Generation and use of an equivalent of difluoroacetamide or difluoroacetate anions

Article abstract of DOI:10.1002/1521-3765(20020703)8:13<2917::AID-CHEM2917>3.0.CO;2-M

Ethers of trifluoroacetaldehyde hemiaminals can undergo dehydrofluorination under basic conditions to provide ethers of difluoroketene hemiaminals. The latter behave as equivalents of difluoroacetamide or difluoroacetate anions towards various electrophil

Full text of DOI:10.1002/1521-3765(20020703)8:13<2917::AID-CHEM2917>3.0.CO;2-M

FULL PAPER
Generation and Use of an Equivalent of Difluoroacetamide or
Difluoroacetate Anions**
Gae»lle Blond, Thierry Billard,* and Bernard R. Langlois*[a]
Dedicated to Professor Dieter Naumann on the occasion of his 60th birthday
Abstract: Ethers of trifluoroacetaldehyde hemiaminals can undergo dehydrofluori-
nation under basic conditions to provide ethers of difluoroketene hemiaminals. The
latter behave as equivalents of difluoroacetamide or difluoroacetate anions towards
various electrophiles, yielding a range of difluoromethylcarbonyl products.
Keywords: hemiaminals
philic addition
substitution ¥ synthetic methods
¥
nucleo-
¥
nucleophilic
difluoroketenes silyl acetals, respectively. These intermediates
can behave, under fluoride activation, as difluoromethylene
anions but their preparation needs specific electrochemical
conditions. The same authors have also demonstrated that
magnesium can be used to promote reductive defluorination.
The resulting a-silyl difluoroacetates can react in the same
way as the Ruppert×s reagent.[8] However, the required excess
of magnesium constitutes an environmental drawback.
Introduction
Because of the particular properties of fluorine, the introduc-
tion of such an element on organic substrates induces dramatic
consequences on their chemical and biological activities.[1]
Among fluorinated compounds, difluoromethylated ones pres-
ent unique biological properties.[2] For this reason, a variety of
methods have been developed for their preparation.[3]
Among them, the introduction of difluoromethylcarbonyl
moieties, which can be functionalized in further steps,
constitutes an attractive strategy. For example, Reformat-
sky-type reactions with halodifluoroacetates are often used
for this purpose[3a, 4] but are limited by lack of availability of
such reagents. Selective defluorination of a trifluoromethyl
group is another fruitful strategy and has been widely studied.
Especially, Portella et al. have shown that difluoroenoxysilanes,
generated from acylsilanes and Ruppert×s reagent (CF3SiMe3),
constitute equivalents of the difluoromethylcarbonyl anion.[5]
Nevertheless, CF3SiMe3 is difficult to use on a larger scale. On
the other hand, Uneyama et al. have reported on the electro-
reductive defluorination of trifluoromethyl ketones[6] or
trifluoroacetic acid esters,[7] in the presence of trimethylsilyl
chloride, which provides a,a-difluoroenol silyl ethers or a,a-
Finally, Dolbier et al. achieved the basic dehydrofluorina-
tion of 1,1-bis(dialkylamino)-2,2,2-trifluorethanes 1 to gener-
ate difluoroketenes aminals 2 which, after reaction with
benzaldehydes, provided b-hydroxy-a,a-difluoropropion-
amides (Scheme 1).[9] Although this strategy is very elegant,
the access to 1 is not easy and limits its synthetic applications.
OH
F
O
F
F
NMe2
NMe2
BuLi
PhC(O)H
CF3CH(NMe2)2
Ph
NMe2
F
1
2
Scheme 1. Synthesis of a,a-difluoropropionamides from Dolbier×s re-
agent.
During our investigations on the potentials of this new
family of fluorinated hemiaminals we are currently develop-
ing,[10, 11] we examined the use of such compounds as
difluoromethylenecarboxyl building blocks.
[a]Dr. T. Billard, Dr. B. R. Langlois, G. Blond
Laboratoire SERCOF (UMR CNRS 5622)
¬
Universite Claude Bernard Lyon 1
√
Bat. Chevreul
43, Bd du 11 novembre 1918, 69622 Villeurbanne (France)
Fax : (‡33)4-7243-1323
Results and Discussion
E-mail: billard@univ-lyon1.fr
bernard.langlois@univ-lyon1.fr
Our first goal was to deprotonate the silylated hemiaminal 3
to obtain, after loss of fluoride, the silylated difluoroketene
hemiaminal 4 (Scheme 2).
[**]Part 3 of the Series: Reactivity of Stable Trifluoroacetaldehyde
hemiaminals. Part 2: T. Billard, B. R Langlois, J. Org. Chem. 2002, 67,
997 1000.
Chem. Eur. J. 2002, 8, No. 13
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2917

T. Billard, B. R. Langlois and G. Blond
FULL PAPER
OMe
N
OSiMe3
OSiMe3
F C
N
F
F
OSiMe3
N
F
F
F
OMe
N
B-
BuLi
F3C
F3C
N
+ LiF
H
H
THF
-78°C → 10°C
5h
NBn
F
NBn
NBn
NBn
NBn
3
5
4
6
Scheme 2. Deprotonation of the silylated hemiaminal 3.
Scheme 4. Deprotonation of the methylated hemiaminal 5.
Different basic systems have been tested to generate 4. It
appeared that hydrides and alcoholates were not strong
enough to deprotonate 3. Also, lithiated amides (LDA or
LiHMDS), even complexed by TMEDA, were not dissociated
enough to be efficient. Surprisingly, silicophilic attack occured
with butyl lithium, instead of the expected deprotonation.
Finally, deprotonation succeeded with KN(SiMe3)2 but the
fluoride anions, arising from a subsequent b-elimination,
desilylated 4 and 3 (which then lose ÀCF3).[10a] The anions thus
formed were protonated by HN(TMS)2, generated in situ, to
provide fluoroform and difluoroacetamide (Scheme 3).
As 6 could not be isolated, its reactivity towards aldehydes
was studied in situ (Table 1).
Notably, 6 reacted very easily with benzaldehyde to yield,
after acidic hydrolysis, the expected compound 7a (entry 1).
Nevertheless, 2-naphtaldehyde delivered a disappointing
result under the same conditions (entry 4). To improve this
Table 1. Reactivity of 6 with aldehydes.
OH
F
O
O
THF
+10°C → r.t.
6
+
+ TfOSiMe3
R
X
R
H
F
18h
x equiv
y equiv
1 equiv
X = OMe : 7 or
X = NR2 : 8
(after acidic hydrolysis)
O
OSiMe3
N
F3C
F3C
N
H
Entry RCHO
6
TfOSiMe3 7 (%)[a]
(x equiv) (y equiv)
8 (%)[a]
H
3
CF3
HN(TMS)2
KN(TMS)2
1
2
3
4
5
6
7
8
9
10
11
12
13
benzaldehyde
benzaldehyde
benzaldehyde
2-naphthaldehyde
2-naphthaldehyde
2-naphthaldehyde
valeraldehyde
(6-methoxy)-2-naphthaldehyde
(6-methoxy)-2-naphthaldehyde
octanaldehyde
1
1
2
1
1
2
2
2
2
2
2
2
2
0
1
2
0
1
2
2
0
2
2
2
2
2
7a: (80) 75
7a: (40)
7a: (45)
7b: (36)
7b: (62)
7b: (70) 60
7c: 50
7d: (20)
7d: 65
7e: 70
F
HN(TMS)2
OSiMe3
F
F
F
O
N
HCF3
N
F
8c: 20
4
8d: 25
8e: 25
8 f: 22
8g: 35
8 h: 10
O
O
HN(TMS)2
HF2C
N
F2C
N
3-formylthiophene
cinnamaldehyde
N-Boc-3-formylindole
7 f: 64
7g: 55
7 h: 80
Scheme 3. Reaction of 3 with KN(TMS)2.
[a]Isolated yield. In parentheses: crude yields determined by 19F NMR with internal
standard (PhOCF3).
Since a silyl group seemed prejudicial for this reaction, we
then turned our attention to the methylated hemiaminal
derivative 5 that we previously described[11] and which is easily
synthesized from 3.[11b]
reaction, we ventured the hypothesis that the fluoride anions,
present in the reaction mixture, could be harmful. Thus, they
were quenched by trimethylsilyl triflate (TfOSiMe3) before
introducing the aldehyde. Thus, the yield of 7b increased
(entry 5) and was optimized with two equivalents of 6 and
TfOSiMe3 (entry 6). Surprisingly, when applied to benzalde-
hyde, these optimal conditions led to worse results (en-
tries 2, 3).
A rapid study of the deprotonation conditions showed that
KN(TMS)2 could not deprotonate 5, probably because of the
less acidic character of the proton, compared with that in 3.[12]
On the contrary, BuLi was able to abstract the hydrogen in a-
position to the CF3 group. A more accurate study of the
reaction conditions underlined the limited stability of the
resulting ketene hemiaminal 6 at room temperature. Finally,
the optimal results, compatible with a reasonable kinetics,
were obtained when slowly warming, for five hours, the
reaction medium from À78 to 108C (Scheme 4).
Nevertheless, despite these two opposite results, the
procedure using TfOSiMe3 was applied to other aldehydes
since benzaldehyde, which is well known to be very reactive,
could constitute an exception (Table 1). Generally, good
yields were reached. In contrast to Dolbier×s reagent 2,[9]
6
¬
¬
Abstract in French: Les ethers d×hemiaminals du trifluoro-
reacted also with enolizable aldehydes to deliver the corre-
sponding carbinols (entries 7, 10). However, a mixture of
;ester 7 (major product) and amide 8 (in around 20% yield)
was usually obtained. These two compounds arised from the
hydrolysis of the resonance forms of the adduct resulting from
the nucleophilic attack of 6 on the aldehyde substrate
(Scheme 5).
¬
¬
¬
acetaldehyde subissent, en milieu basique, une deshydrofluo-
¡
¬
¬
ration pour conduire a des ethers d×hemiaminals de difluoro-
¬ ¡
¬
¬
cetenes. Ces derniers peuvent alors reagir comme des equiva-
¬
¬
¬
lents d×anions de derives de l×acide difluoroacetique envers
divers electrophiles pour fournir des composes difluorome-
thyles varies.
¬
¬
¬
¬
¬
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Stable Hemiaminals
2917 2922
atoms of 6 are no longer chelated by lithium and both iminium
or oxonium forms can be considered. After reaction with
aldehyde and hydrolysis, they lead to ester 7 and amide 8,
respectively. Nevertheless, because of a better overlap of the
orbitals of nitrogen doublets with p electrons,[14] a higher
weight can be attributed to the iminium resonance form and,
consequently, the ester is the major product.
The case of naphthaldehyde, from which no amide was
formed even in the presence of TfOSiMe3, can be interpreted
by the fact that this aldehyde is reactive enough that it doesn×t
need any activation. Thus, the rapid process without activa-
tion matched the one with TfOSiMe3 activation so that the
amount of amide formed was too low to be either detected or
isolated.
In contrast, simple ketones such as benzophenone, chalcone
or acetophenone were not reactive enough to undergo
nucleophilic attack from 6, even with Lewis acid activation
(BF3 ¥ Et2O, Bu2BOTf, TfOSiMe3, ...), whereas activated
ketones, such as a-ketoesters, did react (see Table 3, entry 2).
Since very reactive substrates were needed, our interest was
then focused on acyl chlorides (Table 2).
O
OMe
N
amide
ester
R
R
O
F
F
NBn
NBn
F
F
OMe
N
R
H
O
OMe
N
NBn
6
F
F
Scheme 5. Synthesis of esters or amides from 6.
The fact that this phenomenon occured only when TfO-
SiMe3 was added (entries 8, 9) and that this additive increased
the overall yield of products led us to propose the mechanism
shown in Scheme 6.
Bu
Li
Ph
O
Li
R
H
F
Ph
N
H
N
F
N
C
F
O
N
F2
H3C
O
CH3
F
Table 2. Reaction of 6 with acyl chlorides.
O
O
O
Ph
O
R
H
N
THF
+10°C → r.t.
+ TfOSiMe3
Ph
+
6
R
N
Li
R
Cl
F
F
NBn
N
18h
N
O
F
F
1equiv
x equiv
y equiv
F
F
H3C
9
Li
CH3
F
N
9 (%)[a]
O
Entry
R
x (equiv)
y (equiv)
6
F
1
2
3
4
5
6
Ph
Ph
Ph
1
1
2
2
2
2
0
1
2
2
2
2
9a: 25 (35)
9a: (50)
9a: 70 (80)
9b: 57 (60)
0
TfOSiMe3
O
FSiMe3
R
H
cyclopropyl
tert-butyl
Ph2N
Ph
N
0
Ph
N
[a]Isolated yield. In parentheses crude yield determined by 19F NMR with
internal standard (PhOCF3).
OTf
Li
H
O
N
O
F
N
F
+
Li
R
F
F
O
O
H
R
CH3
CH3
In this case, fluoride anions must always be quenched
(entries 1, 2); otherwise, acyl fluorides, which are generally
less reactive than chlorides, were formed.[15] This hypothesis
was verified by the absence of any reaction between benzoyl
fluoride and 6. As for aldehydes, the best results were
obtained with two equivalents of 6 and TfOSiMe3 (entry 3)
but, in contrast to aldehydes, amides 9 were exclusively
formed.
TfO
Ph
O
Li
R
H
F
F
H3C
H3C
F
OTf
O
N
F
N
N
H
R
O
TfO
Li
O
N
This result can be explained by a subsequent Krapcho-type
reaction from the chloride anions liberated in the medium
(Scheme 7).
Ph
Scheme 6. Mechanism of reaction of 6 with aldehydes.
This hypothesis has been confirmed by hydrolyzing the
crude mixture resulting from 6 and benzaldehyde, with a
aqueous saturated LiCl solution: Amide 8a was exclusively
obtained instead of ester 7a. The same result was observed
from N-Boc-3-formylindole which delivered amide 8h
(Scheme 8).
To extend the scope of reagent 6, its reactivity towards
miscellaneous electrophiles was also investigated (Table 3).
As already mentioned, in contrast with unactivated ke-
tones, a-keteoesters reacted nicely with 6 and delivered the
ester product only.
After deprotonation of 5, the lithium fluoride generated
forms a rather tight ion pair in which lithium interacts with
both the nitrogen and the oxygen atoms of 6. When no
trimethylsilyl triflate was added, the iminium formation is
only favored because the strong chelation of lithium cation by
the oxygen doublets prevents their conjugation with the p
system. Thus, only the ester is obtained after hydrolysis.
When TfOSiMe3 is added, lithium triflate is formed as a
loose ion pair and, because of its mild Lewis acid character,[13]
activates the aldehyde. Consequently, nitrogen and oxygen
Chem. Eur. J. 2002, 8, No. 13
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T. Billard, B. R. Langlois and G. Blond
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Cl
O
F
F
OMe
N
Me
+
N
O
O
N
N
N
Cl
Cl
F
F
NBn
NBn
R
R
N
O
F
F
OMe
N
F
F
NBn
NBn
NBn
R
Cl
6
+ Cl
O
Me
O
O
6
N
12
NBn
Cl
N
F
F
6
F
F
Scheme 9. Reaction of 6 with Vilsmeier×s salt.
O
O
Conclusion
R
N
F
F
NBn
In summary, this work demonstrates that hemiaminals of
fluoral are not only trifluoromethylating agents but also very
efficient sources of equivalents of difluoromethylcarboxyl
anions which can be transferred on various electrophiles. The
exploitation of this strategy for synthetic applications is under
study in our laboratory and will be reported in due course.
9
Scheme 7. Krapcho-type reaction after the attack of acyl chlorides by 6.
OH
F
O
O
F
F
OMe
N
1) THF / 18h
2) LiCl aq.
+
R
N
R
H
F
Experimental Section
NBn
NBn
6
General remarks: Solvents were distilled prior use. Other reagents were
used as received. 1H, 13C and 19F NMR spectra were recorded in CDCl3 at
300, 75 and 282 MHz, respectively. Chemical shifts are given in ppm
relative to TMS (1H, 13C) or CFCl3 (19F) as internal references. Coupling
constants are given in Hertz. Flash chromatography was performed on
Merck silica gel 60M (0.04 0.063 mm). Melting points (uncorrected) were
determined in capillary tubes on a B¸chi apparatus. Reagent 5 was
prepared according to our previous work.[11b]
R
crude yield isolated yield
8a Ph
70%
55%
8h
65%
50%
N
Boc
Scheme 8. Selective formation of 8.
General procedure for the reaction with aldehydes: A solution of BuLi
(2.5m in hexanes, 0.8 mL, 2 mmol) was added at À788C, under nitrogen, to
a solution of 5 (0.576 g, 2 mmol) in dry THF (2 mL). The temperature was
allowed to rise slowly (for 5 h) to 0 ! 108C. Then, trimethylsilyl trifluoro-
methanesulfonate (0.360 mL, 2 mmol) was added, followed, 10 min later,
by the aldehyde (1 mmol). After 2 h, the cooling bath was removed and the
mixture stirred for 18 h at room temperature. The reaction mixture was
then hydrolyzed with aqueous 1m HCl (2 mL) for 1 h and extracted with
dichloromethane. The organic solution was dried over Na2SO4 and
evaporated under vacuo. The crude product was then purified by flash
chromatography (eluents are indicated in parentheses).
Table 3. Reactions of 6 with miscellaneous electrophiles.
O
El
THF
6
+
El
+
TfOSiMe3
X
r.t. / 18h
F
F
y equiv
x equiv 1equiv
10-12
Entry El
x
y
Yield (%)[a]
O
PhSe
N
1
2
PhSeCl
2
2
10: 60 (70)
11: 85
F
F
NBn
General procedure for the reaction with aldehydes followed by LiCl
hydrolysis: The same procedure was applied but hydrolysis with HCl was
replaced by a treatment with a saturated LiCl aqueous solution.
O
Ph OH
MeO
methyl phenyloxoacetate
2
2
OMe
General procedure for the reaction with acid chlorides or benzeneselenenyl
chloride: The same procedure was applied but hydrolysis with HCl was
replaced by aqueous hydrolysis.
F
F
O
O
NBn
NBn
F2C
F2C
N
N
General procedure for the reaction with Vilsmeier×s salt: The same
procedure was applied but with 4 equiv 5, BuLi and TfOSiMe3 and
hydrolysis with HCl was replaced by aqueous hydrolysis.
N
3
4
Vilsmeier×s salt[b]
Vilsmeier×s salt[b]
2
4
2
4
12: 50
12: 73
O
Methyl 2,2-difluoro-3-hydroxy-3-phenylpropanoate (7a): (petroleum
ether/ether 19:1 then 4:1, yellow oil). 1H NMR: d ˆ 7.44 7.34 (m, 5H),
5.16 (dd, J ˆ 16.1, J ˆ 7.1 Hz, 1H), 3.84 (s, 3H); 13C NMR: d ˆ 164.6 (dd,
J ˆ 32.8, J ˆ 31.0 Hz), 134.92 (d, J ˆ 1.7 Hz), 129.7, 128.8, 128.1, 114.4 (dd,
J ˆ 259.5, J ˆ 253.7 Hz), 74.0 (dd, J ˆ 28.2, J ˆ 24.1 Hz), 53.9; 19F NMR: d ˆ
À113.6 (dd, J ˆ 262.7, J ˆ 7.1 Hz, 1F), À121.4 (dd, J ˆ 262.7, J ˆ 16.1 Hz,
1F); elemental analysis calcd (%) for C10H10F2O3: C 55.56, H 4.66; found: C
55.34, H 4.84.
[a]Isolated yield. In parentheses crude yield determined by 19F NMR with
internal standard (PhOCF3). [b]Commercial form or from DMF/POCl 3
.
In the case of benzeneselenenyl chloride or chloroiminium
chloride, the amidic product was exclusively obtained, again,
because of a subsequent Krapcho reaction (entry 1). The
Vilsmeier×s salt provided a di-substituted compound (en-
tries 3, 4) since the first attack of 6 on this substrate led, after
addition elimination, to another iminium salt which is able to
react again with 6 (Scheme 9).
1-(4-Benzylpiperazino)-2,2-difluoro-3-hydroxy-3-phenyl-1-propanone
(8a): (petroleum ether/ether 4:1, yellow oil). 1H NMR: d ˆ 7.37 7.28 (m,
10H), 5.28 (dd, J ˆ 21.9, J ˆ 3.0 Hz, 1H), 3.70 (m, 4H), 3.54 (s, 2H), 2.54
2.44 (m, 4H); 13C NMR: d ˆ 162.85 (t, J ˆ 28.9 Hz), 137.8, 135.0 (d, J ˆ
1.6 Hz), 129.5, 129.1, 128.8, 128.8 (t, J ˆ 1.1 Hz), 128.4, 127.8, 115.4 (dd, J ˆ
259.1, J ˆ 267.3 Hz), 74.0 (dd, J ˆ 29.1, J ˆ 23.1 Hz), 53.3, 52.9, 46.2 (dd, J ˆ
6.9, J ˆ 5.8 Hz), 43.5; 19F NMR: d ˆ À103.7 (dd, J ˆ 291.1, J ˆ 3.0 Hz, 1F),
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Chem. Eur. J. 2002, 8, No. 13

Stable Hemiaminals
2917 2922
À118.2 (dd, J ˆ 291.1, J ˆ 21.9 Hz, 1F); elemental analysis calcd (%) for
(m, 1H), 5.27 (m, 1H), 3.87 (s, 3H), 3.2 (brs, 1H); 13C NMR: d ˆ 164.4 (dd,
J ˆ 31.3, J ˆ 32.9 Hz), 136.1 (d, J ˆ 2.2 Hz), 126.9 (t, J ˆ 1.7 Hz), 126.7, 125.1
(t, J ˆ 1.4 Hz), 114.2 (dd, J ˆ 259.1, J ˆ 254.1 Hz), 70.7 (dd, J ˆ 25.3, J ˆ
28.5 Hz), 53.9; 19F NMR: d ˆ À113.8 (dd, J ˆ 262.7, J ˆ 8.0 Hz, 1F), À120.9
(dd, J ˆ 262.7, J ˆ 16.1 Hz, 1F); elemental analysis calcd (%) for
C8H8F2O3S: C 43.24, H 3.63, S 14.43; found: C 42.96, H 3.65, S 14.05.
C20H22F2N2O2: C 66.65, H 6.15, N 7.77; found: C 66.92, H 6.18, N 8.06.
Methyl 2,2-difluoro-3-hydroxy-3-(2-naphthyl)propanoate (7b): (petroleum
1
ether/ether 9:1 then 4:1, white solid). M.p. 908C; H NMR: d ˆ 7.88 7.85
(m, 4H), 7.58 7.51 (m, 3H), 5.35 (dd, J ˆ 15.8, J ˆ 7.5 Hz, 1H), 3.87 (s, 3H);
13C NMR: d ˆ 164.5 (dd, J ˆ 32.7, J ˆ 31.0 Hz), 134.1, 133.3, 132.3 (t, J ˆ
1.1 Hz), 128.7, 128.6, 128.1, 127.9 (t, J ˆ 1.1 Hz), 127.1, 126.8, 125.1 (t, J ˆ
1.4 Hz), 114.4 (dd, J ˆ 259.9, J ˆ 253.9 Hz), 74.3 (dd, J ˆ 28.0, J ˆ 24.1 Hz),
53.9; 19F NMR: d ˆ À113.3 (dd, J ˆ 263.5, J ˆ 7.9 Hz, 1F), À120.8 (dd, J ˆ
263.5, J ˆ 15.6 Hz, 1F); elemental analysis calcd (%) for C14H12F2O3: C
63.16, H 4.54; found: C 63.03, H 4.89.
1-(4-Benzylpiperazino)-2,2-difluoro-3-hydroxy-3-(3-thienyl)-1-propanone
(8 f): (petroleum ether/acetone 9:1, white solid). M.p. 1018C; 1H NMR: d ˆ
7.44 (m, 1H), 7.36 7.28 (m, 6H), 7.21 (m, 1H), 5.36 (dd, J ˆ 20.4, J ˆ 3.2 Hz,
1H), 3.72 (m, 4H), 3.57 (s, 2H), 2.52 (m, 4H); 13C NMR: d ˆ 162.7 (t, J ˆ
28.8 Hz), 137.4, 136.1 (d, J ˆ 1.7 Hz), 129.6, 128.8, 127.9, 127.5 (t, J ˆ 1.7 Hz),
125.8, 124.9 (t, J ˆ 1.4 Hz), 115.2 (dd, J ˆ 267.0, J ˆ 258.8 Hz), 71.1 (dd, J ˆ
23.6, J ˆ 30.2 Hz), 63.0, 53.3, 52.8, 46.1 (dd, J ˆ 6.9, J ˆ 5.8 Hz), 43.3; 19F
NMR: d ˆ À104.0 (dd, J ˆ 290.8, J ˆ 3.2 Hz, 1F), À117.0 (dd, J ˆ 290.8, J ˆ
20.4 Hz, 1F); elemental analysis calcd (%) for C18H20F2N2O2S: C 59.00,
H 5.50, N 7.65; found: C 59.31, H 5.47, N 7.92.
Methyl 2,2-difluoro-3-hydroxyheptanoate (7c): (petroleum ether/acetone
19:1, yellow viscous oil). 1H NMR: d ˆ 4.03 (dddd, J ˆ 9.8, J ˆ 14.9, J ˆ 7.4,
J ˆ 2.8 Hz, 1H), 3.92 (s, 3H), 1.72 1.22 (m, 6H), 2.4 (brs, 1H), 0.94 (t, J ˆ
7.2 Hz, 3H); 13C NMR: d ˆ 164.6 (dd, J ˆ 32.9, J ˆ 31.3 Hz), 115.2 (dd, J ˆ
256.9, J ˆ 254.1 Hz), 72.1 (dd, J ˆ 27.2, J ˆ 25.0 Hz), 53.8, 29.2 (dd, J ˆ 3.0,
J ˆ 1.9 Hz), 27.7, 22.7, 14.2; 19F NMR: d ˆ À114.9 (dd, J ˆ 264.1, J ˆ 7.4 Hz,
1F), À122.9 (dd, J ˆ 264.1, J ˆ 14.9, 1F); elemental analysis calcd (%) for
C8H14F2O3: C 48.98, H 7.19; found: C 49.15, H 7.28.
Methyl (E)-2,2-difluoro-3-hydroxy-5-phenyl-4-pentenoate (7g): (petrole-
um ether/acetone 19:1, yellow viscous oil). 1H NMR: d ˆ 7.45 7.27 (m,
5H), 6.82 (d, J ˆ 16.0 Hz, 1H), 6.26 (dd, J ˆ 6.5, J ˆ 16.0 Hz, 1H), 4.77
(dddd, J ˆ 6.5, J ˆ 14.3, J ˆ 7.9, J ˆ 1.2 Hz, 1H), 3.92 (s, 3H), 2.9 (brs, 1H);
13C NMR: d ˆ 164.3 (dd, J ˆ 31.3, J ˆ 32.4 Hz), 136.4, 136.1, 129.1, 129.0,
127.3, 121.9 (dd, J ˆ 3.3, J ˆ 2.2 Hz), 114.5 (dd, J ˆ 258.0, J ˆ 254.1 Hz), 73.3
(dd, J ˆ 25.0, J ˆ 28.3 Hz), 53.9; 19F NMR: d ˆ À113.9 (dd, J ˆ 263.5, J ˆ
7.9 Hz, 1F), À121.3 (dd, J ˆ 263.5, J ˆ 14.3 Hz, 1F); elemental analysis
calcd (%) for C12H12F2O3: C 59.50, H 4.99; found: C 59.63, H 5.13.
1-(4-Benzylpiperazino)-2,2-difluoro-3-hydroxy-1-heptanone (8c): (Petro-
leum ether/acetone 19:1, yellow viscous oil). 1H NMR: d ˆ 7.34 7.28 (m,
5H), 4.08 (m, 1H), 3.76 (m, 2H), 3.67 (m, 2H), 3.55 (s, 2H), 2.51 (m, 4H),
1.68 1.27 (m, 6H), 0.94 (t, J ˆ 7.127, 3H); 13C NMR: d ˆ 162.7 (t, J ˆ
29.427), 137.8, 129.5, 128.8, 127.8, 116.5 (dd, J ˆ 265.4, J ˆ 259.327), 72.2
(dd, J ˆ 28.3, J ˆ 24.427), 63.1, 53.4, 52.9, 46.2 (dd, J ˆ 7.1, J ˆ 5.527), 43.3,
28.2 (dd, J ˆ 3.3, J ˆ 2.227), 28.1, 22.9, 14.4; 19F NMR: d ˆ À107.1 (d, J ˆ
291.127, 1F), À118.7 (dd, J ˆ 291.1, J ˆ 19.5 Hz, 1F); elemental analysis
calcd (%) for C18H26F2N2O2: C 63.51, H 7.70, N 8.23; found: C 63.39, H 7.61,
N 7.94.
(E)1-(4-Benzyl-piperazin-1-yl)-2,2-difluoro-3-hydroxy-5-phenylpent-4-en-
1-one (8g): (petroleum ether/acetone 19:1, white solid). M.p. 968C;
1H NMR: d ˆ 7.45 7.28 (m, 10H), 6.86 (d, J ˆ 16.0 Hz, 1H), 6.34 (dd,
J ˆ 6.2, J ˆ 16.0 Hz, 1H), 4.82 (dddd, J ˆ 6.2, J ˆ 17.2, J ˆ 1.2, J ˆ 5.5 Hz,
1H), 3.77 (m, 2H), 3.70 (m, 2H), 3.56 (s, 2H), 2.53 (m, 4H); 13C NMR: d ˆ
162.4 (t, J ˆ 28.8 Hz), 137.7, 136.6, 135.4, 129.6, 129.0, 128.8, 128.5, 127.8,
127.2, 122.7 (t, J ˆ 3.0 Hz), 115.8 (dd, J ˆ 265.4, J ˆ 259.9 Hz), 73.6 (dd, J ˆ
28.5, J ˆ 24.7 Hz), 53.4, 52.9, 46.2 (dd, J ˆ 7.1, J ˆ 5.5 Hz), 43.3; 19F NMR:
d ˆ À105.1 (dd, J ˆ 290.5, J ˆ 5.5 Hz, 1F), À114.8 (dd, J ˆ 290.5, J ˆ
17.2 Hz, 1F); elemental analysis calcd (%) for C22H24F2N2O2: C 68.38, H
6.26, N 7.25; found: C 68.52, H 6.02, N 7.32.
Methyl 2,2-difluoro-3-hydroxy-3-(6-methoxy-2-naphthyl) propanoate (7d):
(Petroleum ether/acetone 9:1, beige solid). M.p. 1058C; 1H NMR: d ˆ 7.83
(s, 1H), 7.78 7.71 (m, 2H), 7.52 (m, 1H), 7.21 7.14 (m, 2H), 5.31 (dd, J ˆ
15.9, J ˆ 7.9 Hz, 1H), 3.94 (s, 3H), 3.86 (s, 3H); 13C NMR: d ˆ 164.6 (dd,
J ˆ 31.0, J ˆ 36.7 Hz), 158.6, 135.3, 130.14, 130.11, 128.8, 127.7, 127.5, 125.8
(t, J ˆ 1.4 Hz), 119.7, 114.5 (dd, J ˆ 253.0, J ˆ 259.6 Hz), 106.0, 74.2 (dd, J ˆ
28.0, J ˆ 24.1 Hz), 55.7, 53.9; 19F NMR: d ˆ À113.6 (dd, J ˆ 262.9, J ˆ
7.9 Hz, 1F), À120.8 (dd, J ˆ 262.9, J ˆ 15.9 Hz, 1F); elemental analysis
calcd (%) for C15H14F2O4: C 60.81, H 4.76; found: C 60.98, H 4.83.
Methyl 2,2-difluoro-3-hydroxy-3-(N-Boc-1H-indol-3-yl) propanoate (7 h):
(petroleum ether/acetone 19:1, yellow viscous oil). 1H NMR: d ˆ 8.15 (d,
J ˆ 8.1 Hz, 1H), 7.75 (s, 1H), 7.69 (d, J ˆ 7.7 Hz, 1H), 7.37 7.22 (m, 2H),
5.47 (dd, J ˆ 16.3, J ˆ 7.7 Hz, 1H), 3.85 (s, 3H), 1.67 (s, 9H); 13C NMR: d ˆ
164.5 (dd, J ˆ 31.0, J ˆ 32.7 Hz), 149.9, 135.8, 129.1, 125.9, 125.2, 123.3,
120.4, 115.6, 115.3 (d, J ˆ 2.8 Hz), 114.7 (dd, J ˆ 253.6, J ˆ 259.1 Hz), 84.8,
68.3 (dd, J ˆ 25.0, J ˆ 29.4 Hz), 53.9, 28.5; 19F NMR: d ˆ À113,2 (dd, J ˆ
259.5, J ˆ 7.7 Hz, 1F), À120.3 (dd, J ˆ 259.5, J ˆ 16.3 Hz, 1F); elemental
analysis calcd (%) for C17H19F2NO5: C 57.46, H 5.69; found: C 57.25, H 5.37.
1-(4-Benzylpiperazino)-2,2-difluoro-3-hydroxy-3-(6-methoxy-2-naphthyl)-
1-propanone (8d): (Petroleum ether/acetone 9:1, beige solid). M.p. 1308C;
1H NMR: d ˆ 7.91 (s, 1H), 7.80 7.76 (m, 2H), 7.59 (m, 1H), 7.38 7.27 (m,
5H), 7.22 7.17 (m, 2H), 5.42 (dd, J ˆ 20.9, J ˆ 3.2 Hz, 1H), 4.35 (brs, 1H),
3.94 (s, 3H), 3.71 (m, 4H), 3.52 (s, 2H), 2.52 (m, 2H), 2.43 (m, 2H);
13C NMR: d ˆ 162.9 (dd, J ˆ 29.4, J ˆ 28.3 Hz), 158.4, 137.7, 135.6, 134.15,
134.11, 129.5, 128.85, 128.80, 128.1, 127.8, 126.9, 126.7 (t, J ˆ 1.6 Hz), 119.4,
115.6 (dd, J ˆ 258.5, J ˆ 267.3 Hz), 106.0, 74.2 (dd, J ˆ 29.1, J ˆ 23.0 Hz),
63.1, 55.7, 53.3, 52.9, 46.2 (t, J ˆ 6.3 Hz), 43.5; 19F NMR: d ˆ À103.4 (dd, J ˆ
291.4, J ˆ 3.2 Hz, 1F), À117.8 (dd, J ˆ 291.4, J ˆ 20.9 Hz, 1F); elemental
analysis calcd (%) for C25H26F2N2O3: C 68.17, H 5.95, N 6.36; found: C
67.95, H 6.02, N 6.07.
1-(4-Benzylpiperazino)-2,2-difluoro-3-hydroxy-3-(N-Boc-1H-indol-3-yl)-
1-propanone (8 h): (petroleum ether/acetone 19:1, yellow solid). M.p.
1508C; 1H NMR: d ˆ 8.19 (d, J ˆ 8.1 Hz, 1H), 7.76 (s, 1H), 7.70 (d, J ˆ
7.7 Hz, 1H), 7.35 7.25 (m, 7H), 5.59 (dd, J ˆ 21.4, J ˆ 2.7 Hz, 1H), 3.73 (m,
4H), 3.55 (s, 2H), 2.56 2.45 (m, 4H), 1.69 (s, 9H); 13C NMR: d ˆ 162.7 (t,
J ˆ 28.8 Hz), 149.9, 137.7, 135.8, 129.7, 129.5, 128.8, 127.8, 126.1, 124.9, 123.2,
120.6, 115.8 (dd, J ˆ 267.6, J ˆ 259.3 Hz), 115.6, 115.1 (d, J ˆ 1.6 Hz), 84.3,
68.9 (dd, J ˆ 23.4, J ˆ 31.0 Hz), 63.1, 53.3, 52.9, 46.3 (dd, J ˆ 6.6, J ˆ 5.5 Hz),
43.5, 28.6; 19F NMR: d ˆ À103.9 (dd, J ˆ 291.1, J ˆ 2.7 Hz, 1F), À117.0 (dd,
J ˆ 291.1, J ˆ 21.4 Hz, 1F); elemental analysis calcd (%) for C27H31F2N3O4:
C 64.92, H 6.25, N 8.41; found: C 64.64, H 6.19, N 8.27.
Methyl 2,2-difluoro-3-hydroxydecanoate (7e): (petroleum ether/acetone
19:1, yellow oil). 1H NMR: d ˆ 4.03 (dddd, J ˆ 2.7, J ˆ 9.8, J ˆ 15.0, J ˆ
7.5 Hz, 1H), 3.92 (s, 3H), 2.3 (brs, 1H), 1.71 1.20 (m, 12H), 0.90 (t, J ˆ
6.7 Hz, 3H); 13C NMR: d ˆ 164.6 (dd, J ˆ 31.3, J ˆ 32.9 Hz), 115.2 (dd, J ˆ
256.9, J ˆ 254.1 Hz), 72.1 (dd, J ˆ 25.3, J ˆ 27.4 Hz), 53.8, 32.1, 29.6, 29.52
(dd, J ˆ 1.4, J ˆ 1.9 Hz), 29.47, 25.6, 23.0, 14.5; 19F NMR: d ˆ -115.0 (dd, J ˆ
264.1, J ˆ 7.5 Hz, 1F), À123.0 (dd, J ˆ 264.1, J ˆ 15.0 Hz, 1F); elemental
analysis calcd (%) for C11H20F2O3: C 55.45, H 8.46; found: C 55.53, H 8.73.
1-(4-Benzylpiperazino)-2,2-difluoro-3-phenyl-1,3-propanedione (9a): (pe-
troleum ether/ether 4:1, yellow oil). 1H NMR: d ˆ 8.13 8.08 (m, 2H), 7.67
(m, 1H), 7.55 7.48 (m, 2H), 7.36 7.28 (m, 5H), 3.69 (m, 4H), 3.55 (s, 2H),
2.50 (m, 4H); 13C NMR: d ˆ 187.1 (t, J ˆ 26.9 Hz), 160.5 (t, J ˆ 27.2 Hz),
137.4, 135.2, 132.0 (t, J ˆ 1.1 Hz), 130.6 (t, J ˆ 2.7 Hz), 129.6, 129.2, 128.8,
127.9, 112.1 (t, J ˆ 264.5 Hz), 63.0, 53.2, 52.7, 46.0 (t, J ˆ 4.7 Hz), 43.6; 19F
NMR: d ˆ À102.9 (s); elemental analysis calcd (%) for C20H20F2N2O2: C
67.03, H 5.62, N 7.82; found: C 67.15, H 5.97, N 7.59.
1-(4-Benzylpiperazino)-2,2-difluoro-3-hydroxy-1-decanone (8e): (petrole-
um ether/acetone 19:1, yellow viscous oil). 1H NMR: d ˆ 7.36 7.27 (m,
5H), 4.18 (m, 1H), 3.76 (m, 2H), 3.68 (m, 2H), 3.55 (s, 2H), 2.52 (m, 4H),
1.68 1.21 (m, 12H), 0.9 (t, J ˆ 6.4 Hz, 3H); 13C NMR: d ˆ 162.75 (dd, J ˆ
29.1 Hz), 137.7, 129.5, 128.8, 127.8, 116.5 (dd, J ˆ 259.1, J ˆ 265.1 Hz),72.24
(dd, J ˆ 24.1, J ˆ 28.5 Hz), 63.1, 53.4, 52.8, 46.2 (dd, J ˆ 7.1, J ˆ 5.5 Hz), 43.2,
32.2, 29.8, 29.6, 28.5 (dd, J ˆ 3.6, J ˆ 1.9 Hz), 25.9, 23.0, 14.5; 19F NMR: d ˆ
À103.4 (d, J ˆ 291.4 Hz, 1F), À117.8 (dd, J ˆ 291.4, J ˆ 20.6 Hz, 1F);
elemental analysis calcd (%) for C21H32F2N2O2: C 65.94, H 8.43, N 7.32;
found: C 66.09, H 8.67, N 7.68.
1-(4-Benzylpiperazino)-3-cyclopropyl-2,2-difluoro-1,3-propanedione (9b):
1
(petroleum ether/acetone 9:1, yellow viscous oil). H NMR: d ˆ 7.34 7.28
(m, 5H), 3.66 (m, 4H), 3.54 (s, 2H), 2.49 (m, 4H), 2.31 (m, 1H), 1.31 1.15
(m, 4H); 13C NMR: d ˆ 198.2 (t, J ˆ 27.4 Hz), 160.1 (t, J ˆ 26.9), 137.8,
129.5, 128.8, 127.8, 111.3 (t, J ˆ 265.7 Hz), 63.1, 53.3, 52.8, 45.9 (t, J ˆ
4.7 Hz), 43.5, 17.3, 14.0; 19F NMR: d ˆ À109.2 (s); elemental analysis calcd
Methyl 2,2-difluoro-3-hydroxy-3-(3-thienyl)propanoate (7 f): (petroleum
ether/acetone 9:1, yellow viscous oil). 1H NMR: d ˆ 7.42 7.32 (m, 2H), 7.18
Chem. Eur. J. 2002, 8, No. 13
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0813-2921 $ 17.50+.50/0
2921

T. Billard, B. R. Langlois and G. Blond
FULL PAPER
(%) for C17H20F2N2O2: C 63.34, H 6.25, N 8.69; found: C 63.53, H 6.18, N
9.02.
[3]For a review see: a) M. J. Tozer, T. F. Herpin, Tetrahedron 1996, 52,
8619 8683; b) J. M. Percy, Contemp. Org. Synth. 1995, 251 268; c) K.
Uneyama, J. Synth. Org. Jpn. 1993, 51, 232 246.
[4]a) J. Fried, E. A. Hallinan, Tetrahedron Lett. 1984, 25, 2301 2302;
b) M. Kuroboshi, T. Ishihara, Bull. Chem. Soc. Jpn 1990, 63, 428 437;
c) R. W. Lang, B. Schaub, Tetrahedron Lett. 1988, 29, 2943 2946;
d) T. Tsukamoto, T. Kitazume, J. Chem. Soc. Perkin Trans. 1 1993,
1177 1181.
[5]a) C. Portella, T. Brigaud, O. Lefebvre, R. Plantier-Royon, J. Fluorine
Chem. 2000, 101, 193 198; b) R. Plantier-Royon, C. Portella,
Carbohydr. Res. 2000, 327, 119 146.
[6]K. Uneyama, K. Maeda, T. Kato, T. Katagiri, Tetrahedron Lett. 1998,
39, 3741 3744.
[7]a) K. Uneyama, G. Mitzutani, Chem. Commun. 1999, 613 614; b) K.
Uneyama, G. Mitzutani, K. Maeda, T. Kato, J. Org. Chem. 1999, 64,
6717 6723.
[8]a) H. Amii, T. Kobayashi, Y. Hatamoto, K. Uneyama, Chem.
Commun. 1999, 1323 1324; b) H. Amii, T. Kobayashi, K. Uneyama,
Synthesis 2000, 2001 2003.
[9]a) Y. Xu, W. R. Dolbier Jr, X. X. Rong, J. Org. Chem. 1997, 62, 1576
1577; b) Y. Ding, J. Wang, K. A. Abboud, Y. Xu, W. R. Dolbier Jr,
N. G. J. Richards, J. Org. Chem. 2001, 66, 6381 6388.
[10]a) T. Billard, B. R. Langlois, G. Blond, Tetrahedron Lett. 2000, 41,
8777 8780; b) T. Billard, B. R. Langlois, G. Blond, Eur. J. Org. Chem.
2001, 1467 1471; c) G. Blond, T. Billard, B. R. Langlois, Tetrahedron
Lett. 2001, 42, 2473 2475.
1-(4-Benzylpiperazino)-2,2-difluoro-2-(benzeneselenenyl)-1-ethanone
(10): (petroleum ether/acetone 19:1, yellow solid). M.p. 578C; 1H NMR:
d ˆ 7.78 7.73 (m, 2H), 7.48 7.28 (m, 8H), 3.69 (m, 4H), 3.55 (s, 2H), 2.49
(m, 4H); 13C NMR: d ˆ 160.6 (t, J ˆ 25.0 Hz), 138.0, 137.9, 130.2, 129.6,
129.5, 128.9, 127.8, 124.5, 123.9 (t, J ˆ 306.5 Hz), 63.1, 53.4, 52.9, 46.2 (t, J ˆ
5.2 Hz), 44.1; 19F NMR: d ˆ À71.2 (s); elemental analysis calcd (%) for
C19H20F2N2OSe: C 55.75, H 4.92, N 6.84, Se 19.29; found: C 56.04, H 4.87, N
6.99, Se 18.95.
Dimethyl 2,2-difluoro-3-hydroxy-3-phenylsuccinate (11): (petroleum
1
ether/acetone 9:1, yellow oil). H NMR: d ˆ 7.84 7.80 (m, 2H), 7.44 7.40
(m, 3H), 4.5 (brs, 1H), 3.96 (s, 3H), 3.85 (s, 3H); 13C NMR: d ˆ 170.9, 163.5
(dd, J ˆ 31.3, 32.4 Hz), 133.6, 129.7, 128.6, 127.4 (t, J ˆ 1.9 Hz), 113.5 (dd,
J ˆ 262.9, J ˆ 265.7 Hz), 77.5 (t, J ˆ 31.8 Hz), 54.8, 54.0; 19F NMR: d ˆ
À108.7 (d, J ˆ 268.5 Hz, 1F), À115.1 (d, J ˆ 268.5 Hz, 1F); elemental
analysis calcd (%) for C12H12F2O5: C 52.56, H 4.41; found: C 52.81, H 4.49.
1,5-Bis(4-benzylpiperazino)-3-(dimethylamino)-2,2,4,4-tetrafluoro-1,5-
pentanedione (12): (petroleum ether/acetone 9:1, yellow viscous oil).
1H NMR: d ˆ 7.31 7.27 (m, 10H), 4.9 (tt, J ˆ 15.8, J ˆ 13.7 Hz, 1H), 3.82
3.62 (m, 8H), 3.54 (s, 4H), 2.66 (s, 6H), 2.50 (m, 8H); 13C NMR: d ˆ 161.6
(t, J ˆ 27.6 Hz), 137.9, 129.5, 128.8, 127.8, 119.4 (t, J ˆ 265.5 Hz), 63.9 (quint,
J ˆ 21.1 Hz), 63.1, 53.5, 53.0, 46.3 (brs), 44.0, 43.7; 19F NMR: d ˆ À101.1
(dd, J ˆ 293.7, J ˆ 15.8 Hz, 2F), À106.2 (dd, J ˆ 293.7, J ˆ 13.7 Hz, 2F).
[11]a) G. Blond, T. Billard, B. R. Langlois, J. Org. Chem. 2001, 66, 4826
4830; b) T. Billard, B. R. Langlois, J. Org. Chem. 2002, 67, 997 1000.
[12]C. Hansch, A. Leo, R. W. Taft, Chem. Rev. 1991, 91, 165 195.
Acknowledgements
The authors thank the French ministry and the CNRS for a financial
support.
¬
[13]a) J. Auge , F. Leroy, Tetrahedron Lett. 1996, 37, 7715 7716; b) H.
Firouzabadi, B. Karimi, S. Eslami, Tetrahedron Lett. 1999, 40, 4055
4058; c) V. G. Saraswathy, S. Sankararaman, J. Org. Chem. 1994, 59,
4665 4670.
[14]A. F. Carey, R. J. Sundberg, Advanced Organic Chemistry, Vol. A,
Plenum Press, New York, 1990, p. 422.
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Chem. Res. 1996, 29, 268 274; b) L. A. Carpino, D. Ionescu, A. El-
Faham, Tetrahedron Lett. 1998, 39, 241 244.
[1]B. E. Smart, J. Fluorine Chem. 2001, 109, 3 11.
[2]a) J. T. Welch, S. Eswarakrishnan, Fluorine in Bioorganic Chemistry,
Wiley, New York, 1991; b) Biomedical Frontiers of Fluorine Chemistry
(Eds.: I. Ojima, J. R. McCarthy, J. T. Welch), ACS Symposium Series
639, American Chemical Society, Washington DC, 1996; c) Fluorine-
containing Amino Acids. Synthesis and Properties (Eds.: V. P. Kukhar,
V. A. Soloshonok), Wiley, Chichester, 1995; d) T. Hiyama, Organo-
fluorine Compounds: Chemistry and Properties, Springer, Berlin,
2000, Chapter 5, pp. 137 182.
Received: February 7, 2002 [F3860]
2922
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Chem. Eur. J. 2002, 8, No. 13