Nucleophilic introduction of fluorinated alkyl groups into aldehydes and ketones using the corresponding alkyl halide with samarium(II) iodide

Article abstract of DOI:10.1039/a606048j

Fluorinated alkyl groups such as PhCF₂, C₆F₁₃, CF₃CCl₂ and CF₂CO₂Et are nucleophilically introduced into an aldehyde or ketone using fluorinated alkyl halides with SmI₂

Full text of DOI:10.1039/a606048j

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Nucleophilic introduction of fluorinated alkyl groups into aldehydes
and ketones using the corresponding alkyl halide with samarium(II)
iodide
Masato Yoshida,* Daiki Suzuki and Masahiko Iyoda
Department of Chemistry, Faculty of Science, Tokyo Metropolitan University, Hachioji,
Tokyo 192-03, Japan
Fluorinated alkyl groups such as PhCF , C F , CF CCl and CF CO Et are nucleophilically introduced
2
6
13
3
2
2
2
into an aldehyde or ketone using fluorinated alkyl halides with SmI ; the reaction proceeds effectively at
2
room temperature to give the corresponding alcohol. F urthermore, the synthesis of PhCF SiM e ,
2
3
i
C F SiM e and C F SiM e Pr is achieved by reaction of the halide with SmI in the presence of the silyl
6
13
3
6
13
2
2
chloride; the resultant fluoroalkylated silyl compounds are used as reagents for nucleophilic
fluoroalkylation. 2-Chloro-3,3,3-trifluoropropene derivatives are also prepared selectively by the reaction
i
of CF CCl with an excess of SmI in the presence of an aldehyde and Pr OH .
3
3
2
Nucleophilic introduction of a fluorinated alkyl group into
organic molecules is an important route for the synthesis of
organofluorine compounds. Although organometallic reagents
have recently played important and versatile roles for nucleo-
philic alkylation, their applicability to fluorine analogues is very
1
limited. This is due to the thermal instability and low nucleo-
philicity of fluoroalkyl metallic reagents. Fluoroalkyllithium
and Grignard reagents are very unstable, undergoing α- or β-
elimination of the fluoride ion whilst, in contrast, fluoroalkyl-
zinc, -copper and -mercury reagents are stable, but have low
nucleophilicity. Thus, development of a novel method for the
nucleophilic introduction of a fluorinated alkyl group into
organic molecules is of importance. In continuing our efforts
to develop novel synthetic methods for organofluorine com-
pounds, we have been investigating nucleophilic fluoroalkyl-
ation using a fluoroalkyl halide with samarium() iodide
Scheme 1
(
SmI ), and the results are reported here.
2
We investigated the introduction of CF Cl into aromatic
PhCF Cl and the electrophile in benzene were added to a solu-
2
2
rings and successive conversion of the chlorine into other func-
tion of SmI in THF in the presence of HMPA. In the reaction
2
2
tional groups. In the course of our study, we found that SmI
with octan-2-one, the alcohol 1a and PhCF H were obtained in
2
2
was a very useful reagent for the one-electron reductive cleavage
38 and 50% yields, respectively [Scheme 2, eqn. (1)]. Probably,
of the C᎐Cl bond of PhCF Cl, leading to the PhCF radical
the PhCF anionic species attacked both the carbonyl carbon
2
2
2
and chloride ion; these results have been reported in our previ-
and the α-hydrogen of octan-2-one to give the alcohol 1a
3
ous papers. Now we have found that the PhCF radical, thus
and PhCF H, respectively. The anionic species was also very
2
2
formed, is further reduced to the PhCF anion with SmI . To a
reactive towards TMSCl, giving PhCF SiMe almost quantita-
2
2
2
3
solution of PhCF Cl in benzene in the presence of HMPA and
tively [Scheme 2, eqn. (2)]. The applicability of this Barbier type
2
a proton source such as 2-dimethylaminoethanol (DMAE) or
reaction to aldehydes or ketones was, however, very limited;
i
propan-2-ol (Pr OH), a THF solution of SmI was added at
SmI –HMPA reacted with benzaldehyde or acetophenone
2
2
room temperature. The reaction was complete within 5 min,
much faster than with PhCF Cl, and the desired alcohol was
2
and then work-up gave PhCF H as the sole product (Scheme 1).
not obtained. Therefore a two-step procedure was examined;
PhCF Cl was added to a solution of SmI –HMPA in THF
2
In the presence of CH OD (MeOD), PhCF D was obtained
3
2
2
2
almost exclusively; this means that the reduction proceeds pre-
under nitrogen, and then octan-2-one was added stepwise to
the resulting solution. In the two-step procedure, neither the
dominantly along an ionic path via the PhCF anionic species
2
(Scheme 1: mechanism).
desired alcohol nor PhCF H was obtained. Probably, the
2
In the absence of HMPA, the reaction was very slow, requir-
ing more than 3 h for the disappearance of the colour of SmI2.
reactive PhCF2 anion equivalent was formed initially by the
reaction of PhCF Cl with SmI –HMPA but immediately con-
2
2
The reduction potential of the C᎐Cl bond in PhCF Cl is
verted to a more stable species, which no longer reacted with
these electrophiles. Unfortunately, the nature of the reactive
anionic intermediate is not yet clear.
2
4
relatively high, and SmI alone is not enough for the reduction
2
o
+2
+3
5
[
E
(Sm /Sm ) = Ϫ1.55 V]. However, the reduction of
aq
PhCF Cl could be achieved by the addition of HMPA; employ-
These results prompted us to investigate the reaction of a
2
ing HMPA as an additive to SmI is known to enhance its
reductive ability.
perfluoroalkyl halide with SmI for comparison with that of
2
2
6
PhCF Cl. A solution of C F I and an aldehyde or ketone (10
2
6
13
Thus, the reaction of PhCF Cl with SmI in the presence of
equiv. to C F I) in benzene was added to a solution of SmI in
2
2
6
1
3
2
an electrophile such as octan-2-one, acetophenone, benzalde-
hyde or trimethylsilyl chloride (TMSCl) was investigated;
THF. The reaction of C F I proceeded at room temperature
6 13
without HMPA, and was complete within 1 min. After treat-
J. Chem. Soc., Perkin Trans. 1, 1997
643

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Scheme 2
i
1
13
19
ment with MeOH, yields of the products were determined by
tion with Pr Me SiCl and was characterized by H, C and
F
2
1
9
F NMR spectroscopy based on C F I (Scheme 3). The yields
NMR spectroscopy (see Experimental section).
6
13
Fluoroalkylsilane derivatives have recently been recognized
as convenient reagents for the introduction of fluoroalkyl
groups into carbonyl compounds, and facile methods for their
7
preparation have been investigated. The method using SmI
2
described here is expected to be novel and practically useful
for the preparation of PhCF SiMe , C F SiMe and C F -
2
3
6
13
3
6
13
i
SiMe Pr . The reactivity of CF SiMe has been extensively
investigated, but little is known about the reactions of PhCF -
2
3
3
7
Scheme 3
2
SiMe and C F SiMe . Thus, we investigated the reaction of
3
6
13
3
of the adducts of C6F
13
to aldehydes were not good and a
these silyl compounds with aldehydes and a ketone. The reac-
tion was carried out in THF in the presence of a catalytic
amount of tetrabutylammonium fluoride (TBAF) to give the
alcohols 1 and 2.
considerable amount of the reduced product (C F H) was
6
13
obtained (Scheme 3). Thus reaction with the ketone did
not occur.
The production of C F H in the reaction with PhCHO is
6
13
likely to be due to hydrogen abstraction from THF by the
initially formed C6F13 radical. In order to confirm this, we
examined the reaction with MeOD (Scheme 4). The reaction of
PhCF SiMe was treated with the aldehydes to give the alco-
2
3
hols 1b and 1c in good yields (Table 1). However, reactivity
of the carbonyl carbon of the ketone was low (Table 1), and
a considerable amount of PhCF H was produced by reaction
2
with the α-hydrogen of the ketone. As mentioned previously,
the corresponding alcohols were not obtained from reaction
of PhCF Cl with SmI –HMPA in the presence of an aldehyde,
Scheme 4
2
2
C F I with SmI in the presence of MeOD gave both C F D
because the aldehyde was reduced much faster than PhCF
Therefore, PhCF SiMe is important as an efficient reagent for
the introduction of the PhCF unit into the aldehyde. Similarly,
2
Cl.
6
13
2
6
13
and C F H in the ratio of 68:32. This means that 32% of the
2
3
6
13
C6F13 radical abstracted hydrogen mainly from THF and about
8% of the C6F13 radical was further reduced with SmI to a
2
i
6
C F13SiMe and C F13SiMe Pr were treated with aldehydes to
6 3 6 2
2
C6F13 anionic species. The result is much different from that
observed in PhCF Cl; PhCF D was obtained almost exclusively
give the corresponding alcohol in moderate to good yields
(Table 1), but did not react with the ketone.
2
2
from PhCF Cl. Probably this is due to the higher reactivity of
The synthetic utility of SmI
tion of fluorinated alkyl groups such as CF
CF CO Et was further investigated. The 1,1-dichloro-2,2,2-
trifluoromethyl (CF CCl ) unit has recently been the focus of
2
for the nucleophilic introduc-
2
the C6F13 radical for hydrogen abstraction compared to the
PhCF radical. When CH CN was used as a solvent, the ionic
3
CCl and
2
2
3
2
2
path in C6F13 to give C F D was increased to 84%. The yield of
3
2
6
13
C F H on reaction with C H CHO was higher than that with
PhCHO (Scheme 3). This suggests that during reaction with
attention because of its versatility in the synthesis of organo-
fluorine compounds with potential importance in industry and
6
13
7
15
8
9
C H CHO, proton abstraction from the α-hydrogen of the
because the reactions of CF CCl with Zn and PbBr –Al,
3 3 2
10
7
15
aldehyde by the anionic species occurs in addition to hydro-
gen abstraction by the radical.
upon electroreduction are known to be useful for introduc-
tion of the group into electrophiles. Thus, the reaction of
The C6F13 anionic species reacted with trimethylsilyl chloride
efficiently, and a silylated product was obtained in 68% yield
CF
investigated. A solution of CF
to CF CCl ) in benzene was added to a solution of SmI
equiv. to CF CCl ) under nitrogen. The reaction was completed
3
CCl
3
with SmI
2
in the presence of an electrophile was
CCl and an aldehyde (2 equiv.
(2.4
3
3
(
Scheme 5); C F SiMe was not isolated in a pure form due
3
3
2
6
13
3
3
3
within 10 min and after treatment of the mixture with MeOH,
1
9
the product yields were determined by F NMR spectroscopy
using PhCF3 as an internal standard. The alcohols 3 were
obtained in moderate yields (Scheme 6).
Further reduction of the Cl in 3 with SmI is expected; on
2
i
Scheme 5
reaction of 3 with SmI in the presence of Pr OH, the olefins 4
2
were obtained selectively; other possible olefins 5 were absent
(Scheme 7). The presence of Pr OH was essential for the select-
1
9
i
to its high volatility and the yield was determined by F NMR
spectroscopy based on C F I using PhCF as an internal stand-
ive formation of 4. Both 4b and 5b were obtained in the ratio of
6
13
3
i
i
ard. Conveniently, pure C F SiMe Pr was obtained by reac-
19:81 by the reaction of 3b with SmI in the absence of Pr OH.
6
13
2
2
6
44
J. Chem. Soc., Perkin Trans. 1, 1997

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Table 1 Reaction of R SiR RЈ with aldehydes and a ketone
Table 2 Reaction of XCF CO Et with SmI in the presence of alde-
F
2
2
2
2
hydes or ketones
1
2
3
a
R SiR R R
Electrophile
Product
Yield (%)
F
PhCF SiMe
Me(CH ) (CO)Me
1a
1b
1c
2a
2b
2a
2b
12
70
58
47
41
55
63
2
3
3
3
2 5
PhCF SiMe
PhCHO
Me(CH ) CHO
2
PhCF SiMe
2
2 6
C6F13SiMe3
C6F13SiMe3
PhCHO
Me(CH ) CHO
2
6
i
i
C6F13SiMe Pr
PhCHO
Me(CH ) CHO
2
C6F SiMe Pr
13
2
2
6
a
RCORЈ
X
Product
Yield (%)
a
19
Determined by F NMR spectroscopy based on R SiR RЈ.
F
2
Me(CH ) CHO
Br
Cl
Br
Br
Cl
Br
Cl
Br
Cl
Br
Cl
Br
Br
Cl
Br
6a
67 (67)
74
2
6
Ph(CH ) CHO
6b
6c
87 (79)
2
2
b
c
Ph(Me)CHCHO
93 (90)
b
91
MeCO(CH ) Me
6d
6e
6f
85 (71)
94
56 (58)
29
99 (91)
89
2
5
PhCOMe
Cyclohexanone
PhCOPh
6g
6h
46 (47)
b
c
4
-tert-Butyl-
91 (72)
b
cyclohexanone
PhCHO
91
6i
27
Scheme 6
a
19
The yields were determined by F NMR spectroscopy using PhCF as
3
an internal standard based on XCF CO Et; XCF CO Et (1.0 mmol)
2
2
2
2
and carbonyl compound (2.0 mmol) were used for the reaction. Isolated
yields based on carbonyl compound are shown in parenthesis; the reac-
tions were performed using BrCF CO Et (1.0 mmol) and carbonyl
2
2
b
compound (0.9 mmol) (see Experimental section). Ratios of the iso-
mers determined by F NMR spectroscopy: in 6c 42:58 (X = Br),
0:60 (X = Cl) and in 6h 51:49 (X = Br), 51:49 (X = Cl). Total yield
1
9
c
4
of the two isomers.
tion of BrCF CO Et with SmI . The SmI -induced reactions
2
2
2
2
were complete within 1 min at room temperature for both
BrCF CO Et and ClCF CO Et. Zn-induced reactions of
2
2
2
2
ClCF CO Et failed under the reaction conditions which were
2
2
normally effective with BrCF CO Et (reflux in THF for 30
2
2
min), and required high temperature (70 ЊC), longer reaction
1
6
time (20 h) and a solvent of higher polarity such as DMF.
It is, therefore, of particular importance to note that the reac-
tion of inexpensive ClCF CO Et with SmI was complete at
2
2
2
room temperature within 1 min in THF, although electro-
chemically induced intermolecular coupling of ClCF CO Me
2
2
Scheme 7
with an aldehyde has been reported to take place effectively in
DMF.
10
Application of SmI to the Reformatsky-type reaction was
In summary, although SmI has recently been recognized to
2
2
also successful, and a part of this work has been reported as a
be an effective one-electron reducing reagent, and is used in a
variety of organic syntheses, its utility in organofluorine chem-
1
1
5
preliminary communication. The Reformatsky-type reaction
is known to be one of the most useful methods for the construc-
tion of α,α-difluorinated compounds from XCF CO R (X = I,
istry for the formation of reactive species from fluorinated
1
7
2
2
alkyl halides has been less developed. In our study, SmI has
2
1
2
Br or Cl), Zn being used to induce the reaction. After the
been shown, when used with various fluorinated alkyl halides,
to induce the nucleophilic introduction of the corresponding
1
3
initial report of Hallinan and Fried, several modified methods
have been investigated mainly concerned with activation of the
alkyl groups. Since SmI is readily available and easy to handle,
2
1
4
Zn to realize the reaction efficiently by the use of additives or
the procedure described here is expected to be convenient and
practically useful for the synthesis of organofluorine
compounds.
1
5
sonicating conditions. We have found that SmI , as an altern-
2
ative reagent to Zn, induced the reactions of XCF CO Et
2
2
(
X = Cl and Br) with aldehydes and ketones effectively at room
temperature to give 2,2-difluoro-3-hydroxy esters 6. Unfortu-
Experimental
nately, the reaction of BrCF CO Et with an ester (RCO Et),
amide (RNHCOMe) or imine (R CH᎐NR ) was not realized by
SmI2.
2
2
2
1
2
Melting points were measured with a Yanaco MP-500D
melting point apparatus, and are uncorrected. H, C and
1
13
19
F
When a solution of XCF CO Et (X = Cl or Br) and an alde-
NMR spectra were taken with a JEOL JNM EX400 (400 MHz
H, 100 MHz C and 376 MHz F NMR) spectrometer.
2
2
1
13
19
hyde or ketone in THF was added to a solution of SmI in THF
2
at room temperature under nitrogen, the colour of the solution
turned from purple to yellow at once, indicating the end of the
reaction. Reasonable yields were obtained for both aldehydes
and ketones, other than benzaldehyde (see Table 2). Benzalde-
Fluorine chemical shifts are given in ppm from external
CF CO H. J Values are recorded in Hz. Mass spectra were
3
2
obtained with a JEOL JMS AX-505W spectrometer with a
JEOL JMA 5000 mass data system using an electron-impact
(EI) ionization technique at 70 eV. Gel-permeation chrom-
hyde itself reacted with SmI and prevented the effective reac-
2
J. Chem. Soc., Perkin Trans. 1, 1997
645

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atography (GPC) was performed by means of a JAI model
LC-908 liquid chromatograph equipped with two JAIGEL-1H
columns (20 × 600 mm) with chloroform as eluent.
δ (376 MHz, CDCl from ex. CF CO H) Ϫ28.95 and Ϫ32.82
F 3 3 2
+
(ABq, JF F 252, d, JH F 9.2); m/z 234 (M ), 127 and 107.
Similarly, 1-(phenyldifluoromethyl)nonanol 1c was obtained
as colourless crystals from hexane, mp 48.7–49.5 ЊC (Found: C,
70.56; H, 9.01. C H OF requires C, 70.28; H, 8.65%);
Materials
1
5
22
2
Samarium() iodide (SmI ) was used as a THF solution (0.1
δ (400 MHz, CDCl ) 7.49–7.51 (m, 2 H), 7.41–7.44 (m, 3 H),
3.90–3.99 (m, 1 H), 1.99 (s, 1 H), 1.25–1.61 (m, 12 H) and 0.86
2
H
3
Ϫ1
mol l ); it was synthesized from samarium powder by reac-
1
8
tion with I in THF under nitrogen according to the literature,
(t, 3 H, J 6.84); δ (100 MHz, CDCl ) 134.4 (t, J 25.7), 130.0,
2
C
3
or obtained from Aldrich Co. Ltd., as a THF solution (0.1 mol
l ). Samarium ingots (99.9% purity) were obtained from
128.3, 125.9, 121.7 (t, J 246), 74.4 (t, J 30.4), 31.7, 30.0, 29.3,
Ϫ1
29.1, 25.5, 22.6 and 14.0; δ (376 MHz, CDCl3 from ex.
F
Soekawa Chemicals Co. Ltd., and were powdered with a rasp.
CF CO H) Ϫ31.47 and Ϫ32.57 (ABq, J 249, d, J 9.8); m/z
256 (M ), 129 and 127.
3
2
+
H F
The concentration of SmI was determined by iodometry prior
2
1
8
to use as described in the literature. PhCF Cl was prepared by
2
the reaction of benzene with bis(chlorodifluoroacetyl) peroxide
as described in our previous paper. Due to the high volatility
Reaction of C F SiMe with carbonyl compounds
C F SiMe was obtained as a THF solution by reaction of
6 13 3
6
13
3
2
of PhCF Cl, complete separation from benzene was difficult.
C F I with SmI in the presence of Me SiCl. To a solution of
6 13 2 3
2
Ϫ1
Therefore, a benzene solution of PhCF Cl (0.15–0.20 mol l )
SmI (2.2 mmol) in THF was added C F I (1.0 mmol) and
2
2
6
1
3
was prepared and used for the reactions described; the concen-
tration of the solution was determined by F NMR spec-
Me SiCl (10 mmol) in benzene (2 ml) under nitrogen at room
3
1
9
temperature with stirring. The characteristic colour of SmI2
disappeared within 1 min. C F SiMe and THF were distilled
troscopy using PhCF as an internal standard. Perfluorohexyl
3
6
13
3
iodide (C F I) was obtained from F-Tech. Inc. and distilled
from the reaction mixture, and the concentration of the former
6
13
1
9
prior to use. 1,1,1-Trichloro-2,2,2-trifluoroethane (CF CCl )
was determined by F NMR spectroscopy using PhCF as an
3
3
3
and ethyl bromodifluoroacetate (BrCF CO Et) were available
internal standard. The solution of C F SiMe in THF was
2
2
6
13
3
from Tokyo Kasei Kogyo Co. Ltd., and purified by distillation
prior to use. Tetrabutylammonium fluoride (1 mol l in THF)
used in the following reactions without further purification. A
solution of C F SiMe (1.0 mmol) and benzaldehyde (10
Ϫ1
6
13
3
was also available from Tokyo Kasei Kogyo Co. Ltd., and dried
over molecular sieves (MS-4A) prior to use. Ether refers to
diethyl ether.
mmol) in THF (2 ml) was dried over MS-4A for 1 h, after which
TBAF was added to it. The resulting solution was stirred at
room temperature under nitrogen for 1 h after which aq. HCl (1
Ϫ1
mol l ; 20 ml) was added and stirring continued for 1 h at room
Reaction of PhCF Cl with SmI in the presence of an electrophile
temperature. After this the mixture was extracted with ether
(3 × 20 ml) and the combined extracts were washed with water,
2
2
To a solution of SmI (2.5 mmol) in THF was added PhCF Cl
2
2
(
1.0 mmol), octan-2-one (10 mmol) in benzene (5 ml) and then
dried (MgSO ) and evaporated. Purification of the residue with
4
1
9
HMPA (7.5 mmol) under nitrogen at room temperature with
stirring. After 1 min, aq. HCl (1 mol dm ) was added to the
GPC gave the corresponding alcohol 2a as a colourless oil.
3
19
Similarly, 2b was obtained.
mixture and the organic products were extracted with ether
i
(3 × 20 ml). The combined extracts were washed with water,
Synthesis of C F SiMe Pr
6
13
2
dried (MgSO ) and evaporated. Purification of the residue with
GPC gave the corresponding alcohol 1a.
To a solution of SmI (2.2 mmol) in THF was added C F I (1.0
4
2
6
13
i
mmol) and Pr Me SiCl (10 mmol) in benzene (2 ml) under
2
1
-Phenyl-1,1-difluoro-2-methyloctan-2-ol 1a: colourless oil
nitrogen at room temperature with stirring. After 1 min, aq.
HCl (1 mol dm ) was added to the mixture which was then
3
(
Found: C, 70.21; H, 8.92. C H OF requires C, 70.28; H,
1
5
22
2
8
3
.65%); δ (400 MHz, CDCl ) 7.48–7.55 (m, 2 H), 7.38–7.45 (m,
H), 1.26 (s, 3 H), 1.16–1.59 (m, 10 H) and 0.87 (t, 3 H, J 6.84);
extracted with ether (3 × 20 ml). The combined extracts were
H
3
washed with water, dried (MgSO ) and evaporated. Purification
4
i
δ (100 MHz, CDCl ) 134.3 (t, J 26.7), 129.7, 127.8, 126.9, 123.1
of the residue with GPC gave C F SiMe Pr ; δ (400 MHz,
C
3
6
13
2
H
(t, J 251), 75.7 (t, J 28.5), 35.5, 31.8, 29.8, 22.8, 22.6, 20.3 and
CDCl ) 1.12–1.21 (m, 1 H), 1.06 (d, 6 H, J 6.8) and 0.25 (s, 6 H);
3
1
4.0; δ (376 MHz, CDCl3 from ex. CF CO H) Ϫ32.7 and
δ (100 MHz, CDCl ) 17.0, 11.3 and Ϫ7.9; δ (376 MHz, CDCl
from ex. CF CO H) Ϫ5.5 (t, 3 F, J 9.2), Ϫ43.3 (2 F), Ϫ46.6
3 2
F
2
2
C
3
F
3
+
Ϫ33.5 (ABq, J 247); m/z 256 (M ), 129 and 127.
Similarly, (phenyldifluoromethyl)trimethylsilane (PhCF2-
SiMe ) was obtained: δ (400 MHz, CDCl ) 7.28–7.45 (m, 5 H)
(2 F), Ϫ47.5 (2 F), Ϫ50.0 (2 F) and Ϫ50.8 (2 F).
3
H
3
i
and 0.142 (s, 9 H); δ (100 MHz, CDCl ) 138.2 (t), 128.8, 128.2,
Reaction of C F SiMe Pr with carbonyl compounds
C
3
6
i
13
2
1
24.6 and Ϫ4.86; δ (376 MHz, CDCl from ex. CF CO H)
C F SiMe Pr (1.0 mmol) and benzaldehyde (10 mmol) in THF
F
3
3
2
6
13
2
+
+
Ϫ37.0 (s, 2 F); m/z 200 (M ), 127, 108, 77 and 73 (Found: M ,
00.0827. C H F Si requires M, 200.0832).
(2 ml) were dried over MS-4A for 1 h, after which TBAF was
added to the mixture. This was then stirred at room temperature
2
1
0
14
2
Ϫ1
under nitrogen for 1 h. Aq. HCl (1 mol l ; 20 ml) was then
Reaction of PhCF SiMe with carbonyl compounds
added to the solution which was stirred at room temperature for
a further 1 h. Finally, the mixture was extracted with ether
(3 × 20 ml) and the combined extracts were washed with water,
2
3
A solution of PhCF SiMe (1.0 mmol) and benzaldehyde (10
2
3
mmol) in THF (2 ml) was dried over molecular sieves (MS-4A),
after which tetrabutylammonium fluoride (TBAF; 0.1 mmol)
was added to it at room temperature under nitrogen. The result-
ing solution was stirred at room temperature for 1 h after which
dried (MgSO ) and evaporated. Purification of the residue with
4
GPC gave the corresponding alcohol 2a as a colourless oil.
Similarly, the reaction with CH (CH ) CHO was performed to
3
2 6
Ϫ1
aq. HCl (1 mol l ; 20 ml) was added and stirring continued
give 2b.
at room temperature for 1 h. The mixture was then extracted
with ether (3 × 20 ml) and the combined extracts were washed
Reaction of CF CCl with SmI in the presence of a carbonyl
3
3
2
with water, dried (MgSO ) and evaporated. Purification of the
residue with GPC gave the corresponding alcohol 1b.
compound
A solution of CF CCl (0.05 mmol) and aldehyde (0.10 mmol)
4
3
3
1
,2-Diphenyl-2,2-difluoroethanol 1b: colourless crystals from
hexane, mp 90.5–91.0 ЊC (Found: C, 71.80; H, 5.29. C H OF
2
in benzene was added to a solution of SmI (0.12 mmol) in
2
THF under nitrogen at room temperature with stirring. The
resulting solution was allowed to react at room temperature for
7 min after which it was treated with MeOH. Yields of the
1
4
12
requires C, 71.79; H, 5.16%); δ (400 MHz, CDCl ) 7.16–7.39
m, 10 H), 5.04 (t, 1 H, JH F 9.2) and 2.99 (s, 1 H); δ (100 MHz,
CDCl ) 135.8, 133.7 (t, J 25.8), 129.9, 128.5, 127.82, 127.77,
H
3
(
C
1
9
products were determined by F NMR spectroscopy using
3
1
27.71, 126.2 (t, J 5.5), 121.1 (t, J 248) and 76.7 (t, J 30.3);
PhCF3 as an internal standard. Product 3 and the recovered
6
46
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
aldehyde could not be completely separated so the following
method was employed for the isolation of 3.
difluoro-3-hydroxy-3-methylnonanoate 6d (71%) as a colourless
oil; δ (CDCl ) 4.36 (q, 2 H, J 7.2), 2.04 (s, 1 H), 1.60 (t, 2 H, J
H
3
A solution of CF CCl (1.26 mmol) and 2-phenylpropion-
aldehyde (1.1 mmol) in benzene (2 ml) was added to a stirred
8.1), 1.37 (t, 3 H, J 7.2), 1.30–1.47 (m, 8 H), 1.32 (s, 3 H) and
0.89 (t, 3 H, J 6.8); δ (CDCl ) 163.8 (t, J 33.1), 116.1 (t, J 259),
3
3
C
3
solution of SmI (2.7 mmol) in THF, and stirring continued for
74.6 (t, J 24), 62.9, 35.2, 31.7, 29.7, 22.52, 22.46, 19.7, 14.0 and
13.9; δ (CDCl ; ppm from external CF CO H) Ϫ40.4 and
2
Ϫ1
1
0 min. After treatment with aq. HCl (1 mol l ; 20 ml) the
F
3
3
2
+
mixture was extracted with hexane (3 × 20 ml) and the com-
Ϫ42.4 (ABq, J 253) (Found: M , 252.1509. C H F O requires
12 22 3 3
bined extracts were washed with water, dried (MgSO ) and
M, 252.1537).
4
evaporated. The residue was purified by column chroma-
tography with silica gel (Daisogel IR-60) using CH Cl as
eluent. The corresponding alcohol 3a (135 mg) was obtained in
The reaction of 4-tert-butylcyclohexanone gave two stereo-
isomers of ethyl 2,2-difluoro-2-(1Ј-hydroxy-4Ј-tert-butylcyclo-
hexyl)acetate 6h in an almost 1:1 ratio, the separation of which
was effected by gel-permeation chromatography. Each of the
isomers could not be separated completely, but the chemical
2
2
4
7
2
1
1
3% isolated yield based on the aldehyde; δ (400 MHz, CDCl )
H
3
.20–7.31 (m, 5 H, Ph), 4.06 (t, 1 H, J 6.8), 2.92–2.97 (m, 1 H),
.70–2.76 (m, 1 H), 2.34 (s, 1 H, OH), 2.28–2.36 (m, 1 H) and
.90–2.01 (m, 1 H); δ (100 MHz, CDCl ) 140.5, 128.6, 128.4,
1
13
19
shifts of the H, C and F NMR could be determined.
6h Isomer 1: Colourless oil; δ (CDCl ) 4.34 (q, 2 H, J 6.8),
C
3
H
3
26.3, 122.1 (q, J 285), 88.3 (q, J 31.3), 75.1, 33.0 and 31.6;
2.29–2.36 and 1.40–1.85 (m, 8 H), 2.15 (s, 1 H), 1.36 (t, 3 H, J
6.8), 0.95–1.13 (m, 1 H) and 0.87 (s, 9 H); δ (CDCl ) 163.8 (t, J
δ (376 MHz, CDCl from ex. CF CO H) 1.41 (s, 3 F); m/z 288
F
3
3
2
C
3
+
+
(
M + 2), 286 (M ), 233, 214, 177 and 69 (Found: M , 286.0118,
31.2), 116.0 (t, J 258), 73.3 (t, J 23.9), 62.8, 47.2, 32.3, 30.2,
27.4, 21.3 and 13.9; δ (CDCl ; ppm from external CF CO H)
C H F OCl requires M, 286.0139).
1
1
11
3
2
F
3
3
2
+
Similarly, 3b was obtained in 43% isolated yield, and charac-
Ϫ43.8 (s, 2 F) (Found: M , 278.1650. C H F O requires M,
14 24 2 3
8
terized by comparison with the reported spectral data.
278.1639).
6h Isomer 2: Colourless oil; δ (CDCl ) 4.35 (q, 2 H, J 6.8),
Alcohol 3c was also obtained in 26% isolated yield; δ (400
H
H
3
MHz, CDCl ), 4.08 (t, 1 H, J 8.1), 2.17 (br s, 1 H), 1.94–2.02 (m,
2.48 (s, 1 H), 2.30–2.35 and 1.43–1.83 (m, 8 H), 1.36 (t, 3 H, J
6.8), 1.07–1.17 (m, 1 H) and 0.86 (s, 9 H, s); δ (CDCl ) 163.8 (t,
3
1
H), 1.59–1.64 (m, 2 H), 1.29–1.42 (m, 9 H) and 0.89 (t, 3 H,
C
3
J 6.8); δ (100 MHz, CDCl ) 122.2 (q, J 284), 88.4 (q, J 31.2),
J 31.2), 117.4 (t, J 261), 72.5 (t, J 23.9), 62.9, 46.2, 33.7, 32.3,
27.5, 23.1 and 13.9; δ (CDCl ; ppm from external CF CO H)
C
3
7
5.9, 31.7, 31.6, 29.2, 29.1, 25.7, 22.6 and 14.0; δ [376 MHz,
F
F
3
3
2
+
CDCl –THF (1:1) from ex. CF CO H] 1.3 (s, 3 F); m/z 282
Ϫ36.0 (s, 2 F) (Found: M , 278.1717. C H F O requires M,
3
3
2
14 24 2 3
+
+
(
M + 2), 280 (M ), 262, 226 and 69 (Found: M , 280.0607.
278.1639).
C H F OCl requires M, 280.0608).
Similarly, 2-phenylpropionaldehyde gave the corresponding
two diastereoisomers 6c in the ratio of 1:1.4. These isomers
were also separated by gel-permeation chromatography; pure
isomer 2 was obtained, but isomer 1 could not be separated
from isomer 2 completely.
1
0
17
3
2
Selective preparation of the olefin 4
After CF CCl (1.0 mmol) had reacted with 2-phenylpropion-
3
3
aldehyde (0.9 mmol) in the presence of a slight excess of SmI2
2.2 mmol), additional SmI (2.0 mmol) was added to the reac-
(
6c Isomer 1: Colourless oil; δ (CDCl ) 7.25–7.34 (m, 5 H),
2
H
3
i
tion mixture with Pr OH. The resulting mixture was stirred for a
further 1 h at room temperature under nitrogen, after which it
was treated with aq. HCl (1 mol l ; 40 ml) and extracted with
4.25 (q, 2 H, J 6.8), 4.21–4.27 (m, 1 H), 3.17 (quint, 1 H, J 7.3),
2.38 (br s, 1 H), 1.41 (d, 3 H, J 7.3) and 1.32 (t, 3 H, J 6.8);
δ (CDCl ) 163.5 (t, J 33.1), 141.3, 128.8, 128.3, 127.3, 114.9 (t,
Ϫ1
C
3
hexane (3 × 20 ml). The combined extracts were washed with
J 258), 75.2 (t, J 23.9), 63.0, 40.5, 18.5 and 13.8; δ (CDCl ; ppm
F 3
water, dried (MgSO ) and evaporated. The resulting residue was
from external CF CO H) Ϫ32.0 (d, J 263, 1 F) and Ϫ47.8
3 2 F F
+
4
purified by column chromatography (Daisogel IR-60) using
hexane as eluent to give the corresponding Z-olefin, Z-4a, (38
mg; total yield from the aldehyde: 18%). Similarly, Z-4b and
Z-4c were obtained in 32 and 35% yields, respectively. New
compounds 4a and 4c were characterized from their spectral
data.
(dd, JF F 263, JH F 18.3) (Found: M , 258.1099. C H F O
13 16 2 3
requires M, 258.1067).
6c Isomer 2: Colourless oil; δ (CDCl ) 7.23–7.32 (m, 5 H),
H
3
4.20–4.34 (m, 1 H), 4.13 (q, 2 H, J 6.8), 3.15 (quint, 1 H, J 7.1),
2.39 (s, 1 H), 1.40 (d, 3 H, J 7.1) and 1.28 (t, 3 H, J 6.8);
δ (CDCl ) 163.6 (t, J 33.1), 142.9, 128.5, 127.9, 126.9, 114.7 (t,
C
3
Compound 4a: δ (400 MHz, CDCl ) 7.17–7.32 (m, 5 H, Ph),
J 258), 74.9 (t, J 23.9), 63.0, 39.6, 16.2 and 13.8; δ (CDCl ; ppm
H
3
F 3
6
.48 (t, 1 H, J 7.1), 2.77 (t, 2 H, J 7.1) and 2.65 (q, 2 H, J 7.1);
from external CF CO H) Ϫ38.5 (dd, J 266, JH F 9.2, 1 F),
3 2 F F
+
δ (100 MHz, CDCl ) 140.1, 133.3, 128.6, 128.3, 126.4, 121.9 (q,
Ϫ43.3 (dd, JF F 266, JH F 13.8) (Found: M , 258.0974. C H -
C
3
13 16
J 36.7), 120.3 (q, J 272), 38.6 and 29.7; δ (376 MHz, CDCl
F O requires M, 258.1067).
The reaction with benzophenone gave 6g as colourless crys-
F
3
2
3
+
from ex. CF CO H) 6.3 (s, 3 F); m/z 236 (M + 2), 234 (M ),
3
2
+
1
99 and 91 (Found: M , 234.0429. C H F Cl requires M,
tals from hexane, mp 82.0–82.5 ЊC (Found: C, 66.63; H, 5.26.
C H O F requires C, 66.65; H, 5.28%); δ (CDCl ) 7.53–7.55
1
1
10
3
2
34.0423).
Compound 4c: δ (400 MHz, CDCl ) 6.46 (t, 1 H, J 7.33),
1
7
16
3
2
H
3
(m, 4 H), 7.29–7.35 (m, 6 H), 4.17 (q, 2 H, J 7.0), 3.94 (s, 1 H,
OH) and 1.11 (t, 3 H, J 7.0); δ (CDCl ) 164.0 (t, J 32.1), 139.6,
H
3
2
0
2
.26–2.32 (m, 2 H), 1.45–1.48 (m, 2 H), 1.29–1.31 (m, 8 H) and
C
3
.89 (t, 3 H, J 7.08); δ (100 MHz, CDCl ) 134.7, 120.5 (q, J
128.2, 128.0, 127.3, 114.3 (t, J 265), 79.5 (t, J 23.9), 63.2 and
13.5; δ (CDCl ; ppm from external CF CO H) Ϫ33.6 (s, 2 F);
C
3
72), 121.2 (q, J 38.6), 31.7, 29.1, 29.0, 28.0, 27.6, 22.6 and 14.0;
F
3
3
2
+
δ (376 MHz, CDCl from ex. CF CO H) 6.5 (s, 3 F); m/z 230
m/z 306 (M ), 290, 261 and 231.
All the other known products 6a, 6b, 6e, 6f and 6i
F
3
3
2
+
+
13
14
14
13
13
(
M + 2), 228 (M ), 199, 143 and 69 (Found: M , 228.0871.
1
13
19
C H F Cl requires M, 228.0893).
were characterized by H, C, F NMR and mass spectroscopy.
1
0
16
3
Typical procedure for Reformatsky reaction of BrCF CO Et
2
2
References
using SmI for the isolation of the 2,2-difluoro-3-hydroxy ester
2
BrCF CO Et (1.0 mmol) and octan-2-one (0.9 mmol) in THF
2
2
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J. Chem. Soc., Perkin Trans. 1, 1997
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Paper 6/06048J
Received 2nd September 1996
Accepted 24th October 1996
1
986, 2043.
6
48
J. Chem. Soc., Perkin Trans. 1, 1997