Utilization of perfluoroalkanoate-derived aluminium acetals as the convenient fluorinated aldehyde precursors

Article abstract of DOI:10.1016/j.tet.2011.05.007

Aluminium acetals from the DIBAL partial reduction of perfluoroalkanoates 1 were successfully employed as the convenient and useful fluorinated aldehyde precursors, and reactions of such intermediates with sodium salts from some β-dicarbonyl compounds 2 a

Full text of DOI:10.1016/j.tet.2011.05.007

Tetrahedron 67 (2011) 4845e4851
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Utilization of perfluoroalkanoate-derived aluminium acetals as the convenient
fluorinated aldehyde precursors
*
Sumika Aoki, Tomoko Kawasaki-Takasuka, Takashi Yamazaki
Division of Applied Chemistry, Institute of Engineering, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei 184-8588, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Aluminium acetals from the DIBAL partial reduction of perfluoroalkanoates 1 were successfully em-
ployed as the convenient and useful fluorinated aldehyde precursors, and reactions of such intermediates
with sodium salts from some b-dicarbonyl compounds 2 as well as their possible utility as the Michael
acceptors after transformation to the corresponding alkylidene malonates 8 were also demonstrated.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 11 April 2011
Received in revised form 2 May 2011
Accepted 3 May 2011
Available online 10 May 2011
Keywords:
Fluorinated compounds
Aluminium acetals
Michael reactions
Decarboxylation
Dehydration
1. Introduction
realized, skip of the isolation process would be quite helpful for
handling of fluorine-containing compounds with higher volatility,
Aldehydes have wide recognition as one of the most typical and
useful electrophiles conveniently employed in the field of synthetic
organic chemistry. Effective electrophilic activation of the carbonyl
carbon atom is known to be realized by direct attachment of
and, of course, important from the economical as well as ecological
points of view. Because our literature search revealed that quite
limited numbers of reports have been appeared6,7 thus far on the
basis of this concept, we have decided to start our investigation for
establishment of efficient utilization of intermediary aluminium
acetals prepared from the DIBAL reduction of appropriate esters 1
with a Rf group for the reaction with anionic nucleophiles derived
a
perfluoroalkyl (Rf) group due to its strongly electron-
withdrawing nature, which causes significant decrease of LUMO
energy levels.1 As a consequence, RfCHO readily accepts nucleo-
philic attack even by such weak reagents as water or alcohols to
very easily and smoothly afford the corresponding thermodynam-
from b-keto carbonyl compounds 2. Moreover, synthetic utility of
the products 3 obtained was also clarified by way of the formal
dehydration, followed by conjugate addition of hydrazines and an
alcohol molecule.
2
ically stable hydrates RfCH(OH)2 or hemiacetals RfCH(OH)OR, re-
spectively. In addition to problems associated with generation
methods of RfCHO from these derivatives3 usually requiring very
harsh conditions, this characteristic property allowed to consider
them as convenient as well as potential aldehyde precursors.4
However, as long as we concern, commercially available hydrates
and/or hemiacetals as well as their distributors are quite limited at
present. This inconvenience would be one of the major reasons why
this interesting synthetic process has not been employed fre-
quently in the field of synthetic organofluorine chemistry. At this
point, because preparative schemes to access these hemiacetals are
usually by way of conventional hydride reduction,5 we have
reached to an idea to use the intermediary metal acetals as the
intriguing in situ generated aldehyde precursors. If this concept is
2. Results and discussions
2.1. Reaction of aluminium acetals with
compounds
b-carbonyl
First of all, methyl tridecafluoroheptanoate 1a was employed as
the representative perfluoroalkanoate and its reaction after the
partial reduction with DIBAL has been studied in detail with so-
dium enolate derived from diethyl malonate 2a and sodium hy-
dride as the model nucleophile (Table 1). 1.2 equiv of DIBAL was
subjected to an Et2O solution of 1a at ꢀ80 ꢁC, and to this mixture
containing the resultant intermediary aluminium acetal was in-
troduced the sodium salt of 2a formed in THF in a separate flask
at ꢀ80 ꢁC and the temperature was increased after 5 min. Room
* Corresponding author. E-mail address: tyamazak@cc.tuat.ac.jp (T. Yamazaki).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.007

4846
S. Aoki et al. / Tetrahedron 67 (2011) 4845e4851
In spite of the selection of the best conditions as above, soon it
Table 1
appeared that sometimes this procedure gave inconsistent chem-
ical yields in a range of ca. 30%. After our detailed search, this dis-
crepancy was found to stem from the combination ratio of two
different solvents, CH2Cl2 as Solv 1 and THF as Solv 2 in Table 2.
Actually, increase of the CH2Cl2/THF ratio from 1/5 to 2/1 rendered
the total polarity to be lowered and the yield to be largely de-
creased from 82% to 43%. This was understood from the standpoint
of the role of THF as a Lewis base, which would coordinate to the
aluminium atom of the DIBAL reduction intermediate with ade-
quately weakening the AleO bond. Then, the corresponding alde-
hyde would be readily released to be quickly trapped by the
nucleophile. Thus, our initial irreproducibility was concluded on
the basis of the use of the different amount of THF not only as the
reaction solvent but also as the rinsing liquid after transfer of the
sodium salt of malonate to the other flask, and was completely
solved by strict control of the CH2Cl2/THF ratio to 1/5.
Investigation of reaction conditions (1)
Entry
Time 1 (h)
Temp (ꢁC)
Time 2 (h)
Yielda (%)
1
2
3
4
5
6
7
8
0.5
0.5
0.5
0.5
0.5
1.0
2.0
3.0
0
0
1.0
3.0
1.0
24.0
1.0
1.0
19
26
47
38
47
52
61
43
rt
rt
60
rt
rt
rt
Because we successfully found out the best and reproducible
process for the reaction of 1a and 2a, various esters 1 were treated
1.0
1.0
under these conditions with some
b-dicarbonyl compounds 2
a
Determined by 1H NMR spectroscopy.
whose results are summarized in Table 3. Nucleophilic attack of
diethyl malonate 2a proceeded nicely to aluminium acetals from
tridecafluoroheptanoate (1a), trifluoroacetate (1b), and penta-
fluoropropionate (1c) to furnish the corresponding adducts in good
to excellent yields (entries 1e3). In the case of 3a, a small amount of
impurity was noticed by 1H NMR, which was proved to be the
corresponding methyl ester formed by alcohol exchange of the
original ethyl ester 3a. Formation of such a byproduct would be
mediated by the ‘waste’ i-Bu2AlOMe eliminated from the alumin-
ium acetal when the aldehyde was liberated.8 The fact that this
problem was not encountered when 1a was reacted with dimethyl
malonate 2b supported this assumption and a similar level of
chemical yield was recorded for the adduct 3d (entry 4). Synthesis
of 3b with a CF3 group was reported by only two researchers until
now,9 both starting from the isolated trifluoroacetaldehyde hemi-
acetals as the CF3 source. It is the clear predominance of the present
method that the intermediary aluminium acetals were not required
to be isolated for obtaining a similar outcome.
temperature was found to be sufficient (entries 1,3, and 5) and 1 h
stirring after mixing both solutions (Time 2) seemed to be appro-
priate for the construction of the desired alcohol 3a in good
chemical yield (entries 3 and 4). It is interesting to note that the
duration of the DIBAL reduction also affected the yield to some
extent (entries 3, 6, 7, and 8), and 2 h at ꢀ80 ꢁC was found to be the
best out of other time conditions examined.
At the next stage, the solvent effect was briefly checked both for
the DIBAL partial reduction and the enolate formation from 2a
(Table 2). For the former instance, relatively low polar solvents
were usually preferred for avoidance of overreduction,7 and CH2Cl2
was actually proved to work adequately (entries 1,3, and 5). When
the formation of the sodium salt from 2a was performed in DMF
with high polarity and this mixture was added to the other solution
containing the aluminium acetal, only a sluggish result was
obtained possibly due to stronger coordinating property of this
solvent. On the other hand, efficiency of THF was unexpectedly
similar to the one of Et2O (entries 1 vs 3) in spite of their Lewis
basicity difference. As a consequence, in connection with the re-
sults in Table 1, entry 7 in Table 2 was eventually determined to be
the conditions of choice for the construction of 3a.
Table 3
DIBAL-mediated reaction of perfluoroalkanoates 1 with b-dicarbonyl compounds 2
Table 2
Investigation of reaction conditions (2)
Entry
Rf
1
R1
R2
R3
3
Yielda,b (%)
1
2
3
4
5
6
7
8
C6F13
CF3
C2F5
C6F13
C6F13
C2F5
CHF2
CClF2
a
b
c
a
a
c
Me
Et
CO2Et
CO2Et
CO2Et
CO2Me
C(O)Me
C(O)Me
CO2Et
CO2Et
CO2Et
CO2Et
CO2Me
CO2Et
CO2Et
CO2Et
CO2Et
a
b
c
d
e
f
82
64
67
74
Me
Me
Me
Me
Et
68 [55:45]
47 [51:49]
(62)
NaH
2a
d
e
g
h
Entry
Solv 1
Solv 2
(equiv)
Yielda (%)
Me
CO2Et
(36)
a
Isolated yields are shown and the ones determined by 1H NMR are described in
1
2
3
4
Et2O
Et2O
THF
THF
THF
THF
DMF
THF
THF
THF
THF
THF
1.2
1.2
1.2
2.2
3.3
1.2
3.3
1.1
1.1
1.1
2.0
3.0
1.1
3.0
47
18
41
51
59
69
82
parenthesis.
b
In the brackets are shown the diastereomer ratios.
5
Esters 1a and 1c were also employed to form a new carbon-
6
CH2Cl2
CH2Cl2
7b
ecarbon bond with ethyl 3-oxobutanoate 2c and the resultant
adducts 3e and 3f were produced in good yields in a stereo random
manner (entries 5 and 6). On the other hand, 1,3-diphenylpropane-
a
Determined by 1H NMR spectroscopy.
DIBAL reduction was performed for 2 h.
b

S. Aoki et al. / Tetrahedron 67 (2011) 4845e4851
4847
1,3-dione (R2¼R3¼PhC(O)) as well as ethyl nitroacetate (R2¼CO2Et,
R3¼NO2) were not the adequate reagents and construction of the
corresponding adducts was confirmed in only 10e20% yields.
Difluoro- or chlorodifluoroacetate (1d or 1e) were treated in the
same system to afford the desired products 3g or 3h, respectively,
but because of inseparability from the excess amount of malonate
used, their purification were not carried out at this stage.
For the clarification of the mechanism to access to the byproduct
7a as mentioned above, the isolated 4a was subjected to the same
decarboxylation condition in the presence of malonate 2a to result
in the recovery of 4a in 89% yield (Scheme 2). In contrast, the other
possible substrate 8a actually led to the formation of 7a in 25%
yield. Comparison of these independent reactions unambiguously
indicated that the production of 7a would be initiated by the de-
hydration of 3a to form 8a at the first stage, which could further
accept Michael addition of diethyl malonate 2a present in a crude
mixture, followed by hydrolysisedecarboxylation, both by the ac-
tion of Lewis acidic LiCl.
2.2. Synthetic utilization of fluorine-containing malonate
derivatives 3
As described in the previous section, because of their close Rf
values, the crude mixture containing 3 and 2 was employed for the
next decarboxylation step without further tedious purification.
With referring to the method described in the literature,10 a variety
of conditions were examined to the model substrate 3a. As shown
in Table 4, search for the optimal reaction time and an amount of
H2O clarified that 6 h and 22.5 equiv were the best, respectively
(entries 1e3), while elongation of the time seemed to decrease the
yield (entry 4). It is interesting to note that, during this trans-
formation, the C6F13-containing glutarate 7a was concomitantly
formed as a byproduct to some extent (entries 1e3). Different
substrates 3b, 3c, 3h, and 3g were also treated under the conditions
Scheme 2. Reaction of 4a and 8a under the decarboxylation condition.
Then, even under the same reaction conditions, what factor af-
fected the different outcome when starting from 3a and 3g: thus the
former afforded 4a but the latter a mixture of 5g and 6g, not 4g? This
discrepancy would be elucidated as follows. Due to significant
electron-withdrawing nature of a Rf group, its attachment geminal
to the hydroxy moiety is believed to strengthen the neighboring
RfeCeO bond.11 Moreover, because of difference in electron-
withdrawing ability,12 electron density of the oxygen atom proxi-
mate to the C6F13 moiety in 3a should be lower than the one in 3g.
Thus, because this effect might render the C6F13eCeO bond stronger
and this oxygen less Lewis basic, the LiCl-mediated dehydration of
3a was assumed to be more difficult than the case of 3g. On the other
hand, smooth activation of an ester group in 3a was realized by this
Lewis acid because the carbonyl oxygen atom is two more bonds
apart from the C6F13 moiety. This is our interpretation why the
present sharp contrast in reactivity was observed.
Table 4
Decarboxylation of 3
Entry
Rf
3
H2O (equiv)
Time (h)
4
Yielda (%)
1
2
3
4
5
6
7
C6F13
C6F13
C6F13
C6F13
CF3
a
a
a
a
b
c
3.3
15
2
5
6
15
6
a
a
a
a
b
c
75 (20)
81 (16)
94 (3)
74
quant
66
22.5
30
22.5
22.5
22.5
C2F5
CClF2
6
6
h
h
75
a
In the parenthesis was shown the yield of the corresponding glutarate 7a.
Although alkylidene malonates 8 seems to be readily accessible
from 3 by the formal dehydration, it was quite interesting to note
that 8 with a Rf group at the terminal carbon atom were reported
only for the one possessing a CF3 group 8b,4k,13 and their syntheses
basically followed the same protocol: thus, as shown in Eq. 1,
conversion of the commercially available CF3-containing hemi-
acetals to the corresponding N,O-acetals, then introduction of
malonate, followed by acid-mediated deamination afforded 8b in
about 40% overall yield. So, construction of 8 was carried out from
a couple of substrates 3 for opening a new route to access to these
interesting compounds possessing not only a CF3 group but some
other Rf moieties starting from more versatile and easy-to-handle
perfluoroalkanoates 1.
shown in entry
3 and the corresponding 3-hydroxy-3-per-
fluoroalkylated propionates 4 were obtained in high yields (entries
5e7). On the other hand, 3g (Rf¼CHF2) was the special case and
a mixture of mono- and bisethoxycarbonylated glutarates 5g and
6g was isolated in 78 and 17% yields, respectively, without de-
tection of the desired 4g (Scheme 1).
Theoretically, 1 equiv of AcCl and Et3N were required for acet-
ylation of the hydroxy group, and introduction of another equiv of
Scheme 1. Decarboxylation of 3g.

4848
S. Aoki et al. / Tetrahedron 67 (2011) 4845e4851
the same base would facilitate smooth elimination of an acetic acid
molecule to furnish 8 initiated by removal of the acidic methine
proton. As shown in Table 5, the desired compounds 8 were cleanly
constructed by the action of AcCl and Et3N in refluxing CH2Cl2.
Although the reason was not clarified yet, 3b and 3c seemed to be
less reactive than the case of 3a, and twice amounts of both re-
agents were required for attainment of good isolated yields of the
products 8.
Table 5
Dehydration from 3
Entry Rf
3
AcCl (equiv) Et3N (equiv) Time (h)
8
Yielda (%)
1
2
3
4
5
C6F13e
a
b
b
c
1.5
1.5
3.0
1.5
3.0
3.0
3.0
6.0
3.0
6.0
6
4
4
4
4
a
b
b
c
93
CF3e
CF3e
C2F5e
C2F5e
2b (>99)b
70
52b (43)b
61
Scheme 3. Reaction of 8a with three hydrazines and EtOH.
c
c
a
In the parenthesis was shown the recovery of 3.
b
Determined by 1H NMR.
contaminated by the regioisomer with the methyl group at the 2-
position.14 On the other hand, only Michael addition proceeded by
the action of phenyl hydrazine toward 8a. In the case of methyl-
hydrazine, the more electronegative and sterically not quite en-
cumbered nitrogen atom with a CH3 group would preferentially
Alkylidenemalonates 8 thus obtained were expected to be ex-
cellent Michael acceptors due to three electron-withdrawing sub-
stituents installed to the one ethylene unit, and the reaction of 8a
with hydrazine hydrate was carried out for validation of their utility
(Table 6). As our expectation, conjugate addition of hydrazine was
very quick either in ethanol or methylene chloride and almost
complete conversion was confirmed even after 5 min at ambient
temperature (entries 1 and 2). The product obtained was not the
simple Michael adduct but the pyrazolidin-3-one 9a as the result of
the intramolecular cyclization after the initial 1,4-addition. Efficient
increase of the yield of 9a was realized by the application of the
non-aqueous workup method (see the Experimental section),
which successfully attained much better material balance. Further
brief investigation on the amount of NH2NH2$H2O, reaction time,
and temperature allowed us to determine the conditions shown in
entry 8 as the best, which were employed for the reaction of 8a
with three representative hydrazines whose results are described
in Scheme 3.
attack the b-carbon to the ester moiety, followed by the cyclization
to furnish 10a. If the opposite reaction order is operative, the
intramolecular Michael reaction of the initially formed amide
should proceed in a 5-endo-trig manner, which is known to be the
disfavored mode on the basis of the Baldwin’s rule.15 This in-
terpretation is supported by the regiospecific formation of 11a,
where only conjugate addition by the possibly more anionic and
less hindered nitrogen atom was observed. Although relative ste-
reochemistry of the chiral centers in 9a and 10a has not been
clarified yet, the anti isomer was believed to be predominantly
obtained. This expectation was on the basis of the fact that (1) these
products possessed an acidic proton at the 4-position where the
ready epimerization would be occurred under the reaction condi-
tions employed and (2) the anti model isomer (carbomethoxy and
CF3 groups at the 4 and 5 positions of 9a (R¼H), respectively) was
calculated16 to be 4.3 kcal/mol more stable than the corresponding
cis counterpart.
Table 6
Reaction of 8 with hydrazine
It was also observed that the 1,4-addition of EtOH to 8a was
facilitated in the presence of either LiCl or EtONa, leading to the
construction of 12a in high yields. Much smoother reaction under
the latter conditions would be understood as the reflection of the
low LUMO energy levels of 8a, while the other Lewis acid-catalyzed
reaction should be retarded by the lower HOMO level, rendering
the coordination of LiCl more or less difficult.
Entry
Solv
NH2NH2 (equiv)
Temp (ꢁC)
Time (min)
Yielda (%)
1
2
3
4
EtOH
EtOH
EtOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
1.1
1.1
1.1
1.1
1.1
2.2
1.1
1.1
rt
rt
0
0
0
0
5
30
5
5
5
5
60
60
50
32
46
48
73
60
83
98 (80)
2.3. Conclusion
5b
6b
7b
8b
As shown above, we have successfully demonstrated the utility
of aluminium acetals, readily obtained by the partial reduction of
perfluoroalkanoates 1 by DIBAL, for the smooth acceptance of the
ꢀ30
ꢀ80
nucleophilic attack of anionic species from
b-dicarbonyl com-
a
Yields determined by 1H NMR and in the parenthesis is shown the isolated yield.
Non-aqueous workup was performed.
b
pounds. The fact that no isolation of intermediary Rf-containing
hemiacetals is required is the strong indication of the advantage
of the present method from the standpoint of efficiency. Our in-
terest in this area prompted us to study further synthetic applica-
tion of such aluminium acetals, which will be published in due
course.
Unsubstituted and methylated hydrazines furnished the corre-
sponding pyrazolidin-3-one 9a and 10a in good yields, respectively,
and it is worth noting that the latter product 10a was not

S. Aoki et al. / Tetrahedron 67 (2011) 4845e4851
4849
3. Experimental section
3.1. General
t, J¼6.9 Hz), 3.76 (1H, d, J¼2.7 Hz), 4.25e4.36 (4H, m), 4.78 (1H, d,
J¼9.9 Hz), 4.88 (1H, tdd, J¼2.8, 9.9, 21.9 Hz).13C NMR
d 13.8,13.9, 49.2,
62.6, 62.8, 69.3 (dd, J¼21.4, 28.9 Hz),111.3 (qt, J¼39.5, 251.6 Hz),118.2
(tq, J¼35.6, 284.3 Hz),165.8,168.6.19F NMR
ꢀ122.22 (1F, dd, J¼21.8,
d
Most of reactions where an organic solvent was employed were
performed under argon with magnetic stirring using flame-dried
glassware. Unless otherwise noted, materials were obtained from
commercial suppliers including anhydrous THF, Et2O, and CH2Cl2
and were used without further purification. Analytical thin-layer
chromatography (TLC) was routinely used for monitoring reactions
by generally using a mixture of n-hexane and ethyl acetate (v/v).
274.7 Hz), ꢀ121.51 (1F, d, J¼276.1 Hz), ꢀ83.23 (3F, br s). IR (neat)
n
3470, 2988, 2944, 29,411, 1751, 1468, 1448, 1374, 1301, 1218, 1194,
1159, 1096, 1030, 1004, 864, 731, 688 cmꢀ1
Anal. Calcd for
C10H13F5O5: C, 38.97; H, 4.25. Found: C, 39.16; H, 4.20.
.
3.2.4. Dimethyl
2-(2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoro-1-hydrox-
yhexyl)malonate, 3d. Yield 74%. Rf¼0.33 (AcOEt:hexane¼1:4). Mp
Spherical neutral silica gel(63e210
m
m or 40e50
m
m)was employed
39e41 ꢁC. 1H NMR
d
3.82 (1H, d, J¼3.0 Hz), 3.83 (3H, s), 3.86 (3H, s),
for usual column or flush chromatography, respectively. 1H, 13C, and
19F NMR spectra were recorded (1H: 300 MHz; 13C: 75 MHz; 19F:
283 MHz) at 25 ꢁC whose data were reported as follows: chemical
4.66 (1H, d, J¼9.9 Hz), 4.89 (1H, ddt, J¼3.0, 9.9, 22.2 Hz). 13C NMR
d
d
49.5, 53.2, 53.4, 69.6 (dd, J¼23.6, 26.0 Hz), 166.2, 168.7. 19F NMR
ꢀ128.03 (1F, dm, J¼292.0 Hz), ꢀ126.64 (1F, dm, J¼298.8
shift (
d
scale) in parts per million (ppm) downfield from Me4Si (
d
Hz), ꢀ124.66 (1F, br d, J¼301.0 Hz), ꢀ124.19 (1F, br d, J¼214.2
Hz), ꢀ123.11 (1F, br d, J¼214.2 Hz), ꢀ123.01 (2F, br s), ꢀ122.50 (1F,
br d, J¼214.2 Hz), ꢀ118.98 (1F, br d, J¼280.7 Hz), ꢀ81.94 (3F, t,
0.00 for 1H and 13C NMR) or C6F6 (
d
ꢀ162.2 for 19F NMR) as internal
standards, number of protons or fluorines, multiplicity (singlet, s;
doublet, d; triplet, t; quartet, q; multiplet, m; broad peak, br; etc.),
and coupling constants (J in Hz). 13C NMR spectra were usually
reported only for carbons without fluorine atoms because of sig-
nificant multiple coupling between these nuclei, rendering visuali-
zation extraordinarily difficult even after a long data acquisition
time. Infrared (IR) spectra were reported in wave number (cmꢀ1).
J¼10.8 Hz). IR (neat)
n 3474, 1759, 1730, 1446, 1322, 1229, 1195, 1143,
1117, 1092, 1023, 935, 745, 700, 659 cmꢀ1
C12H9F13O5: C, 30.02; H, 1.95. Found: C, 30.31; H, 1.95.
. Anal. Calcd for
3.2.5. Ethyl
2-acetyl-4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluoro-3-hydr-
oxy-nonanoate, 3e. Due to difficult identification between the
major and the minor isomers, NMR data were described in a set of
two peaks. Yield 68%. dr¼55:45. Rf¼0.67 (AcOEt:hexane¼1:1). 1H
3.2. Reaction of aluminium acetals with active methylene
compounds
NMR
d
1.31 (3H, t, J¼7.2 Hz) and 1.34 (3H, t, J¼7.2 Hz), 2.35 (3H, s)
and 2.39 (3H, s), 3.83 (1H, d, J¼3.9 Hz) and 3.96 (1H, d, J¼4.8 Hz),
4.28 (2H, q, J¼7.2 Hz) and 4.33 (2H, q, J¼7.2 Hz), 4.36 (1H, d,
J¼4.8 Hz) and 4.47 (1H, d, J¼5.4 Hz), 4.82e5.02 (1H, m). 13C NMR
3.2.1. Diethyl 2-(2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoro-1-hydroxyhe-
ptyl)malonate, 3a. To a CH2Cl2 (3.0 mL) solution of methyl trideca-
fluoroheptanoate 1a (1.134 g, 3.00 mmol) was slowly added DIBAL
(0.86 M, 3.8 mL, 3.3 mmol) at ꢀ80 ꢁC under an argon atmosphere and
stirring was continued for 2 h at that temperature. To a THF (10 mL)
solution of NaH (0.235 g, 9.78 mmol) in a different flask was added
diethyl malonate (1.36 mL, 9.03 mmol) at 0 ꢁC under an argon at-
mosphere and stirring was continued for 30 min. The latter mixture
was introduced to the former with the aid of cannula and after
transfer of the mixture, the inside of the flask was washed with the
additional 5 mL of THF. The resultant mixture was reacted at ꢀ80 ꢁC
for 5 min, followed by at room temperature for 1 h, and then was
quenchedwith1MHClaqsoastomakethepHofthemixtureat6to7.
The solutionwas filtered with the aid of a pad of Celite, and the filtrate
was extracted three times with AcOEt, and the combined AcOEt layer
was washed with satd NaCl aq. The organic layer was dried over an-
hydrous Na2SO4, filtered, and the volatiles were evaporated in vacuo
to give a crude material, which waschromatographed ona silicagelto
afford 1.250 g (2.460 mmol) of the title compound 3a. Yield 82%.
d
13.79 and 13.83, 29.2 and 31.4, 55.3 and 56.6, 62.71 and 62.75,
69.0 (dd, J¼21.4, 27.2 Hz) and 70.1 (dd, J¼21.1, 28.5 Hz), 165.8 and
168.9, 198.4 and 204.0. 19F NMR
ꢀ128.18 (1F, dm, J¼284.9 Hz),
ꢀ126.73 (1F, dm, J¼280.4 Hz), ꢀ125.87 to ꢀ122.12 (8F, m), ꢀ82.05
(3F, t, J¼10.3 Hz). IR (neat) 3473, 2990, 1745, 1720, 1364, 1239,
1201, 1146, 1121, 1021, 847, 811, 733 cmꢀ1
Anal. Calcd for
C13H11F13O4: C, 32.65; H, 2.32. Found: C, 32.88; H, 2.42.
d
n
.
3.2.6. Ethyl
2-acetyl-4,4,5,5,5-pentafluoro-3-hydroxypentanoate,
3f. Due to difficult identification between the major and the minor
isomers, NMR data were described in a set of two peaks. Yield 47%.
dr¼51:49. Rf¼0.63 (AcOEt:hexane¼1:1). 1H NMR
d 1.31(3H, t,
J¼7.5 Hz) and 1.33 (3H, t, J¼7.5 Hz), 2.35 (3H, s) and 2.39 (3H, s),
3.83 (1H, d, J¼4.2 Hz) and 3.95 (1H, d, J¼4.5 Hz), 4.27 (2H, q,
J¼6.9 Hz) and 4.32 (2H, q, J¼6.9 Hz), 4.44 (1H, s) and 4.47 (1H, s),
4.72e4.91 (1H, m). 13C NMR
d 13.8 and 13.9, 29.3 and 31.4, 55.1 and
56.5, 62.71 and 62.75, 68.5 (dd, J¼21.7, 29.2 Hz) and 69.7 (dd,
Rf¼0.50 (AcOEt:hexane¼1:4). 1H NMR
d
1.31 (3H, t, J¼7.2 Hz), 1.33
J¼21.7, 29.1 Hz), 165.8 and 168.9, 198.4 and 204.1. 19F NMR
(3H, t, J¼7.2 Hz), 3.77 (1H, d, J¼3.3 Hz), 4.28 (2H, q, J¼7.2 Hz),
4.27e4.37 (2H, m), 4.76 (1H, d, J¼9.9 Hz), 4.88 (1H, tdd, J¼2.8, 9.6,
d
ꢀ131.94 (1F, dd, J¼21.6, 272.6 Hz) and ꢀ130.44 (1F, dd, J¼21.6,
272.6 Hz), ꢀ121.03 (1F, d, J¼272.6 Hz) and ꢀ120.99 (1F, dd,
3473,
20.4 Hz). 13C NMR
d
13.7, 13.8, 49.6, 62.6, 62.8, 69.7 (dd, J¼21.7,
J¼272.6 Hz), ꢀ83.09 (3F, s) and ꢀ83.05 (3F, s). IR (neat)
n
28.6 Hz), 165.8, 168.5. 19F NMR
d
ꢀ128.13 (1F, dm, J¼289.4 Hz),
2989, 1744, 1719, 1369, 1195, 1127, 1055, 1020, 862, 725 cmꢀ1. Anal.
Calcd for C9H11F5O4: C, 38.86; H, 3.99. Found: C, 38.95; H, 4.14.
Because the separation of 3g and 3h was difficult from the ex-
cess amount of diethyl malonate present in a crude mixture, as
depicted in the text, they were used for the next decarboxylation
step without further purification.
ꢀ126.70 (1F, dm, J¼285.2 Hz), ꢀ124.77 (1F, dm, J¼305.5 Hz), ꢀ124.26
(1F, dm, J¼214.2 Hz), ꢀ123.19 (1F, dm, J¼214.2 Hz), ꢀ123.07 to
ꢀ122.04 (3F, m), ꢀ119.03 (2F, td, J¼18.4, 278.1 Hz), ꢀ82.05 (3F, t,
J¼10.3 Hz). IR (neat)
n 3480, 2989, 2946, 2913, 2879, 1752,1377,1349,
1239,1349,1203,1146,1121,1097,1029, 862, 744, 699, 656 cmꢀ1. Anal.
Calcd for C14H13F13O5: C, 33.09; H, 2.58. Found: C, 33.17; H, 2.64.
3.3. Decarboxylation
3.2.2. Diethyl 2-(2,2,2-trifluoro-1-hydroxyethyl)malonate, 3b9a. Yield
64%. Rf¼0.39 (AcOEt:hexane¼1:4). 1H NMR 1.29 (3H, t, J¼7.5 Hz),
1.31 (3H, t, J¼7.2 Hz), 3.71 (1H, d, J¼3.9 Hz), 4.22e4.38 (4H, m),
3.3.1. Ethyl 4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluoro-3-hydroxy-nonan-
oate, 4a. To a mixture of LiCl (0.163 g, 3.84 mmol) and the crude 3a
(0.822 g, 0.768 mmol determined by 1H NMR using toluene as an
internal standard) in DMSO (4 mL) was added H2O (0.31 mL,
17.2 mmol), and the whole mixture was heated at 160 ꢁC for 6 h.
After addition of water (30 mL), the usual workup and
4.57e4.75 (2H, m). 19F NMR
d
ꢀ78.97 (d, J¼6.8 Hz).
3.2.3. Diethyl 2-(2,2,3,3,3-pentafluoro-1-hydroxypropyl)-malonate,3c.
Yield 67%. Rf¼0.42 (CH2Cl2). 1H NMR
1.31 (3H, t, J¼7.2 Hz),1.33 (3H,
d

4850
S. Aoki et al. / Tetrahedron 67 (2011) 4845e4851
chromatographic purification by silica gel (AcOEt:hexane¼1:8)
furnished 4a (0.408 g, 0.719 mmol) as a white solid. Yield 94%.
J¼14.1 Hz). 13C NMR
13.7, 13.9, 62.5, 63.1, 126.1 (t, J¼23.6 Hz), 137.3
d
(t, J¼5.0 Hz), 161.3, 162.7. 19F NMR
ꢀ127.28 (2F, m), ꢀ123.94 (4F, s),
d
Rf¼0.50 (AcOEt:hexane¼1:6). Mp 34e35 ꢁC. 1H NMR
d
1.31 (3H, t,
ꢀ122.87 (2F, s), ꢀ112.76 (1F, d, J¼13.6 Hz), ꢀ112.61 (1F, d,
J¼7.2 Hz), 2.73e2.78 (2H, m), 3.52 (1H, d, J¼6.3 Hz), 4.23 (2H, q,
J¼13.8 Hz), ꢀ81.91 (3F, s). IR (neat)
n 3480, 3074, 2990, 2945, 2911,
J¼7.2 Hz), 4.58e4.72 (1H, m). 13C NMR
d
14.0, 33.8, 61.6, 67.0 (dd,
2880,1747,1671,1469,1350,1240,1204,1146,1132,1071,1052,1022,
865, 811, 744, 709, 654 cmꢀ1. Anal. Calcd for C14H11F13O4: C, 34.30;
H, 2.26. Found: C, 33.84; H, 2.42.
J¼22.6, 28.9 Hz), 171.1. 19F NMR
d
ꢀ128.01 (1F, dm, J¼289.7 Hz),
ꢀ126.68 (1F, dm, J¼285.2 Hz), ꢀ124.68 (1F, br d, J¼307.8 Hz),
ꢀ124.22 (1F, br d, J¼202.9 Hz), ꢀ123.15 (1F, br d, J¼202.9 Hz),
ꢀ122.90 (2F, br s), ꢀ122.65 (1F, br d, J¼310.3 Hz), ꢀ121.06 (2F, td,
3.4.2. Diethyl 2-(2,2,2-trifluoroethylidene)malonate, 8b13c. Yield
J¼16.1, 282.9 Hz), ꢀ81.99 (3F, t, J¼9.3 Hz). IR (neat)
n
3503, 1725,
69%. Rf¼0.70 (AcOEt:hexane¼1:2). 1H NMR
d
1.33 (3H, t, J¼7.2 Hz),
1323, 1239, 1205, 1146, 1122, 1077, 1019, 744, 705, 651 cmꢀ1. Anal.
Calcd for C11H9F13O3: C, 30.29; H, 2.08. Found: C, 30.16; H, 1.78.
1.34 (3H, t, J¼7.2 Hz), 4.32 (2H, q, J¼7.2 Hz), 4.36 (2H, q, J¼7.2 Hz),
6.77 (1H, q, J¼7.2 Hz). 19F NMR
d
ꢀ63.49 (d, J¼7.3 Hz).
3.3.2. Ethyl 4,4,4-trifluoro-3-hydroxybutanoate, 4b17. Quantitative
3.4.3. Diethyl 2-(2,2,3,3,3-pentafluoropropylidene)malonate, 8c. Yield
yield. Rf¼0.43 (AcOEt:hexane¼1:4). 1H NMR
d
1.30 (3H, t, J¼7.2 Hz),
61%. Rf¼0.59 (AcOEt:hexane¼1:4). 1H NMR
d
1.34 (6H, t, J¼7.2 Hz),
2.64e2.78 (2H, m), 3.47e3.53 (1H, m), 4.22 (2H, q, J¼7.2 Hz),
4.38e4.52 (1H, m).
4.33 (2H, q, J¼7.2 Hz), 4.35 (2H, q, J¼7.2 Hz), 6.74 (1H, t, J¼13.8 Hz).
13C NMR
J¼35.6, 283.7 Hz), 125.9 (t, J¼23.9 Hz), 137.5 (t, J¼5.3 Hz), 161.2,
162.6. 19F NMR
n
d
13.7, 13.8, 62.5, 63.0, 111.3 (qt, J¼39.5, 251.6 Hz), 118.2 (tq,
3.3.3. Ethyl 4,4,5,5,5-pentafluoro-3-hydroxypentanoate, 4c17. Yield
66%. Rf¼0.42 (AcOEt:hexane¼1:4). 1H NMR 1.29 (3H, t, J¼6.9 Hz),
2.72e2.75 (2H, m), 3.56 (1H, d, J¼5.4 Hz), 4.23 (2H, q, J¼6.9 Hz),
d
ꢀ116.61 (2F, d, J¼14.4 Hz), ꢀ85.71 (3F, s). IR (neat)
3471, 3071, 2989, 2945, 2911, 2879, 1746, 1672, 1377, 1338, 1254,
1206, 1134, 1059, 1042, 1019, 866, 761, 728, 695, 607 cmꢀ1. Anal.
Calcd for C10H11F5O4: C, 41.39; H, 3.82. Found: C, 40.91; H, 3.68.
4.46e4.63 (1H, m). 19F NMR
Hz), ꢀ123.94 (1F, d, J¼278.1 Hz), ꢀ83.03 (3F, br s).
d
ꢀ132.79 (1F, dd, J¼18.1, 278.1
3.5. Preparation of glutarate
3.3.4. Ethyl 4-chloro-4,4-difluoro-3-hydroxybutanoate, 4h17. Yield
75%. Rf¼0.43 (AcOEt:hexane¼1:4). 1H NMR
d
1.30 (3H, t, J¼7.2 Hz),
3.5.1. Diethyl 2,4-bis(ethoxycarbonyl)-3-(1,1,2,2,3,3,4,4,5,5,6,6,6-tri-
decafluorohexyl)glutarate, 6a. To a THF (2.0 mL) solution of NaH
(0.014 g, 0.57 mmol) was added diethyl malonate (84 mL,
2.69 (1H, dd, J¼9.0,16.5 Hz), 2.80 (1H, dd, J¼3.0,16.5 Hz), 3.50e3.63
(1H, m), 4.22 (2H, q, J¼7.2 Hz), 4.40e4.56 (1H, m). 19F NMR
(1F, dd, J¼9.0, 166.5 Hz), ꢀ65.52 (1F, dd, J¼9.0, 166.5 Hz).
d
ꢀ67.18
0.56 mmol) at 0 ꢁC and stirring was continued for 30 min at that
temperature. To the resultant mixture was added diethyl
2-(2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoro-hexylidene)malonate 8a
(0.242 g, 0.494 mmol) in 1 mL of THF, and stirring was further
continued for 1 h at 0 ꢁC. After usual workup and chromatographic
purification by silica gel (AcOEt:hexane¼1:8) afforded the title
compound 6a (0.257 g, 0.395 mmol). Yield 80%. Rf¼0.32
(AcOEt:hexane¼1:4). 1H NMR 1.27 (6H, t, J¼7.1 Hz), 1.29 (6H, t,
3.3.5. Diethyl 3-(difluoromethyl)-2-(ethoxycarbonyl)glutarate, 5g. The
reaction of the starting material 3g was the special case, which did not
follow the usual decarboxylation but afforded a mixture of 5g and 6g.
Yield 78%. Rf¼0.44 (AcOEt:hexane¼1:4). 1H NMR
d 1.27 (3H, t,
J¼7.2 Hz), 1.28 (6H, t, J¼7.2 Hz), 2.60e2.75 (2H, m), 3.11e3.27 (1H, m),
3.72 (1H, d, J¼5.7 Hz), 4.16 (2H, q, J¼7.2 Hz), 4.21 (2H, q, J¼7.2 Hz),
4.22 (2H, q, J¼7.2 Hz), 6.16 (1H, dt, J¼3.9, 56.5 Hz). 13C NMR
d
13.9, 14.1,
J¼7.1 Hz), 4.03 (2H, d, J¼4.8 Hz), 4.16e4.45 (9H, m). 13C NMR
d
13.7,
30.2 (t, J¼4.7 Hz), 39.0 (t, J¼21.1 Hz), 49.8 (t, J¼4.3 Hz), 60.9, 61.9, 62.0,
41.0 (t, J¼20.1 Hz), 48.8, 62.0, 62.2, 166.9, 166.9. 19F NMR
d
ꢀ127.34
116.1 (t, J¼242.2 Hz), 167.5, 167.6, 171.2. 19F NMR
d
ꢀ125.35 (1F, ddd,
(2F, m), ꢀ123.94 (2F, br s), ꢀ122.98 (2F, br s), ꢀ121.88 (2F, br s),
J¼16.1, 54.8, 285.2 Hz), ꢀ123.08 (1F, ddd, J¼13.8, 57.1, 285.2 Hz). IR
ꢀ111.01 (2F, m), ꢀ82.03 (3F, t, J¼10.3 Hz). IR (neat)
2910, 2878, 1761, 1467, 1448, 1378, 1348, 1334, 1239, 1209, 1147,
1116,1029, 863, 809, 735, 700, 651 cmꢀ1
Anal. Calcd for
C21H23F13O8: C, 38.78; H, 3.56. Found: C, 38.90; H, 3.60.
n 2987, 2943,
(neat)
n 3460, 2985, 2942, 2909, 2349, 1737, 1467, 1448, 1372, 1339,
1267, 1180, 1132, 1097, 1051, 961, 864 cmꢀ1. Anal. Calcd for C13H20F2O6:
C, 50.32; H, 6.50. Found: C, 50.30; H, 6.36.
.
3.3.6. Diethyl 3-(difluoromethyl)-2,4-bis(ethoxycarbonyl)-glutarate,
3.5.2. Diethyl
rate, 7a. A DMSO (4 mL) solution containing lithium chloride
(0.024 g, 0.566 mmol), water (27 L, 1.5 mmol), and crude diethyl
3-(1,1,2,2,3,3,4,4,5,5,6,6,6-tridecafluorohexyl)-gluta-
6g. Yield 17%. Rf¼0.37 (AcOEt:hexane¼1:4). 1H NMR
d 1.28 (12H, t,
J¼7.2 Hz), 3.48 (1H, qt, J¼6.0, 12.3 Hz), 3.90 (2H, d, J¼5.7 Hz), 4.22
m
(8H, q, J¼7.2 Hz), 6.44 (1H, dt, J¼4.8, 55.9 Hz). 13C NMR
d
13.9, 42.5
2,4-bis(ethoxycarbonyl)-3-(1,1,2,2,3,3,4,4,5,5,6,6,6-tridecafluoroh-
exyl)-glutarate 6a (0.322 g, 0.491 mmol by 1H NMR) was heated to
160 ꢁC for 30 min. After usual workup and chromatographic puri-
fication by silica gel (AcOEt:hexane¼1:8) afforded the title com-
pound 7a (0.105 g, 0.207 mmol). Yield 42%. Rf¼0.44
(t, J¼21.7 Hz), 49.1 (t, J¼4.0 Hz), 62.0, 62.1, 115.7 (t, J¼243.1 Hz),
167.4, 167.5. 19F NMR
d
ꢀ121.24 (dd, J¼13.8, 54.8 Hz). IR (neat)
n
2985, 1737, 1467, 1372, 1335, 1299, 1260, 1224, 1178, 1158, 1095,
1050, 1023, 862, 800 cmꢀ1. Anal. Calcd for C16H24F2O8: C, 50.26; H,
6.33. Found: C, 50.59; H, 6.30.
(AcOEt:hexane¼1:6). 1H NMR
d
1.27 (6H, t, J¼7.2 Hz), 2.52 (2H, dd,
J¼7.5, 16.8 Hz), 2.77 (2H, dd, J¼5.1, 16.8 Hz), 3.41e3.60 (1H, m), 4.17
3.4. Formal dehydration
(4H, q, J¼7.2 Hz). 13C NMR
d
14.0, 32.8, 35.3 (t, J¼21.0 Hz), 61.2,
170.2. 19F NMR
d
ꢀ127.42 (2F, m), ꢀ124.07 (2F, m), ꢀ123.22 (2F, m),
3.4.1. Diethyl
2-(2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoro-hexylidene)
ꢀ121.80 (2F, m), ꢀ116.48 (2F, m), ꢀ82.06 (3F, t, J¼10.3 Hz). IR (neat)
2987, 2943, 2911, 1745, 1448, 1428, 1378, 1301, 1240, 1205, 1146,
1095, 1025, 960, 809, 735, 701, 651 cmꢀ1
Anal. Calcd for
malonate, 8a. To a CH2Cl2 (4 mL) solution of the crude 3a (0.794 g,
0.703 mmol by 1H NMR using toluene as an internal standard) and
acetyl chloride (0.11 mL, 1.55 mmol) was slowly added triethyl-
amine (0.45 mL, 3.22 mmol) at 0 ꢁC and after 5 min, the mixture
was refluxed for 6 h. The usual workup and chromatographic pu-
rification by silica gel (AcOEt:hexane¼1:8) afforded the title com-
pound 8a (0.306 g, 0.625 mmol). Yield 89%. Rf¼0.67
n
.
C15H15F13O4: C, 35.59; H, 2.99. Found: C, 36.06; H, 3.37.
3.6. Michael addition of hydrazines and ethanol
3.6.1. 4-(Ethoxycarbonyl)-5-(1,1,2,2,3,3,4,4,5,5,6,6,6-trideca-
fluorohexyl)pyrazolidin-3-one, 9a. To a CH2Cl2 (3 mL) solution of 8a
(0.493 g, 1.01 mmol) was added hydrazine monohydrate (54 mL,
(AcOEt:hexane¼1:4). 1H NMR
d
1.33 (3H, t, J¼7.2 Hz), 1.34 (3H, t,
J¼7.2 Hz), 4.33 (2H, q, J¼7.2 Hz), 4.35 (2H, q, J¼7.2 Hz), 6.78 (1H, t,

S. Aoki et al. / Tetrahedron 67 (2011) 4845e4851
4851
1.11 mmol) at ꢀ80 ꢁC and stirring was continued for 1 h at that
temperature. Addition of anhydrous Na2SO4, filtration at room
temperature, and evaporation of the volatiles were carried out in
this order. The obtained crude material was recrystallized from
a mixture of AcOEt:hexane¼1:5 to furnish a white solid (0.383 g,
0.804 mmol). Yield 80%. Rf¼0.75 (AcOEt). Mp 129e130 ꢁC. 1H NMR
ꢀ
ꢀ
pp 3e46; (b) Begue, J.-P.; Bonnet-Delpon, D. Bioorganic and Medicinal Chemistry
of Fluorine; Wiley: Hoboken, NJ, 2008.
2. Recently, molecular structure of these compounds were studied. See, Kanno, N.;
Tonokura, K.; Hurley, M. D.; Wallington, T. J. J. Fluorine Chem. 2008, 129,
1187e1192.
€ €
3. (a) Landge, S. M.; Borkin, D. A.; Torok, B. Tetrahedron Lett. 2007, 48, 6372e6376
(Using concd H2SO4 and microwave); (b) Ogoshi, H.; Mizushima, H.; Toi, H.;
Aoyama, Y. J. Org. Chem. 1986, 51, 2366e2368 (Using H3PO4); (c) Golding, B. T.;
Sellars, P. J.; Watson, W. P. J. Fluorine Chem. 1985, 30, 153e158 (Using P2O5).
4. (a) Funabiki, K.; Matsunaga, K.; Gonda, H.; Yamamoto, H.; Arima, T.; Kubota, Y.;
Matsui, M. J. Org. Chem. 2011, 76, 285e288; (b) Chaume, G.; Barbeau, O.; Lesot,
P.; Brigaud, T. J. Org. Chem. 2010, 75, 4135e4145; (c) Milcent, T.; Hinks, N.;
Bonnet-Delpon, D.; Crousse, B. Org. Biomol. Chem. 2010, 8, 3025e3030; (d) Ti-
tanyuk, I. D.; Vorob’eva, D. V.; Osipov, S. N.; Beletskaya, I. P. Russ. J. Org. Chem.
2010, 46, 619e623; (e) Gulevich, A. V.; Shpilevaya, I. V.; Nenajdenko, V. G. Eur. J.
Org. Chem. 2009, 3801e3808; (f) Bigotti, S.; Meille, S. V.; Volonterio, A.; Zanda,
M. J. Fluorine Chem. 2008, 129, 767e774; (g) Gulevich, A. V.; Shevchenko, N. E.;
(acetone-d6)
d
1.28 (3H, t, J¼7.2 Hz), 3.62 (1H, d, J¼3.9 Hz), 4.25
(2H, q, J¼7.2 Hz), 4.84 (1H, m), 5.91 (1H, d, J¼8.1 Hz), 8.97 (1H, s).
13C NMR (acetone-d6)
d
14.3, 49.0, 60.5 (dd, J¼20.2, 27.6 Hz), 62.8,
167.8, 168.9. 19F NMR (acetone-d6)
ꢀ80.05 (3F, t, J¼10.1 Hz). IR (KBr)
d
ꢀ125.50 to ꢀ115.45 (10F, m),
n
3290, 3199, 3082, 2997, 1740,
1711, 1369, 1319, 1231, 1197, 1151, 1121, 646 cmꢀ1. Anal. Calcd for
C12H9F13N2O3: C, 30.27; H, 1.46; N, 5.88. Found: C, 30.04; H, 1.46;
N, 5.76.
€
Balenkova, E. S.; Roschenthaler, G.-V.; Nenajdenko, V. G. Tetrahedron 2008, 64,
11706e11712; (h) Yanai, H.; Mimura, H.; Kawada, K.; Taguchi, T. Tetrahedron
2007, 63, 2153e2160; (i) Zhang, F.-L.; Peng, Y.-Y.; Liao, S.-H.; Gong, Y.-F. Tetra-
3.6.2. 4-(Ethoxycarbonyl)-5-(1,1,2,2,3,3,4,4,5,5,6,6,6-trideca-fluo-
rohexyl)-1-methylpyrazolidin-3-one, 10a. Yield 61%. Rf¼0.42
ꢀ
hedron 2007, 63, 4636e4641; (j) Truong, V. L.; Menard, M. S.; Dion, I. Org. Lett.
2007, 9, 683e685; (k) Kato, K.; Gong, Y.-F. J. Fluorine Chem. 2004, 125, 767e773;
(l) Matsutani, H.; Poras, H.; Kusumoto, T.; Hiyama, T. Chem. Commun. 1998,
1259e1260; (m) Loh, T.-P.; Li, X.-R. Chem. Commun. 1996, 1929e1930; (n) Ku-
bota, T.; Iijima, M.; Tanaka, T. Tetrahedron Lett. 1993, 33, 1351e1354; (o) Tsu-
kamoto, T.; Kitazume, T. Synlett 1992, 977e979; For the N,O-acetal, see, Takaya,
J.; Kagoshima, H.; Akiyama, T. Org. Lett. 2000, 2, 1577e1579.
5. (a) Hallian, E. A.; Kramer, S. W.; Houdek, S. C.; Moore, W. M.; Jerome, G. M.;
Spangler, D. P.; Stevens, A. M.; Shieh, H. S.; Manning, P. T.; Pitzele, B. S. Org.
Biomol. Chem. 2003, 1, 3527e3534 (NaBH4); (b) Ono, N.; Kawamura, H.; Mar-
uyama, K. Bull. Chem. Soc. Jpn. 1989, 62, 3386e3388 (LiAlH4); (c) Terasawa, T.;
Ikekawa, N.; Morisaki, M. Chem. Pharm. Bull. 1986, 34, 931e934 (DIBAL); (d)
Hudlicky, M. J. Fluorine Chem. 1981, 18, 383e405 (Red-Al).
(AcOEt:hexane¼1:4). Mp 102e104 ꢁC. 1H NMR (DMSO-d6)
d 1.22
(3H, t, J¼7.2 Hz), 2.64 (3H, s), 3.30e3.36 (1H, m), 4.20 (2H, q,
J¼6.9 Hz), 4.45 (1H, dd, J¼7.7, 20.0 Hz), 10.4 (1H, s). 13C NMR
(DMSO-d6)
d
13.8, 47.6, 47.8, 62.2, 64.9 (dd, J¼17.3, 28.6 Hz), 165.0,
167.3. 19F NMR (acetone-d6)
d
ꢀ126.30 to ꢀ119.05 (9F, m), ꢀ117.36
to ꢀ115.29 (1F, m), ꢀ79.97 (3F, t, J¼10.1 Hz). IR (KBr)
n
3191, 3178,
3083, 2997, 1735, 1711, 1370, 1319, 1344, 1322, 1064, 1016, 699,
665 cmꢀ1. Anal. Calcd for C13H11F13N2O3: C, 31.85; H, 2.26; N, 5.71.
Found: C, 31.68; H, 1.86; N, 5.57.
6. (a) Thenappan, A.; Burton, D. J. J. Org. Chem. 1990, 55, 4639e4642; (b) Ishihara,
T.; Hayashi, H.; Yamanaka, H. Tetrahedron Lett. 1993, 34, 5777e5780; (c) Lanier,
M.; Pastor, R. J. Fluorine Chem. 1995, 75, 35e40; (d) Haas, A. M.; Hagele, G. J.
Fluorine Chem. 1996, 78, 75e82; (e) Ishihara, T.; Takahashi, A.; Hayashi, H.;
€
3.6.3. Diethyl 2-[2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoro-1-(2-phenyl-
hydrazino)heptyl]malonate, 11a. Yield 71%. Rf¼0.48 (AcOEt:
Yamanaka, H.; Kubota, T. Tetrahedron Lett. 1998, 39, 4691e4694.
hexane¼1:4). 1H NMR
1.24 (3H, t, J¼7.2 Hz), 1.31 (3H, t, J¼7.2 Hz),
d
7. In the case of non-fluorinated substrates, see the following examples. (a) Ta-
kacs, J. M.; Halle, M. A.; Seely, F. L. Tetrahedron Lett. 1986, 27, 1257e1260; (b)
Kiyooka, S.; Suzuki, K.; Shirouchi, M.; Kaneko, Y.; Tanimori, S. Tetrahedron Lett.
1993, 34, 5729e5732; (c) Razavi, H.; Polt, R. J. Org Chem. 2000, 65, 5693e5706.
8. We have actually confirmed by 1H NMR that subjection of the preformed i-
Bu2AlOMe (from the reaction of DIBAL and MeOH) to a THF solution of 2a at
3.83 (1H, d, J¼3.0 Hz), 4.15e4.35 (4H, m), 4.44 (1H, td, J¼10.0,
18.6 Hz), 4.91 (1H, dd, J¼2.4, 10.2 Hz), 5.68 (1H, d, J¼2.4 Hz), 6.82
(3H, m), 7.19 (2H, m). 13C NMR
d
13.9, 49.4, 61.7 (d, J¼20.4 Hz), 62.1,
62.7, 113.1, 119.9, 129.0, 148.4, 167.3, 167.4. 19F NMR
d
ꢀ128.11 (1F, br
0
ꢁC for 0.5 h afforded the same peak at 3.76 by 1H NMR.
d
d, J¼273.6 Hz), ꢀ126.65 (1F, br d, J¼275.9 Hz), ꢀ124.61 (1F, br d,
J¼296.5 Hz), ꢀ124.09 (1F, br d, J¼146.1 Hz), ꢀ123.04 (1F, br d,
J¼152.9 Hz), ꢀ122.43 (1F, br d, J¼303.3 Hz), ꢀ122.89 (1F, dm,
J¼303.3 Hz), ꢀ121.67 (1F, dm, J¼303.3 Hz), ꢀ119.41 (1F, dm,
J¼285.2 Hz), ꢀ114.58 (1F, dm, J¼289.7 Hz), ꢀ82.02 (3F, t, J¼9.0 Hz).
9. (a) Colantoni, D.; Fioravanti, S.; Pellacani, L.; Tardella, P. A. J. Org. Chem. 2005, 70,
9648e9650; (b) Uneyama, K.; Itano, N. Denki Kagaku Oyobi Kogyo Butsuri Ka-
gaku 1994, 62, 1151e1153.
10. Carson, C. A.; Kerr, M. A. Angew. Chem., Int. Ed. 2006, 45, 6560e6563.
11. (a) Shinohara, N.; Haga, J.; Yamazaki, T.; Kitazume, T.; Nakamura, S. J. Org. Chem.
1995, 60, 4363e4374; (b) Smart, B. J. Fluorine Chem. 2001, 109, 3e11.
12. For example, pKas of CF3CO2H and CHF2CO2H were reported to be 0.50 and 1.33.
SeeLange’s Handbook of Chemistry, 14th ed.; Dean, J. A., Ed.; McGraw-Hill: New
York, NY, 1992; Section 8.
IR (neat) n 3337, 2986, 1747, 1605, 1497, 1474, 1375, 1348, 1239, 1207,
1147, 1122, 1070, 1027, 906, 866, 809, 752, 734, 696, 658 cmꢀ1. Anal.
Calcd for C20H19F13N2O4: C, 40.15; H, 3.20; N, 4.68. Found: C, 39.97;
H, 3.23; N, 4.51.
13. (a) Wen, L.-L.; Shen, Q.-L.; Lu, L. Org. Lett. 2010, 12, 4655e4657; (b) Fioravanti,
S.; Colantoni, D.; Pellacani, L.; Tardella, P. A. J. Org. Chem. 2005, 70, 3296e3298;
(c) Blond, G.; Billard, T.; Langlois, B. R. J. Org. Chem. 2001, 66, 4826e4830.
14. For determination of the regioisomers, we have relied on the clear chemical
shift difference between NH hydrogen: thus, in the case of compounds with
the eC(O)NH1NH2e framework, H1 usually appeared at the lower field (8 to
10 ppm) than the case of H2 (around 4 ppm). See, (a) Sibi, M. P.; Soeta, T. J. Am.
Chem. Soc. 2007, 129, 4522e4523; (b) Gaede, B. J.; McDermott, L. L. J. Heterocycl.
3.6.4. Diethyl 2-(1-ethoxy-2,2,3,3,4,4,5,5,6,6,7,7,7-trideca-fluoroheptyl)
malonate, 12a. To an EtOH (3 mL) solution of 8a (0.489 g, 1.00 mmol)
was added NaOEt (0.035 g, 0.51 mmol) and the whole solution was
stirred for 3 h at room temperature. After usual workup and purifi-
cation by silica gel column chromatography (AcOEt:hexane¼1:4)
afforded 0.439 g (0.819 mmol) of the title compound 12a. Yield 82%.
Chem. 1993, 30, 49e54; (c) Pouchert, C. J.; Behnke, J. Aldrich Library of 13C and 1
FT NMR Spectra; Aldrich Chemical: Milwaukee, WI, 1993.
15. (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734e736; (b) Baldwin, J. E.;
Cutting, J.; Dupont, W.; Kruse, L.; Silberman, L.; Thomas, R. C. J. Chem. Soc.,
Chem. Commun. 1976, 736e738.
H
Rf¼0.49 (AcOEt:hexane¼1:4). 1H NMR
d
1.14 (3H, t, J¼6.9 Hz), 1.28
16. Computation was carried out by Gaussian 03W using B3LYP/6-31þG) level of
theory, and 8 and 5 independent conformers were located for syn- and anti-
isomers, respectively, with the energy difference of 4.29 kcal/mol between the
most stable each conformers Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scu-
seria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.;
Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.;
Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.;
Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.;
Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.;
Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.;
Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.;
Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.;
Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez,
C.; Pople, J. A. Gaussian 03, Revision B. 03; Gaussian: Wallingford, CT, 2004.
17. Jagodzinska, M.; Huguenot, F.; Zanda, M. Tetrahedron 2007, 63, 2042e2046.
(3H, t, J¼7.2 Hz), 1.31 (3H, t, J¼7.2 Hz), 3.77 (2H, dq, J¼2.4, 6.9 Hz), 3.91
(1H, d, J¼8.4 Hz), 4.17e4.40 (4H, m), 4.75 (1H, dddd, J¼1.8, 4.2, 8.1,
17.1 Hz). 13C NMR
d 13.8, 14.0, 15.1, 52.7, 62.2, 62.3, 69.9, 76.0 (dd,
J¼21.1, 27.9 Hz), 165.6, 165.9. 19F NMR
ꢀ128.16 (1F, br d, J¼287.2 Hz),
d
ꢀ126.79 (1F, br d, J¼289.7 Hz), ꢀ125.17 to ꢀ123.20 (6F, m), ꢀ121.43
(1F, br d, J¼268.4 Hz), ꢀ116.95 (1F, dm, J¼285.2 Hz), ꢀ82.09 (3F, t,
J¼9.2 Hz). IR (neat)
n 2987, 2941, 2909, 1759, 1747, 1449, 1373, 1316,
1240, 1204, 1147, 1027, 699, 658 cmꢀ1. Anal. Calcd for C16H17F13O5: C,
35.83; H, 3.20. Found: C, 35.84; H, 3.20.
References and notes
1. (a) Yamazaki, T.; Taguchi, T.; Ojima, I. Unique properties of fluorine and their
relevance to medicinal chemistry and chemical biology In Fluorine in Medicinal
Chemistry and Chemical Biology; Ojima, I., Ed.; John Wiley: New York, NY, 2009;