, and 4). MeLi was found to be less potent and
EtMgBr did not work at all for the present purpose
(Table 2, entries 3 and 5). Despite only moderate success, it
is notable that the same adduct 5a was formed in 39% yield
after potassium tert-butoxide treatment (Table 2, entry 6),
while the corresponding in situ prepared Li and Na alkox-
ides proved to be totally insufficient for abstraction of the
proton in 1c. The more polar solvent THF furnished a slug-
gish result, with the formation of a variety of products indi-
cated by 19F NMR spectroscopy. An Et2O/hexane (1:9)
mixed solvent did not work efficiently (Table 2, entry 8), so
we determined the initial conditions (Table 2, entry 1) as the
best for this reaction, after a brief check of the reaction tem-
perature (Table 2, entry 9).
ꢀ80
72
[a] Calculated by 19F NMR spectroscopy on the basis of 1-naphthalde-
hyde. [b] Isolated yield. [c] 76% of 1-(1-naphthyl)propanol was obtained.
[d] Et2O/hexane=1:9.
Compared with nBuLi, an easy-to-handle base like
tBuOK was quite advantageous and, thus, its potential was
further investigated. Extensive studies on the reaction pa-
rameters attained, at most, 40% chemical yield of 5b when
PhCHO was used as the electrophile under similar condi-
tions as described in Table 2. Our working hypothesis that
this result would stem from the instability of the anion of 1c
with potassium as the counter cation[10] led us to generate
this active species in the presence of electrophiles so as to
enable its capture as quickly as possible. To our delight, con-
struction of 5b was realized in 76% yield by addition of 1c
(1.6 equiv) to a mixture of tBuOK (1.2 equiv) and benzalde-
hyde (1 equiv) at ꢀ208C, followed by 5 h stirring at the
same temperature. As shown in Scheme 1, further improve-
ment was also possible by changing the reaction tempera-
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9201

T. Yamazaki et al.
5a with nBuLi in THF at ꢀ808C smoothly affected dechlor-
odefluorination to furnish the corresponding allylic alcohol
6a in 86% yield, while the same conditions in the less polar
solvent Et2O led to a drastic reduction in the amount of 6a
formed (Scheme 2). Raising the reaction temperature was
Scheme 1. Formation of 5b by reaction with tBuOK.
ture (ꢀ208C, 0.5 h, then ꢀ80 to 08C, 4.5 h; 82% yield) or in-
creasing the amount of 1c employed (4 equiv; 93% yield).
Utilization of the two different established reaction proto-
cols with a variety of electrophiles led to successful conver-
sion of 1c into tetrafluorinated alcohols 5; the results are
summarized in Table 3. The nBuLi- and tBuOK-mediated
Scheme 2. Formation of allylic alcohol 6a.
Table 3. Preparation of alcohols 5.
found to permit the undesired entry of a butyl moiety, to
some extent, at the terminal fluorinated carbon atom and
7a was produced as a byproduct.[4b,8a] It was also clarified
that instability of 6a,[12] especially under vacuum in a rotary
evaporator, sometimes invoked an abrupt reaction in the
flask (indicated by, for example, sudden colorization) to give
a complex mixture of unidentified materials. Due to these
characteristics of 6a, we decided to progress to the subse-
quent hydrolysis step, to obtain the corresponding a-fluoro-
a,b-unsaturated carboxylic acids 8, without further purifica-
tion of this labile alcohol.
Successful conversion to the desired acids 8 was realized
by quenching the reaction mixture that contained the allylic
alkoxide Int-3 (Scheme 3) by addition of an aqueous solu-
tion of H2SO4 (1:1 v/v)[13] then stirring for 24 h at ambient
temperature.[14] However, 5e–5g (Table 4, entries 5–7) were
found to be inappropriate substrates under these conditions.
In the case of 5 f, the same treatment furnished a crude mix-
R1
R2
Product
Isolated yield [%] (d.r.)[a]
nBuLi
tBuOK
[b]
1
2
3
4
5
6
7
8
9
1-C10H7
Ph
H
H
H
H
H
H
H
H
5a
5b
5c
5d
5e
5 f
5g
5h
5i
73 (61:39)
83 (60:40)
89 (57:43)
90 (59:41)
72 (60:40)
74 (52:48)
81 (51:49)
82 (56:44)
85 (40:60)
–
83[c] (51:49)
82 (51:49)
82 (51:49)
33 (56:44)
trace
p-MeOC6H4
p-H3CC6H4
p-F3CC6H4
C9H19
PhCH2CH2
(E)-PhCH=CH
Ph
[b]
–
12[d] (54:46)
0
CH3
[a] Diastereomeric ratio (d.r.) was determined by 19F NMR spectroscopy.
[b] Not attempted. [c] 87% isolated yield was obtained after reaction in
THF at ꢀ408C for 1 h. [d] Yield was determined by 19F NMR spectrosco-
py.
pathways usually recorded similar yields of 5, but there are
some points worth noting for the latter system) electrophiles
with the carbonyl a proton were not applicable (Table 3, en-
tries 6, 7, and 9), due to the requirement for premixing of
the carbonyl compound with tBuOK; 2) the strongly elec-
tron-withdrawing nature of the CF3 group in p-
(F3C)C6H4CHO was likely to promote the Cannizzaro reac-
tion, which decreased the chemical yield to some extent[11]
when compared to the nBuLi-mediated protocol (Table 3,
entry 5).
Conversion of alcohols 5 into a-fluoro-a,b-unsaturated car-
boxylic acids 8 by acid hydrolysis: Having successfully syn-
thesized alcohols 5, we next studied their transformation to
trifluorinated allylic alcohols 6. It has already been repor-
ted[9c,f] that a CF3 group rendered the geminal halogen
atoms ready to accept nucleophilic attack of nBuLi due to
its strong electron-withdrawing ability adequately stabilizing
the resultant anion. Such intermediates would experience
subsequent defluorination to form 6. In fact, treatment of
Scheme 3. Plausible mechanism for conversion of Int-3 to 8.
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Utilization of 2-Chloro-1,1,1,2-tetrafluoroethane
FULL PAPER
Table 4. Preparation of a-fluoro-a,b-unsaturated carboxylic acids 8.
R1
R2
Product
Yield[a]
[%]
Selectivity[b]
[%]
1
2
3
4
5
6
7
8
9
1-C10H7
Ph
H
H
H
H
H
H
H
H
8a
8b
8c
8d
8e
8 f
8g
8h
8i
53 (64)
65 (72)
72 (72)
>99
>99
>99
>99
–
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
p-MeOC6H4
p-H3CC6H4
p-F3CC6H4
C9H19
PhCH2CH2
(E)-PhCH=CH
Ph
ACHTUNGTRENNUNG
89 (70)
ACHTUNGTRENNUNG
– (71)[c]
– (59)[d]
– (80)[d]
26[e] (31)[e]
87 (70)
ACHTUNGTRENNUNG
–
–
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
87
62 (73)
ACHTUNGTRENNUNG
Figure 1. Energy profile for the [3,3]-sigmatropic rearrangement.
CH3
[a] Isolated yield obtained after acid hydrolysis. The value in parentheses
represents the yield obtained after mesylate-mediated [3,3]-sigmatropic
rearrangement. [b] Percentage of the (Z)-isomer obtained. [c] NaOH hy-
drolysis for 2 h. [d] NaOH hydrolysis for 5 d. [e] Determined by 19F NMR
spectroscopy.
¼
and the energetic difference (DDE ) between the diastereo-
meric transition states led us to expect that the present reac-
tion should proceed without significant difficulty to afford
the desired a-fluoro-a,b-unsaturated carboxylic acids 8 in a
highly Z-selective manner.
ture from which three sets of peaks were observed by
19F NMR spectroscopy: one was recovered 5 f (23% yield
by 19F NMR spectroscopy), the other two were attributed to
the allylic alcohols 6 f and 7 f (41 and 12% yield by
19F NMR spectroscopy, respectively) on the basis of the typi-
cal olefinic trans F–F couplings (J>100 Hz)[15,16] and the
presence of only one additional peak for the former (the ter-
minal fluorine atom). A similar situation was found for the
crude mixture obtained from 5e. These facts indicated that
an extra stabilizing factor was required for the conversion
from Int-3 to 8. Thus, substrates with electron-rich aromatic
substituents as R1 were considered to effectively stabilize
Int-1, while this was not the case for substrates with elec-
tron-withdrawing groups on the benzene ring, for example,
5e. Alkyl moieties as R1, as in 5 f and 5g, are also inappro-
priate for effective electronic donation to the cationic
center. Because these problems stemmed from the inherent
structures of the substrates, we have explored a different
strategy for the construction of the desired compounds 8.
With these computational results in hand, appropriate re-
action conditions were investigated for this unique rear-
rangement. Quenching the mixture that contained the lithi-
um alkoxide Int-3 by addition of mesyl chloride at ꢀ808C,
followed by 1 h stirring at 08C, effected its smooth conver-
sion to Int-5[18] after the initial mesylate formation from Int-
3.
Similar to our previous work,[17] the rearrangement from
Int-4 (Scheme 3) proceeded in an extremely facile manner
so this intermediate was undetected at any stage of the reac-
tion. Subsequent attack by hydroxide at the positively
charged sulfonate sulfur atom and the successive elimination
of fluoride furnished the acid fluoride, which eventually pro-
duced the desired acid 8 under the conditions employed.
The usual SN2 type reaction to Int-5 was not likely to be
occur because two electronegative fluorine atoms bent
toward the incoming OHꢀ to some extent would refuse the
approach of this nucleophile. At this biphasic hydrolysis
step, it was demonstrated that the presence of a catalytic
amount of quaternary ammonium salt was crucial for attain-
ment of better results. For example, 8b was produced in
72% yield (Table 4, entry 2) but the yield was reduced to
only 44% without the catalyst. Employment of DMF as the
solvent for this hydrolysis stage (Int-5 into 8) facilitated the
NaOH-mediated conversion and afforded the desired prod-
uct 8 in 95% yield. However, the requirement for THF as
the solvent for conversion of 5 to 6, because of the use of
nBuLi, gave the disadvantage of a two-step process from 5
to 8, which included concentration of the solution that con-
tained the relatively labile compound 6. Thus, we eventually
chose the convenient one-pot procedure in THF.
Conversion of alcohols 5 into a-fluoro-a,b-unsaturated car-
boxylic acids 8 by [3,3]-sigmatropic rearrangement of sulfo-
nates: To address the problem encountered above, [3,3]-sig-
matropic rearrangement of mesylates[17] was selected as an
alternative pathway; chemistry previously developed by our
group for the similar terminally difluorinated allylic alco-
hols. Computational analysis of this route was first carried
out (Figure 1)[7] and it was found that the energy barrier of
the transition state TS-(Z) for transformation of the model
species 6j (R=Me; Scheme 2) into the more stable (by
14.11 kcalmolꢀ1) product (Z)-Int-5j (R1 =Me, R2 =H;
Scheme 3) was 23.54 kcalmolꢀ1. The other transition state
TS-(E) and the resultant stereoisomeric product (E)-Int-5j
(R1 =H, R2 =Me; Scheme 3) were found to be 2.68 and
3.16 kcalmolꢀ1 destabilized with respect to TS-(Z) and (Z)-
Int-5j, respectively. The height of the TS-(Z) energy barrier
The rearrangement pathway manifested similar efficiency
to the acid hydrolysis pathway (Table 4, entries 1–4) for con-
struction of the desired acids 8a–d. Moreover, formation of
the acids 8e–h in good to high yields by rearrangement
Chem. Eur. J. 2011, 17, 9200 – 9208
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T. Yamazaki et al.
(Table 4, entries 5–8) was pleasing because the acid-mediat-
ed pathway failed in this respect. An additional advantage
of the rearrangement method is the versatility of intermedi-
ate Int-5. If other nucleophiles behave in a similar manner
to the hydroxide ion Int-5 should accept further attack by a
nucleophile after transformation to the corresponding acid
fluoride (Scheme 3). This is actually the case, and addition
of NaBH4, NaOMe, or BnNHLi readily furnished the corre-
sponding allylic alcohol 9b,[19] a,b-unsaturated ester
10b,[19,20] and amide 11b, respectively, in 70–79% yield
(Scheme 4).
Scheme 5. One-pot synthesis of 8b.
Experimental Section
General methods: All reactions were carried out under an argon atmos-
phere in oven-dried glassware, with magnetic stirring. Analytical TLC
was routinely used for monitoring reactions (hexane/EtOAc). Spherical
neutral silica gel (63–210 mm) was employed for column chromatography.
Anhydrous Et2O, THF, and CH2Cl2 were purchased and used without fur-
ther purification. 1H (300.40 MHz), 13C (75.45 Hz), and 19F NMR spectra
(282.65 Hz) were recorded on a JEOL AL 300 spectrometer in CDCl3,
unless otherwise noted, and chemical shifts (d) were recorded in parts
per million (ppm), downfield from internal tetramethylsilane (Me4Si: d=
0.00 ppm for 1H and 13C NMR spectra) or hexafluorobenzene (C6F6: d=
ꢀ163.00 ppm for 19F NMR spectra). Data are reported in the following
order: multiplicity [(s) singlet; (d) doublet; (t) triplet; (q) quartet;
(quint) quintet; (sex) sextet; (m) multiplet; (br) broad peak], coupling
constants (Hz), number of protons. IR spectra were obtained on a
JASCO A-302 spectrometer and are reported in wavenumbers (cmꢀ1).
Scheme 4. Reaction of the rearranged mesylate with nucleophiles.
Finally, we have modified the stepwise route to 8 from 1c
to a one-pot method for effective reduction of the amounts
of bases and solvents employed, as well as the number of
time-consuming isolation protocols. The first condensation
with benzaldehyde, under the conditions determined above,
furnished the corresponding lithium alkoxide Int-6b, which
was treated with another equivalent of nBuLi after ex-
change of the solvent from Et2O to THF. Int-3b thus
formed was directly hydrolyzed with aqueous solution of
H2SO4, or an aqueous solution NaOH after reaction with
mesyl chloride, to afford the desired a-fluoro-a,b-unsaturat-
ed carboxylic acid (Z)-8b in 47 and 60% overall yield, re-
spectively (Scheme 5).
Elemental analyses were performed with
a Perkin–Elmer Series II
CHNS/O analyzer. Electrospray ionization (ESI) mass spectrometry was
performed on a Thermofisher Exactive spectrometer in both negative
and positive ionization modes.
General workup: The quenched aqueous layer was extracted three times
with EtOAc and the obtained organic layer was treated with anhydrous
Na2SO4. Filtration and evaporation of the organic layer gave crude mate-
rials.
Typical procedure for the preparation of 1-substituted 2-chloro-2,3,3,3-
tetrafluoropropanol (5)
Conclusion
With nBuLi as base: nBuLi (15.0 mL, 24.0 mmol, 1.6m in hexanes) and
benzaldehyde (1.99 mL, 19.6 mmol) were added successively to a solution
of 1c (3.0 mL, 30.0 mmol) in diethyl ether (50 mL) at ꢀ808C. After stir-
ring for 0.5 h at ꢀ808C, then 4.5 h at 08C, the reaction mixture was
quenched with a 1m aqueous solution of HCl (40 mL). The mixture was
extracted with EtOAc (3ꢁ100 mL) and the unreacted aldehyde was re-
moved by washing the combined organic layers with a 30% aqueous so-
lution NaHSO3 (50 mL). The organic phase was dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo to give a crude oil. Purifica-
tion by silica gel column chromatography (CH2Cl2) furnished 5b (83%,
3.962 g, 16.3 mmol), diastereomeric ratio (d.r.)=61:39.
In addition to our calculations which, different from HFC-
134a (1a) and HCFC-133a (1b), clarified the stability of the
anionic species generated from deprotonation of 2-chloro-
1,1,1,2-tetrafluoroethane (HCFC-124, 1c), we have success-
fully demonstrated the facile transformation of 1c to the
synthetically useful intermediates, a-fluoro-a,b-unsaturated
carboxylic acids (8), usually in a Z-specific fashion. The one-
pot sequence for conversion of 1c to 8b was quite efficient
for effective reduction of both the amount of base and sol-
vent employed without detriment to the yield of the prod-
uct.
With tBuOK as base: HCFC 1c (2.1 mL, 21.0 mmol) was added to a solu-
tion of tBuOK (0.678 g, 5.0 mmol) and benzaldehyde (0.51 mL,
5.0 mmol) in diethyl ether (20 mL) at ꢀ208C. After stirring for 0.5 h at
ꢀ208C, followed by 08C for 4.5 h, the reaction mixture was quenched
with a 1m aqueous solution of HCl. General workup and purification by
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Utilization of 2-Chloro-1,1,1,2-tetrafluoroethane
FULL PAPER
silica gel column chromatography (CH2Cl2) furnished 5b (84%, 1.012 g,
4.2 mmol), d.r.=51:49.
51.08C; 1H NMR (CDCl3, 300 MHz): d=3.60 (d, J=5.7 Hz, 1H; major),
3.68 (d, J=4.8 Hz, 1H; minor), 5.21 (dd, J=4.8, 14.7 Hz, 1H; minor),
5.32 (t, J=6.0 Hz, 1H; major), 7.56–7.59 (m, 2H; major+minor), 7.63–
7.67 ppm (m, 2H; major+minor); 13C NMR (CDCl3, 75 MHz): d=73.0
(d, J=26.7 Hz; major), 74.9 (d, J=21.7 Hz; minor), 106.9 (dq, J=253.4,
34.1 Hz; major), 107.1 (dq, J=258.0, 34.1 Hz; minor), 120.4 (qd, J=
284.8, 31.7 Hz; minor), 120.6 (qd, J=285.0, 30.7 Hz; major), 123.7 (q, J=
271.7 Hz; minor), 123.8 (q, J=271.7 Hz; major), 125.0–125.3 (m; major+
minor), 128.3 (d, J=1.9 Hz; major), 128.6 (minor), 131.7 (q, J=32.7 Hz;
major), 131.8 (q, J=32.7 Hz; minor), 138.20 (minor), 138.34 ppm
(major); 19F NMR (CDCl3, 283 MHz): d=ꢀ136.81–ꢀ136.70 (m, 1F;
minor), ꢀ131.38 (quint, J=6.8 Hz, 1F; major), ꢀ79.87 (d, J=6.8 Hz, 3F;
major), ꢀ78.42 (d, J=6.8 Hz, 3F; minor), ꢀ64.36 (s, 3F; minor),
ꢀ64.30 ppm (s, 3F; major); IR (CHCl3): n˜ =590, 620, 640, 660, 720, 830,
Data for 5b: Rf =0.58 (CH2Cl2); b.p. 958C (0.1 kPa); 1H NMR (CDCl3,
300 MHz): d=3.60 (brs, 1H; minor), 3.62 (brs, 1H; major), 5.12 (dd, J=
15.6, 4.5 Hz, 1H; minor), 5.24 (t, J=6.0 Hz, 1H; major), 7.35–7.40 (m,
3H; major+minor), 7.41–7.46 ppm (m, 2H; major+minor); 13C NMR
(CDCl3, 75 MHz): d=73.6 (d, J=26.6 Hz; major), 75.4 (d, J=21.1 Hz;
minor), 107.4 (dq, J=252.5, 33.5 Hz; major), 107.7 (dq, J=258.0,
33.5 Hz; minor), 120.6 (qd, J=285.3, 31.6 Hz; minor), 120.9 (qd, J=
284.7, 31.0 Hz; major), 128.0 (major), 128.1 (minor), 128.2 (major), 128.4
(minor), 129.5 (major), 129.6 (minor), 134.6 (minor), 134.8 ppm (major);
19F NMR (CDCl3, 283 MHz): d=ꢀ136.55–ꢀ136.43 (m, 1F; minor),
ꢀ130.98 (quint, J=6.8 Hz, 1F; major), ꢀ79.54 (d, J=6.8 Hz, 3F; major),
ꢀ78.16 ppm (d, J=4.5 Hz, 3F; minor); IR (neat): n˜ =600, 650, 690, 720,
730, 800, 930, 980, 1020, 1040, 1080, 1170, 1190, 1270, 1370, 1440, 1480,
930, 1020, 1060, 1100, 1160, 1280, 1320, 1410, 1610, 2900, 3000, 3400 cmꢀ1
;
1580, 2850, 3000, 3350 cmꢀ1
; elemental analysis calcd (%) for
elemental analysis calcd (%) for C10H6ClF7O: C 38.67, H 1.95; found: C
38.56, H 1.96.
C9H7ClF4O: C 44.56, H 2.91; found: C 44.56, H 2.91.
Compound 5 f: Prepared with nBuLi: yield=74%; d.r.=52:48. Rf =0.63
(CH2Cl2); b.p. 1148C (0.1 kPa); 1H NMR (CDCl3, 300 MHz): d=0.88 (t,
J=6.8 Hz, 3H), 1.20–1.44 (m, 13H), 1.52–1.83 (m, 3H), 1.86 (d, J=
8.7 Hz, 1H), 2.08 (d, J=8.7 Hz, 1H), 4.04–4.16 ppm (m, 1H); 13C NMR
(CDCl3, 75 MHz): d=13.8, 22.7, 25.4, 25.5, 29.3, 29.4, 29.4, 29.6, 29.7,
30.4, 32.0, 72.1 (d, J=26.6 Hz), 73.3 (d, J=21.05 Hz), 108.5 (dq, J=255.5,
34.2 Hz), 108.8 (dq, J=254.3, 33.5 Hz), 120.8 (qd, J=252.5, 31.6 Hz),
120.9 ppm (qd, J=284.7, 31.0 Hz); 19F NMR (CDCl3, 283 MHz): d=
ꢀ134.52–ꢀ134.41 (m, 1F), ꢀ132.26–ꢀ132.17 (m, 1F), ꢀ79.83 (d, J=
6.8 Hz, 3F), ꢀ78.54 ppm (d, J=6.8 Hz, 3F); IR (neat): n˜ =670, 710,720,
Compound 5a: Prepared with nBuLi: yield=73%, d.r.=61:39. Rf =0.58
(CH2Cl2); b.p. 1258C (0.4 kPa); 1H NMR (CDCl3, 300 MHz): d=2.64 (d,
J=5.1 Hz, 1H; major), 2.71 (d, J=5.1 Hz, 1H; minor), 6.09 (dd, J=5.3,
18.1 Hz, 1H; minor), 6.26 (dd, J=3.9, 4.5 Hz, 1H; major), 7.25–8.11 ppm
(m, 7H; major+minor); 13C NMR (CDCl3, 75 MHz): d=68.2 (d, J=
27.9 Hz; major), 70.6 (d, J=21.1 Hz; minor), 107.3 (dq, J=262.5,
34.5 Hz; major), 108.3 (dq, J=252.3, 33.9 Hz; minor), 114.6–133.7 ppm
(m; major+minor); 19F NMR (CDCl3, 283 MHz): d=ꢀ139.82–ꢀ139.78
(m, 1F; minor), ꢀ129.05 (s, 1F; major), ꢀ80.05 (d, J=6.2 Hz, 3F;
major), ꢀ78.29 ppm (d, J=4.5 Hz, 3F; minor); IR (neat): n˜ =620, 690,
720, 740, 780, 860, 940, 1050, 1080, 1100, 1120, 1190, 1280, 1320, 1360,
1400, 1510, 1600, 1660, 3050, 3400 cmꢀ1; elemental analysis calcd (%) for
C13H9ClF4O: C 53.35, H 3.10; found: C 53.63, H 3.33.
920, 1050, 1110, 1140, 1190, 1290, 1370, 1450, 1640, 2850, 2910, 3130 cmꢀ1
;
elemental analysis calcd (%) for C12H21ClF4O: C 49.23, H 7.23; found: C
49.52, H 7.03.
Compound 5g: Prepared with nBuLi: yield=81%; d.r.=51:49. Rf =0.61
(CH2Cl2); b.p. 1058C (0.2 kPa); 1H NMR (CDCl3, 300 MHz): d=1.86–
2.02 (m, 1H), 2.07–2.19 (m, 2H), 2.09 (d, J=8.4 Hz, 1H), 2.30 (d, J=
6.9 Hz, 1H), 2.68–2.79 (m, 2H), 2.90–3.01 (m, 1H), 4.04–4.12 (m, 1H),
7.20–7.33 ppm (m, 5H); 13C NMR (CDCl3, 75 MHz, major diastereoiso-
mer): d=31.1 (d, J=1.9 Hz), 31.8, 71.4 (d, J=26.6 Hz), 72.4 (d, J=
21.1 Hz), 108.4 (dq, J=254.3, 34.1 Hz), 120.6 (qd, J=284.7, 32.2 Hz),
120.8 (qd, J=285.4, 31.0 Hz), 126.3, 128.3, 128.5, 128.6, 140.3, 140.4 ppm;
19F NMR (CDCl3, 283 MHz): d=ꢀ134.63–ꢀ134.52 (m, 1F), ꢀ132.11 (s,
1F), ꢀ79.78 (d, J=6.8 Hz, 3F), ꢀ78.59 ppm (d, J=4.5 Hz, 3F); IR
(neat): n˜ =700, 740, 830, 920, 1030, 1060, 1120, 1180, 1290, 1360, 1440,
1490, 1590, 2880, 2920, 3020, 3400 cmꢀ1; elemental analysis calcd (%) for
C11H11ClF4O: C 48.81, H 4.10; found: C 48.84, H 4.18.
Compound 5c: Prepared with nBuLi: yield=89%, d.r.=57:43; prepared
with tBuOK: yield=85%, d.r.=51:49. Rf =0.63 (CH2Cl2); 1H NMR
(CDCl3, 300 MHz): d=3.62 (brs, 1H; major+minor), 3.70 (s, 3H;
major+minor), 5.01 (dd, J=4.8, 15.3 Hz, 1H; minor), 5.12 (t, J=6.0 Hz,
1H; major), 6.81–6.86 (m, 2H), 7.30 ppm (d, J=8.4 Hz, 2H; major+
minor); 13C NMR (CDCl3, 75 MHz): d=55.0 (major+minor), 73.1 (d,
J=27.2 Hz; major), 74.9 (d, J=21.1 Hz; minor), 107.5 (dq, J=251.9,
33.5 Hz; major), 107.8 (dq, J=258.8, 33.0 Hz; minor), 113.6 (major),
113.7 (minor), 120.6 (qd, J=284.9, 31.8 Hz; minor), 120.8 (qd, J=285.2,
30.6 Hz; major), 127.1 (minor), 129.3 (d, J=6.0 Hz; major), 129.5
(major+minor), 160.2 (major), 160.2 ppm (minor); 19F NMR (CDCl3,
283 MHz): d=ꢀ135.6–ꢀ135.49 (m, 1F; minor), ꢀ130.74 (quint, J=
6.8 Hz, 1F; major), ꢀ79.17 (d, J=6.8 Hz, 3F; major), ꢀ77.92 ppm (d, J=
4.5 Hz, 3F; minor); IR (neat): n˜ =408, 418, 426, 436, 447, 462, 556, 589,
631, 668, 720, 730, 770, 790, 834, 933, 951, 1031, 1079, 1118, 1214, 1254,
1304, 1444, 1466, 1516, 1587, 1614, 2843, 2913, 2941, 2963,3010,
3460 cmꢀ1; elemental analysis calcd (%) for C10H9ClF4O2: C 44.06, H
3.33; found: C 43.73, H 3.64.
Compound 5h: Prepared with nBuLi: yield=82%; d.r.=56:44. Rf =0.56
(CH2Cl2); b.p. 1158C (0.1 kPa); m.p. 38.0–39.58C; 1H NMR (CDCl3,
300 MHz): d=2.53 (d, J=7.2 Hz, 1H; minor), 2.69 (d, J=6.3 Hz, 1H;
major), 4.74–4.87 (m, 1H; major+minor), 6.15–6.30 (m, 1H; major+
minor), 6.77–6.84 (m, 1H; major+minor), 7.22–7.38 ppm (m, 5H;
major+minor); 13C NMR (CDCl3, 75 MHz): d=73.4 (d, J=27.2 Hz;
minor), 74.5 (d, J=21.7 Hz; major), 107.6 (dq, J=254.3, 33.5 Hz; minor),
107.8 (dq, J=256.8, 34.2 Hz; major), 120.6 (qd, J=285.3, 31.0 Hz; major),
120.8 (qd, J=285.3, 31.0 Hz; minor), 121.3 (d, J=4.4 Hz), 121.6, 127.0,
128.8, 128.9, 135.4 (major), 135.5 (minor), 136.4, 137.0 ppm; 19F NMR
(CDCl3, 283 MHz): d=ꢀ134.03 (dq, J=12.5, 6.8 Hz, 1F; minor), ꢀ131.94
(quint, J=6.9 Hz, 1F; major), ꢀ79.40 (d, J=7.1 Hz, 3F; major),
ꢀ78.49 ppm (d, J=6.8 Hz, 3F; minor); IR (neat): n˜ =680, 730, 740, 840,
930, 960, 1020, 1060, 1100, 1180, 1280, 1380, 1440, 1490, 1580, 1650, 3040,
3340 cmꢀ1; elemental analysis calcd (%) for C11H9ClF4O: C 49.18, H
3.38; found: C 49.12, H 3.46.
Compound 5d: Prepared with nBuLi: yield=90%, d.r.=60:40; prepared
with tBuOK: yield=82%, d.r.=51:49. Rf =0.63 (CH2Cl2); b.p. 1208C
(0.1 kPa); 1H NMR (CDCl3, 300 MHz): d=2.35 (s, 3H; major+minor),
3.03 (d, J=5.4 Hz, 1H; major), 3.06 (d, J=5.1 Hz, 1H; minor), 5.07 (dd,
J=15.4, 5.1 Hz, 1H; minor), 5.18 (t, J=6.0 Hz, 1H; major), 7.16–7.20 (m,
2H; major+minor), 7.32 ppm (dd, J=2.1, 8.1 Hz, 2H; major+minor);
13C NMR (CDCl3, 75 MHz): d=21.0 (major+minor), 73.4 (d, J=
27.3 Hz; major), 75.3 (d, J=21.1 Hz; minor), 107.4 (dq, J=252.5,
33.5 Hz; major), 107.6 (dq, J=225.1, 33.5 Hz; minor), 120.5 (qd, J=
285.4, 31.7 Hz; minor), 120.8 (qd, J=285.3, 30.4 Hz, major), 127.8
(major), 127.9 (minor), 128.1 (major+minor), 129.0 (major+minor),
129.1 (major+minor), 131.8 (major+minor), 139.5 (major), 139.7 ppm
(minor); 19F NMR (CDCl3, 283 MHz): d=ꢀ136.50–ꢀ136.38 (m, 1F;
minor), ꢀ131.16 (quint, J=6.8 Hz, 1F; major), ꢀ79.54 (d, J=6.8 Hz, 3F;
major), ꢀ78.20 ppm (d, J=4.5 Hz, 3F; minor); IR (neat): n˜ =630, 660,
690, 710, 760, 800, 830, 910, 970, 1010, 1050, 1080, 1150, 1250, 1360, 1500,
1600, 2850, 3300 cmꢀ1; elemental analysis calcd (%) for C10H9ClF4O: C
46.80, H 3.53; found: C 46.95, H 3.60.
Compound 5i: Prepared with nBuLi: yield=85%; d.r.=40:60; Rf =0.60
(CH2Cl2); b.p. 1008C (0.1 kPa); 1H NMR (CDCl3, 300 MHz): d=1.87–
1.88 (m, 3H; major+minor), 2.79 (s, 1H; minor), 2.88 (s, 1H; major),
7.31–7.39 (m, 3H; major+minor), 7.54–7.59 ppm (m, 2H; major+
minor); 13C NMR (CDCl3, 75 MHz): d=25.4 (quint, J=1.9 Hz; major),
26.1 (quint, J=1.8 Hz; minor), 77.1 (d, J=21.7 Hz; minor), 77.8 (d, J=
21.7 Hz; major), 110.1 (dq, J=260.5, 32.9 Hz; major), 111.2 (dq, J=262.3,
32.8 Hz; minor), 120.8 (qd, J=286.6, 32.3 Hz; minor), 121.0 (qd, J=
286.6, 32.2 Hz; major), 126.5 (d, J=1.3 Hz; minor), 126.6 (d, J=1.9 Hz;
Compound 5e: Prepared with nBuLi: yield=72%, d.r.=59:41; prepared
with tBuOK: yield=33%, d.r.=56:44. Rf =0.62 (CH2Cl2); m.p. 50.0–
Chem. Eur. J. 2011, 17, 9200 – 9208
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9205

T. Yamazaki et al.
major), 127.9 (major), 128.0 (minor), 128.4 (minor), 128.4 (major), 139.0
(minor), 139.6 ppm (major); 19F NMR (CDCl3, 283 MHz): d=ꢀ130.96 (q,
J=6.8 Hz, 1F; major), ꢀ130.36 (q, J=7.5 Hz, 1F; minor), ꢀ74.93 (d, J=
7.1 Hz, 3F; minor), ꢀ74.75 ppm (d, J=6.8 Hz, 3F; major); IR (neat): n˜ =
620, 650, 710, 740, 760, 800, 920, 940, 990, 1040, 1080, 1140, 1200, 1290,
1340, 1390, 1460, 1510, 1560, 3000, 3050, 3500 cmꢀ1; elemental analysis
calcd (%) for C10H9ClF4O: C 46.80, H 3.53; found: C 46.98, H 3.66.
5.9 mmol, 1.40m in hexanes) was added and the mixture was stirred for
2 h at ꢀ808C. Methanesulfonyl chloride (0.75 mL, 8.0 mmol) was added
at 08C. The mixture was stirred for 1 h at 08C, then a 6m aqueous solu-
tion of NaOH (5.0 mL) and benzyltriethylammonium chloride (0.114 g,
0.50 mmol) were added and stirring was continued for 1 h at RT. General
workup furnished (Z)-8b (60%, 0.497 g, 3.0 mmol).
Data for (Z)-8b: 1H NMR ([D6]acetone, 300 MHz): d=7.05 (d, J=
35.7 Hz, 1H), 7.39–7.49 (m, 3H), 7.70–7.75 (m, 2H), 11.02 ppm (brs,
1H); 13C NMR ([D6]acetone, 75 MHz): d=118.1 (d, J=5.0 Hz), 129.6,
130.5 (d, J=3.1 Hz), 131.0 (d, J=8.1 Hz), 132.2 (d, J=3.8 Hz), 147.9 (d,
J=264.2 Hz), 162.3 ppm (d, J=35.3 Hz); 19F NMR ([D6]acetone,
283 MHz): d=ꢀ123.99 ppm (d, J=36.5 Hz).
Compound Int-5b: nBuLi (0.90 mL, 1.3 mmol, 1.40m in hexanes) was
added to a solution of 5b (0.290 g, 0.99 mmol) in THF (5 mL) at ꢀ808C.
The reaction mixture was stirred for 30 min at ꢀ808C, then nBuLi
(0.90 mL, 1.3 mmol, 1.40m in hexanes) was added to the mixture, which
was stirred at ꢀ808C for 2 h. Methanesulfonyl chloride (0.16 mL,
2.0 mmol) was added and the mixture was stirred for 1 h at 08C. General
workup and purification by silica gel column chromatography (CH2Cl2/
hexane=1:1) furnished (Z)-Int-5b (81%, 0.212 g, 0.80 mmol). Rf =0.69
(CH2Cl2); 1H NMR (CDCl3, 300 MHz): d=3.33 (s, 3H), 6.40 (d, J=
36.0 Hz, 1H), 7.26–7.44 (m, 2H), 7.53–7.58 ppm (m, 3H); 13C NMR
(CDCl3, 75 MHz): d=44.3, 111.7 (q, J=3.3 Hz), 116.7 (td, J=270.2,
39.2 Hz), 128.65 (d, J=32.8 Hz), 128.71, 129.5, 129.6 (d, J=9.9 Hz),
145.3 ppm (dt, J=266.9, 35.8 Hz); 19F NMR (CDCl3, 283 MHz): d=
ꢀ132.21 (dt, J=35.7, 12.0 Hz, 1F), ꢀ74.69 ppm (d, J=13.8 Hz, 2F); IR
(neat): n˜ =518, 693, 760, 876, 964, 1050, 1081, 1147, 1203, 1280, 1301,
1333, 1390, 1420, 1453, 1497, 1700, 2944, 3033; elemental analysis calcd
(%) for C10H9F3O3S: C 45.11; H 3.41. found: C 44.68; H 3.67.
Compound 8c:[21a,b] Prepared by H2SO4 hydrolysis: yield=72%,
Z
Z
isomer only; prepared by mesylate rearrangement: yield=72%,
1
isomer only. H NMR ([D6]acetone, 300 MHz): d=3.86 (s, 3H), 6.92–7.04
(m, 3H), 7.68–7.71 ppm (m, 2H); 13C NMR ([D6]acetone, 75 MHz): d=
55.7, 115.2, 118.0 (d, J=5.0 Hz), 124.6 (d, J=4.4 Hz), 132.8 (d, J=
8.1 Hz), 146.7 (d, J=259.2 Hz), 161.8 (d, J=3.1 Hz), 162.4 ppm (d, J=
34.7 Hz); 19F NMR ([D6]acetone, 283 MHz): d=ꢀ127.11 ppm (d, J=
34.2 Hz).
Compound 8d:[4c,21b] Prepared by H2SO4 hydrolysis: yield=89%,
isomer only; prepared by mesylate rearrangement: yield=70%,
Z
Z
isomer only. 1H NMR ([D6]acetone, 300 MHz): d=2.32 (s, 3H), 6.96 (d,
J=36.0 Hz, 1H), 7.22 (d, J=8.1 Hz, 2H), 7.57 (d, J=8.4 Hz, 2H),
10.23 ppm (brs, 1H); 13C NMR ([D6]acetone, 75 MHz): d=21.4, 118.1 (d,
J=5.0 Hz), 129.3 (d, J=4.3 Hz), 130.4, 130.5 (d, J=8.1 Hz), 140.8 (d, J=
2.5 Hz), 147.5 (d, J=262.9 Hz), 162.3 ppm (d, J=34.8 Hz); 19F NMR
([D6]acetone, 283 MHz): d=ꢀ124.99 ppm (d, J=36.7 Hz).
Compound 8a[4c,21]
Procedure for H2SO4 hydrolysis: nBuLi (1.0 mL, 1.2 mmol, 1.20m in hex-
anes) was added to a solution of 5b (0.282 g, 1.02 mmol) in THF (5 mL)
at ꢀ808C. The reaction mixture was stirred for 30 min at ꢀ808C, then
nBuLi (1.0 mL, 1.2 mmol, 1.20m in hexanes) was added and the mixture
was stirred at ꢀ808C for 2 h. A 1:1 cH2SO4/H2O solution (3.0 mL) was
added and the mixture was stirred for 24 h at RT. General workup fur-
nished (Z)-8a (53%, 0.118 g, 0.55 mmol).
Compound 8e: Prepared by mesylate rearrangement: yield=71%, Z
isomer only. M.p. 203.5–206.08C; 1H NMR ([D6]acetone, 300 MHz): d=
7.13 (d, J=34.8 Hz, 1H), 7.80 (d, J=8.1 Hz, 2H), 7.94 (d, J=8.4 Hz,
2H), 10.09 ppm (brs, 1H); 13C NMR ([D6]acetone, 75 MHz): d=116.4 (d,
J=4.4 Hz), 125.0 (q, J=271.1 Hz), 126.5 (q, J=3.7 Hz), 131.1 (d, J=
2.5 Hz), 131.5 (d, J=8.7 Hz), 136.0 (d, J=2.4 Hz), 149.4 (d, J=269.2 Hz),
161.9 ppm (d, J=35.3 Hz); 19F NMR ([D6]acetone, 283 MHz): d=
ꢀ120.44 (d, J=34.2 Hz, 1F), ꢀ61.79 ppm (s, 3F); IR (KBr): n˜ =722, 775,
839, 1013, 1062, 1129, 1176, 1271, 1319, 1439, 1664, 1708, 2524, 2615,
2683, 2859, 2925, 3079, 3439 cmꢀ1; elemental analysis calcd (%) for
C10H6F4O2: C 51.30, H 2.58; found: C 51.04, H 2.87.
Procedure for mesylate rearrangement: nBuLi (1.5 mL 2.4 mmol, 1.60m in
hexanes) was added to a solution of 5b (0.273 g, 0.99 mmol) in THF
(3 mL) at ꢀ808C. The reaction mixture was stirred for 2 h at ꢀ808C,
then methanesulfonyl chloride (0.125 mL, 1.61 mmol) was added and stir-
ring was continued for 1 h at 08C. A 6 m aqueous solution of NaOH
(1.0 mL) and benzyltriethylammonium chloride (0.022 g, 0.097 mmol)
were added and the mixture was stirred for 1 h at RT. General workup
furnished (Z)-8a (64%, 0.138 g, 0.63 mmol).
Data for (Z)-8a: 1H NMR ([D6]acetone, 300 MHz): d=7.57–7.69 (m,
3H), 7.74 (d, J=33.3 Hz, 1H), 7.96–8.02 (m, 3H), 8.15 ppm (d, J=
8.1 Hz, 1H); 13C NMR ([D6]acetone, 75 MHz): d=114.5 (d, J=4.4 Hz),
124.3, 126.3, 127.0, 127.8, 128.0 (d, J=3.8 Hz), 129.3 (d, J=10.6 Hz),
129.6, 130.8, 132.1, 134.5, 148.9 (d, J=266.0 Hz), 162.2 ppm (d, J=
32.9 Hz); 19F NMR ([D6]acetone, 283 MHz): d=ꢀ123.99 ppm (d, J=
34.2 Hz).
Compound 8 f: Prepared by mesylate rearrangement: yield=59%, Z
isomer only. M.p. 48.5–51.08C; 1H NMR ([D6]acetone, 300 MHz): d=
0.88 (t, J=6.8 Hz, 3H), 1.21–1.35 (m, 12H), 1.46 (quint, J=6.8 Hz, 2H),
2.28 (qd, J=7.4, 2.0 Hz, 2H), 6.28 ppm (dt, J=32.8, 7.9 Hz, 1H);
13C NMR ([D6]acetone, 75 MHz): d=14.4, 23.3, 24.7 (d, J=3.1 Hz), 29.0
(d, J=1.9 Hz), 29.3–30.6 (m), 32.6, 121.3 (d, J=11.8 Hz), 148.8 (d, J=
252.5 Hz), 161.8 ppm (d, J=36.6 Hz); 19F NMR ([D6]acetone, 283 MHz):
d=ꢀ133.29 ppm (d, J=31.9 Hz); IR (CH2Cl2): n˜ =739, 847, 922, 1096,
1266, 1443, 1469, 1672, 1704, 2359, 2852, 2920, 3080 cmꢀ1; HRMS (ESI):
m/z calcd for C12H20FO2: 215.1447, [MꢀH]+; found: 215.1446.
Compound 8g: Prepared by mesylate rearrangement: yield=80%, Z
isomer only. M.p. 98.0–102.08C; 1H NMR ([D6]acetone, 300 MHz): d=
2.57–2.65 (m, 2H), 2.76–2.81 (m, 2H), 5.79 (brs, 1H), 6.29 (td, J=7.7,
32.5 Hz, 1H), 7.18–7.33 ppm (m, 5H); 13C NMR ([D6]acetone, 75 MHz):
d=26.6 (d, J=2.4 Hz), 34.8 (d, J=2.5 Hz), 120.5 (d, J=13.0 Hz), 126.9,
129.2 (d, J=6.2 Hz), 141.7, 148.9 (d, J=253.1 Hz), 161.7 ppm (d, J=
36.6 Hz); 19F NMR ([D6]acetone, 283 MHz): d=ꢀ131.84 ppm (d, J=
31.9 Hz); IR (CH2Cl2): n˜ =696, 745, 837, 921, 991, 1114, 1186, 1281, 1451,
1667, 1691, 2867, 2939, 3025, 3066 cmꢀ1; elemental analysis calcd (%)
C11H11FO2: C 68.03, H 5.71; found: C 67.98, H 5.66.
Compound 8b:[21a,b] Prepared by H2SO4 hydrolysis: yield=65%,
isomer only; prepared by mesylate rearrangement: yield=72%,
isomer only.
Z
Z
One-pot procedure A: nBuLi (3.75 mL, 6.0 mmol, 1.6m in hexanes) was
added to a flask, and a large portion of hexane was removed under re-
duced pressure. Et2O (20 mL) and 1c (1.50 mL, 15.0 mmol) were added
to the flask at ꢀ808C. After 30 min stirring at ꢀ808C benzaldehyde
(0.51 mL, 5.0 mmol) was added. The mixture was stirred for 30 min at
ꢀ808C, then 4.5 h at 08C. The solvent was evaporated under reduced
pressure, THF (20 mL) was added and the mixture was cooled to ꢀ808C.
nBuLi (3.75 mL, 6.0 mmol, 1.6m in hexanes) was added the mixture was
stirred for 2 h at ꢀ808C. A 1:1 (v/v) cH2SO4/H2O solution (10 mL) was
added and stirring was continued for 24 h at RT. General workup fur-
nished (Z)-8b (58%, 0.483 g, 2.9 mmol).
Compound 8i:[21a,b] Prepared by H2SO4 hydrolysis: yield=87%, E/Z=
38:62; prepared by mesylate rearrangement: yield=70%, E/Z=27:73.
1H NMR ([D6]acetone, 300 MHz, Z isomer): d=2.46 (d, J=3.6 Hz, 3H),
1
One-pot procedure B: nBuLi (4.28 mL, 5.9 mmol, 1.40m in hexanes) was
added to a solution of 1c (1.50 mL, 15.0 mmol) in Et2O (20 mL) at
ꢀ808C. After stirring for 30 min at ꢀ808C, benzaldehyde (0.51 mL,
5.0 mmol) was added. After stirring for 30 min at ꢀ808C and 4.5 h at
08C the solvent was evaporated under reduced pressure. THF (20 mL)
was added and the solution was cooled to ꢀ808C. nBuLi (4.28 mL,
7.20–7.60 ppm (m, 5H); H NMR ([D6]acetone, 300 MHz, E isomer): d=
2.15 (d, J=4.8 Hz, 3H), 7.20–7.60 ppm (m, 5H); 13C NMR ([D6]acetone,
75 MHz): d=18.5 (d, J=1.3 Hz; Z), 19.4 (d, J=6.8 Hz; E), 128.36, 128.40
(d, J=3.1 Hz), 128.6, 128.7 (d, J=3.1 Hz), 129.06, 129.10, 138.6 (d, J=
1.8 Hz; Z), 139.4 (d, J=5.6 Hz; E), 144.2 (d, J=252.2 Hz; Z), 145.1 (d,
J=251.2 Hz; E), 161.4 (d, J=36.6 Hz; E), 162.9 ppm (d, J=35.3 Hz; Z);
9206
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Chem. Eur. J. 2011, 17, 9200 – 9208

Utilization of 2-Chloro-1,1,1,2-tetrafluoroethane
FULL PAPER
19F NMR ([D6]acetone, 283 MHz,
Z
isomer): d=ꢀ124.79 ppm (s);
[4] For the preparation of these materials from fluorinated carbon, see
the following: a) J. Burdon, P. L. Coe, I. B. Haslock, R. L. Powell,
Chem. Commun. 1996, 49–50; b) J. M. Bainbridge, S. Corr, M.
Kanai, J. M. Percy, Tetrahedron Lett. 2000, 41, 971–974, and referen-
ces therein; c) N. V. Kirij, D. A. Dontsova, N. V. Pavlenko, Y. L. Ya-
gupolskii, H. Scherer, W. Tyrra, D. Naumann, Eur. J. Org. Chem.
2008, 2267–2272.
[5] a) M. Essers, B. Wibbeling, G. Haufe, Tetrahedron Lett. 2001, 42,
5429–5433; b) E. A. Hallinan, T. J. Hagan, A. Bergmanis, W. M.
Moore, G. M. Jerome, D. P. Spangler, A. M. Stevens, H. S. Shieh,
P. T. Manning, B. S. Pitzele, J. Med. Chem. 2004, 47, 900–906; c) I.
Beria, P. G. Baraldi, P. Cozzi, M. Caldarelli, C. Geroni, S. Marchini,
N. Mongelli, R. Romagnoli, J. Med. Chem. 2004, 47, 2611–2623;
d) T. Noguchi, N. Tanaka, T. Nishimata, R. Goto, M. Hayakawa, A.
Sugidachi, T. Ogawa, Y. Niitsu, F. Asai, T. Ishizuka, K. Fujimoto,
Chem. Pharm. Bull. 2009, 57, 22–33; e) S. Osada, S. Sano, M.
Ueyama, Y. Chuman, H. Kodama, K. Sakaguchi, Bioorg. Med.
Chem. 2010, 18, 605–611.
19F NMR ([D6]acetone, 283 MHz, E isomer): d=ꢀ123.03 ppm (q, J=
4.5 Hz).
Compound 9b:[19] NaBH4 (0.034 g, 0.91 mmol) was added to a solution of
Int-5b (0.080 g, 0.30 mmol) in EtOH (5 mL) at 08C and the mixture was
stirred for 2 h at RT. The reaction was quenched with a 1m aqueous solu-
tion of HCl. General workup and purification by silica gel column chro-
matography afforded the allylic alcohol (Z)-9b (75%, 0.034 g,
0.22 mmol). Rf =0.24 (CH2Cl2); 1H NMR (CDCl3, 300 MHz): d=1.87
(brs, 1H), 4.29 (d, J=14.4 Hz, 2H), 5.78 (d, J=38.8 Hz, 1H), 7.22–7.28
(m, 1H), 7.34 (t, J=7.5 Hz, 2H), 7.51 ppm (d, J=7.8 Hz, 2H); 13C NMR
(CDCl3, 75 MHz): d=61.6 (d, J=32.2 Hz), 107.4 (d, J=6.2 Hz), 127.4 (d,
J=2.5 Hz), 128.4, 128.6 (d, J=7.5 Hz), 132.6 (d, J=2.5 Hz), 158.1 ppm
(d, J=266.0 Hz); 19F NMR (CDCl3, 283 MHz): d=ꢀ114.74 ppm (td, J=
13.7, 38.7 Hz).
Compound 10b:[19,20] NaOMe (0.082 g, 1.5 mmol) was added to a solution
of Int-5b (0.132 g, 0.49 mmol) in MeOH (5 mL) at 08C and the mixture
was stirred for 2 h at RT. The reaction was quenched with a 1m aqueous
solution of HCl (3 mL). General workup and purification by silica gel
column chromatography afforded the allylic alcohol (Z)-10b (79%,
0.071 g, 0.39 mmol). Rf =0.55 (hexane/EtOAc=4:1); 1H NMR (CDCl3,
300 MHz): d=3.90 (s, 3H), 6.93 (d, J=35.1 Hz, 1H), 7.23–7.44 (m, 3H),
7.62–7.66 ppm (m, 2H); 13C NMR (CDCl3, 75 MHz): d=52.5, 117.6 (d,
J=4.4 Hz), 128.7, 129.6 (d, J=3.1 Hz), 130.2 (d, J=8.7 Hz), 130.9 (d, J=
4.4 Hz), 144.7 (d, J=266.7 Hz), 161.7 ppm (d, J=34.1 Hz); 19F NMR
(CDCl3, 283 MHz): d=ꢀ126.90 ppm (d, J=36.4 Hz).
[6] Calculations were carried out with Gaussian 03W at the B3LYP/6-
31+G* level of theory. Gaussian 03, Revision B.03, M. J. Frisch,
G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R.
Cheeseman, J. A. MontgomACTHUNRGTNEeNUG ry, Jr., T. Vreven, K. N. Kudin, J. C.
Burant, J. M. Millam, S. S. Iyengar, J. Tomasi, V. Barone, B. Mennuc-
ci, M. Cossi, G. Scalmani, N. Rega, G. A. Petersson, H. Nakatsuji,
M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida,
T. Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J. E.
Knox, H. P. Hratchian, J. B. Cross, V. Bakken, C. Adamo, J. Jaramil-
lo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R.
Cammi, C. Pomelli, J. W. Ochterski, P. Y. Ayala, K. Morokuma,
G. A. Voth, P. Salvador, J. J. Dannenberg, V. G. Zakrzewski, S. Dap-
prich, A. D. Daniels, M. C. Strain, O. Farkas, D. K. Malick, A. D.
Rabuck, K. Raghavachari, Foresman, J. B. Ortiz, J. V. Cui, Q.
Baboul, A. G. Clifford, S. Cioslowski, J. Stefanov, B. B. Liu, G. Lia-
shenko, A. Piskorz, P. Komaromi, I. Martin, D. J. R. L. Fox, T.
Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayakkara, M. Challa-
combe, P. M. W. Gill, B. Johnson, W. Chen, M. W. Wong, C. Gonza-
lez, J. A. Pople, Gaussian, Inc., Wallingford CT, 2004.
Compound 11b: nBuLi (0.93 mL, 1.5 mmol, 1.6m in hexanes) was added
to benzylamine (0.164 mL, 1.5 mmol) in THF (2 mL) at ꢀ808C and the
mixture was stirred for 30 min at ꢀ808C. The lithium benzylamine salt
solution was added to a solution of Int-5b (0.132 g, 5.0 mmol) in THF
(3 mL) at ꢀ808C and the mixture was stirred for 2 h ꢀ808C. The reaction
was quenched with a 1m aqueous solution of HCl (3 mL). General
workup and purification by silica gel column chromatography afforded
the allylic alcohol (Z)-11b (73%, 0.092 g, 0.36 mmol). M.p. 122.5–
124.08C; Rf =0.54 (hexane/EtOAc=2:1); 1H NMR (CDCl3, 300 MHz):
d=4.59 (d, J=6.0 Hz, 2H), 6.68 (brs, 1H), 6.99 (d, J=37.0 Hz, 1H),
7.27–7.42 (m, 3H), 7.58–7.62 ppm (m, 2H); 13C NMR (CDCl3, 75 MHz):
d=43.6, 113.9 (d, J=4.4 Hz), 127.7, 127.9, 128.7, 128.8, 129.18, 129.21,
130.1 (d, J=8.1 Hz), 131.3 (d, J=3.7 Hz), 149.9 (d, J=274.7 Hz),
160.4 ppm (d, J=29.8 Hz); 19F NMR (CDCl3, 283 MHz): d=
ꢀ131.02 ppm (d, J=38.7 Hz); IR (CH2Cl2): n˜ =689, 753, 1328, 1535, 1644,
[7] a) M. Kanai, J. M. Percy, Tetrahedron Lett. 2000, 41, 2453–2455;
b) P. L. Coe, J. Burdon, I. B. Haslock, J. Fluorine Chem. 2000, 102,
43–50; c) N. A. Barnes, A. K. Brisdon, M. J. Ellis, R. G. Pritchard, J.
Fluorine Chem. 2001, 112, 35–45.
[8] a) S. J. Brown, S. Corr, J. M. Percy, Tetrahedron Lett. 2000, 41, 5269–
5273; b) R. Anilkumar, D. J. Burton, Tetrahedron Lett. 2002, 43,
6979–6982; c) R. Anilkumar, D. J. Burton, J. Fluorine Chem. 2005,
126, 835–843.
2337, 2360, 2925, 3331 cmꢀ1
; elemental analysis calcd (%) for
C16H15FNO: C 75.28, H 5.53, N 5.49; found: C 75.12, H 5.83, N 5.45.
[9] CF3CF2Li: a) P. G. Gassman, N. J. OꢂReilly, J. Org. Chem. 1987, 52,
2481–2490; b) A. A. Kolomeitsev, A. A. Kadyrov, J. Szczepkowska-
Sztolcman, M. Milewska, H. Koroniak, G. Bissky, J. A. Barten, G.-V.
Rçschenthaler, Tetrahedron Lett. 2003, 44, 8273–8277. CF3CCl2 Li:
c) A. Solladiꢃ-Cavallo, S. Quazzotti, J. Fluorine Chem. 1990, 46,
221–228. CF3CCl2Na: d) P. L. Johnson, J. Labelled Compd. Radio-
pharm. 2007, 50, 47–53. CF3CX2ZnX (X: Cl or Br): e) M. Fujita, T.
Hiyama, Bull. Chem. Soc. Jpn. 1987, 60, 4377–4384. CF3CClBrLi:
f) A. Ando, J. Takahashi, Y. Nakamura, N. Maruyama, M. Nishihara,
K. Fukushima, J. Moronaga, M. Inoue, K. Sato, M. Omote, I. Kuma-
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[10] A strong K···F interaction was reported; a) C.-P. Qian, T. Nakai, Tet-
rahedron Lett. 1988, 29, 4119–4122; b) T. Yamazaki, M. Ando, T.
Kitazume, T. Kubota, M. Omura, Org. Lett. 1999, 1, 905–908; c) T.
Yamazaki, S. Kawashita, T. Kitazume, T. Kubota, Chem. Eur. J.
2009, 15, 11461–11464.
[11] Formation of the corresponding carboxylic acid (15% yield) was
confirmed by 13C NMR spectroscopy ([D6]acetone, 75 MHz): d=
124.86 (q, J=271.5 Hz, CF3), 126.32 (q, J=3.7 Hz, CH-C-CF3),
131.15 (CH-C-CO2H), 134.50 (q, J=32.3 Hz, C-CF3), 135.06 (q, J=
1.2 Hz, C-CO2H), 166.53 ppm (CO2H); for the spectroscopic data
see, for example: R. Kuwano, M. Utsunomiya, J. F. Hartwig, J. Org.
Chem. 2002, 67, 6479–6486.
Acknowledgements
The authors gratefully acknowledge the generous gift of 2-chloro-1,1,1,2-
tetrafluoroethane from Dupont–Mitsui Fluorochemicals Co., Ltd.
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Chem. Eur. J. 2011, 17, 9200 – 9208
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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T. Yamazaki et al.
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1-(trifluorovinyl)cyclohexanol, which similarly indicated the instabil-
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Org. Chem. 1963, 28, 839–843.
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[14] It has been disclosed that a similar procedure furnished acid fluoride
when the hydrolysis was performed for a shorter time at lower tem-
perature; see reference [7a].
[18] Intermediate Int-5b was found to be stable enough for isolation by
silica gel column chromatography; sSee the Experimental Section
for its physical properties.
[19] M. Engman, J. S. Diesen, A. Paptchikhine, P. G. Andersson, J. Am.
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[15] Selected NMR data for 6 f: 1H NMR (CDCl3, 300 MHz): d=
3.65 ppm (dt, J=3.9, 6.6 Hz, 1H, HO-CH); 19F NMR (CDCl3,
283 MHz): d=ꢀ104.18 (dd, J=31.9, 79.7 Hz, 1F), ꢀ121.76 (ddd, J=
4.5, 79.7, 113.9 Hz, 1F), ꢀ191.62 ppm (ddd, J=27.4, 31.7, 114.2 Hz,
1F). Selected NMR data for 7 f: 19F NMR (CDCl3, 283 MHz): d=
ꢀ153.48 (dtd, J=4.9, 22.6, 125.5 Hz, 1F), ꢀ153.48 ppm (tdd, J=7.1,
27.4, 125.5 Hz, 1F). These data were obtained from the crude reac-
tion mixture.
Received: March 23, 2011
Published online: July 5, 2011
9208
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Chem. Eur. J. 2011, 17, 9200 – 9208