Efficient synthesis of new fluorinated building blocks by means of hydroformylation

Article abstract of DOI:10.2533/chimia.2014.371

Hydroformylation of fluorinated alkenes is an efficient method for the preparation of fluorinated functionalized building blocks for the synthesis of biologically active target structures. In this article we summarize known hydroformylation reactions of f

Full text of DOI:10.2533/chimia.2014.371

Fluorine Chemistry
CHIMIA 2014, 68, Nr. 6 371
doi:10.2533/chimia.2014.371
Chimia 68 (2014) 371–377 © Schweizerische Chemische Gesellschaft
Efficient Synthesis of New Fluorinated
Building Blocks by means of
Hydroformylation
a
a
b
a
Lidia Fanfoni , Lisa Diab , Tomas Smejkal* , and Bernhard Breit*
Abstract: Hydroformylation of fluorinated alkenes is an efficient method for the preparation of fluorinated
functionalized building blocks for the synthesis of biologically active target structures. In this article we summarize
known hydroformylation reactions of fluorinated olefins and we add new results from our research groups.
Particular attention is paid to the remarkable influence of organofluorine substituents on catalyst activity, regio-
and stereoselectivity of the hydroformylation reaction.
Keywords: Aldehydes · Alkenes · Hydroformylation · Organofluorides · Rhodium
1
. Introduction
Fluorine is a key element commonly
used in modern pharma and agrochemical
products. As a result of the unique elec-
tronic and steric properties, fluorinated
substituents can beneficially influence the
physico-chemical properties, improve bio-
Scheme 1. Efficient synthesis of the herbicide Prosulfurone.
logical activity and modulate metabolism
of active ingredients.[ Th erefore, new
1]
technologies which allow the selective and
cost-efficient synthesis of various fluori-
nated intermediates are highly desirable.
During the last few years, particularly the
toolbox of transition metal-catalyzed reac-
tions for late stage introduction of a single
fluorine atom or small fluorinated moieties
Hydroformylation is a relatively un- 2. Substrates Fluorinated at the
derutilized reaction regarding the use of Double Bond
fluorinated olefins so far. Th is is surpris-
ing considering the fact that it could poten- 2.1 Vinyl Fluoride
tially provide synthetically highly versatile
Th e hydroformylation of vinyl fluoride
intermediates – fluorinated aldehydes. (VF) was studied by Ojima and found to
Moreover, hydroformylation is an example furnish 2-fluoropropanal (2-FPA) exclu-
(
-CF , -CF H, -SCF , …) has been expand-
of a particularly atom-economic catalytic sively irrespective of the catalyst applied
3 2 3
[2]
ing rapidly.
[7]
reaction, which is well established for the (see Scheme 2, Ta ble 1).
synthesis of bulk chemicals on a multiton oselectivity for the branched aldehyde is
Th e high regi-
An alternative strategy exploits de-
rivatization of fluorine-containing sub-
[5]
scale.
most likely caused by the electronegative
Th e aim of this article is to summarize
fluorine substituent which stabilizes the
[
3]
strates. In this context we became in-
terested in transition metal-catalyzed
reactions of fluorinated olefins which are
readily available starting materials (large
amounts of fluorinated monomers are uti-
lized by the polymer industry).
known hydroformylations of fluorinated
alkenes. Particular attention is paid to the
remarkable influence of organofluorine
substituents on catalyst activity, regio- and
stereoselectivity – all factors which are de-
cisive for possible industrial applications.
Some new results from our groups are dis-
One prominent example of this ap-
proach is the elegant synthesis of the
herbicide Prosulfuron using 3,3,3-trifluo-
ropropene in a one-pot reaction sequence
of a palladium-catalyzed Heck reaction
[6]
cussed as well.
Scheme 2. Regioselective hydroformylation of
vinyl fluoride.
[
4]
followed by hydrogenation (Scheme 1).
Table 1. Results of hydroformylation of vinylfluoride.
a
Entry
Cat.
Rh (CO)
CO/H [atm] Substr/Metal T [°C]
l/b
yield
2
[
%]
81
52
46
30
a
b
1
2
3
4
68
68
2000
500
100
100
80
80
0/100
0/100
0/100
0/100
*
Correspondence: Prof. Dr. B. Breit , Dr. T. Smejkal
4
12
a
Institut für Organische Chemie
HRh(CO)(PPh3)3
Ru (CO)
Albert-Ludwigs-Universität Freiburg
Albertstrasse 21, 79104 Freiburg i. Bg., Germany
E-mail: bernhard.breit@chemie.uni-freiburg.de
68
80
3
12
8
b
Syngenta Crop Protection Münchwilen AG
Co (CO)
110
100
2
Schaffhauserstrasse, CH-4332 Stein, Switzerland
E-mail: tomas.smejkal@syngenta.com
a
Conditions: vinyl fluoride 20 mmol, toluene, 18h. isolated product after distillation.

372 CHIMIA 2014, 68, Nr. 6
Fluorine Chemistry
adjacent rhodium-carbon bond formed
during the alkene hydrometalation step.
2
.2 1,1-Difluoroethene
Th e first and only evidence of a suc-
cessful
,1-difluorothene as the substrate dates
back to a German patent from Hoechst in
hydroformylation
applying
Scheme 3. Cobalt-catalyzed hydroformylation
of 1,1-difluoroethene.
Scheme 4. Rhodium-catalyzed hydrofor-
mylation of 1,1-difluoroethene.
1
[
8]
1
953. With Co (CO) as the precatalyst
2 8
under harsh reaction conditions (180 atm
of syngas and 120–140 °C reaction tem-
perature) the main reaction product ob-
served was 3,3-difluoro-1-propanol which
is formed through hydrogenation of the
corresponding aldehyde, with a conversion
of 49% (Scheme 3). Th e aldehyde hydrate
of 3,3-difluoropropanal was found as a by-
product.
Scheme 5. Best rhodium catalyst for hydroformylation of 1,1-difluoroethene.
Since rhodium catalysts show an in-
trinsic higher activity and chemo-
selectivity in the hydroformylation of
olefins we speculated that it should
be possible to develop a hydrofor-
mylation of 1,1-difluoroethylene under
milder reaction conditions (Scheme 4).
However, after screening of a large
number of rhodium complexes together
with a series of monodentate and bidentate
ligands with different steric and electronic
properties as well as exploiting a range of
reactionconditionsonlyverylowhydrofor-
mylation activity was observed. Notably,
the best result in terms of conversion and
regioselectivity was obtained applying the
electron-rich para-anisylphosphine ligand.
With this catalyst system and the condi-
tions indicated in Scheme 5 the hydrate
of the linear aldehyde was obtained (10%
–1
conversion, TO F = 0.22 h , TO N = 5.2).
In order to understand why the hydro-
Fig. 1. Comparison between the energy of the transition states in ethylene and 1,1-difluoroethene
formylation of this particular substrate hydroformylation considering rhodium catalyst bearing PPh as modifying ligand (phenyl substitu-
3
is so difficult we performed high level ents omitted for clarity).
ab initio calculations (CCSD( T) /aug-cc-
pwCVD(Q)Z//BP86/aug-cc-pV TZ ) of the
Scheme 6.
Hydroformylation of
tetrafluoroethylene.
rate and selectivity determining energetic
span of the hydroformylation reaction.
[
9]
For triarylphosphine-modified rhodium
catalysts this is the energy difference start-
ing from the catalyst resting state, the
rhodium-dicarbonyl hydrido diphosphine
complex to the transition state of the hy-
drometalation step. Hence the energetic
span for ethylene as well as for 1,1-difluo- of tetrafluoroethylene has been reported markable dependence of the regioselectiv-
roethylene were calculated and compared to occur under harsh reaction conditions ity of this hydroformylation on the nature
(
Fig. 1).
Indeed, it was found that the ∆∆G
for these two substrates is 4.74 kcal/mol. hydrogenation of the corresponding alde- selectively, using dicobalt octacarbonyl a
(Scheme 6). Also here the product is the of the catalyst was found. While rhodium
alcohol which is derived from a subsequent catalysts furnished the branched aldehyde
T
S
[
8]
In other words, the hydroformylation of hyde. However, the isolated yield was regioselectivity switch in favor of the lin-
,1-difluoroethene is 10000 times slower low (7%).
ear aldehyde was noted. With a chiral plat-
1
than that of ethylene. Presumably, the pres-
ence of a ligand able to raise the electronic
density at the metal might lower the energy 3. Substrate Fluorinated alpha to
of this transition state facilitating the reac- the Double Bond
tion.
3
.1 3,3,3-Trifluoropropene (TFP)
2
.3 1,1,2,2-Tetrafluoroethene
Th e hydroformylation of TF P was first
Scheme 7. Hydroformylation of 3,3,3-trifluoro-
A cobalt-catalyzed hydroformylation studied by Ojima et al.[ Interestingly, a re- propene.
7]

Fluorine Chemistry
CHIMIA 2014, 68, Nr. 6 373
inum catalyst the branched aldehyde was Table 2. Effect of different precatalysts and ligands in the hydroformylation of TFP.
obtained in good enantioselectivity (ee >
9
0%). However, the regioselectivity was
[10]
rather low (Scheme 7).
O
O
PPh 2
Ph 2
Building on these earlier experiments
with the goal to identify more active and
selective catalysts we screened a series
of different precatalysts and ligands in
O
O
N PPh
2
P
PPh 2
P
Ph
H
2
Xan tphos
6-DPPo n
Di op
a
Entry Catalyst
CO/H Substr/Metal T [°C] time
l/b
2
the hydroformylation of TF P ( Ta ble 2).
[
bar]
[h]
24
20
Our self-assembling 6-diphenylphosphi-
[
11]
1
Rh(CO) acac/6-DPPon
20
1000
1200
70
80
5/95
3/97
nopyridone ligand (6-DPPon) together
2
b
with Rh(CO) acac furnished an extremely
2
Rh (CO) /PPh
3
110
2
6
16
competent catalyst (entry 1). Th is com-
3
PtCl (Xantphos)/SnCl
96
130
45
100
100
100
50
80
48
4
96/4
71/29
96/4
2
2
plex delivered the branched aldehyde with
nearly perfect regioselectivity in excellent
yield. In addition, conditions much milder
b
4
PtCl (diop)/SnCl
100
100
100
2
2
5
Co (CO)
24
20
2
8
(
70 °C, 20 bar) and very low catalyst load-
b
6
Co (CO)
130
93/7
2
8
ings could be used. Interestingly, when
a
b
we modified the platinum system with Conditions: ligands 10%, toluene. Conversion > 90%. determined by HRGC. ref. [7].
Xantphos ligand (entry 3) high regioselec-
tivity in favour of the linear aldehyde was
noted.
All fluoro-aldehydes obtained in the
F3C
F3C
COOH
NH 2
H2N
COOH
hydroformylation of TF P, described above,
AcNH 2
O, H2
Co 2 (CO)
AcNH
2
C
CO, H2
80%
7
7
%
may serve as excellent intermediates for
8
Co 2 (CO)
8
[12]
C
O Et
CF 3
the synthesis of fluoro-amino acids and
various other useful heterocycles such as
substituted 2-aminothiophene-3-carboxyl-
2
N
CF 3
O Et
S , Et N
S
1) C
H
Cl 2 CO 2 Et
8
3
S
L
D
A, THF
O
F3C
F3C
D
MF, 6
7
%
H2N
C
2
H2N
N
S
CO 2 Et
1
2
)
[13]
O
ate (1 in Scheme 8) or 2-aminothiazole
4
H2N
NH 2
derivatives (2, 3 and 4 in Scheme 8).[14]
1) Br
2,DC
M
30%
2
)
1
) C
H
Cl 2 CO 2 Et
S
Considering the strong regio-direct-
ing effect of an olefinic trifluoromethyl
substituent in the rhodium-catalyzed hy-
droformylation, 1,1-disubstituted olefins
Na/Me
O
H, Et 2O
CF 3
H2N
N
H2
2
) S
4
0
%
S
N
2
H2N
NH 2
H2N
CF 3
(
Scheme 9) represent an interesting regi-
S
oselectivity problem. Further, if a chiral
ligand were used, both reaction pathways
could provide an asymmetric access to
valuable trifluoromethylated aldehyde
building blocks.
CO 2 Me
N
3
H2N
Scheme 8. Transformation of fluorinated aldehydes to amino acids and hetereocycles.
In general, the formation of linear prod-
ucts from 1,1-disubstituted olefins should
be favored for steric reasons (Keulemans’
Scheme 9.
Hydroformylation
of 2-substituted
3,3,3-trifluoropro-
penes.
[
5b,15]
rule).
On the other hand, the Buchwald
group has shown that this effect may be
overcome if R is another regio-directing
substituent such as R= OAc (Scheme 10).
3
.2 3,3,3-Trifluoroprop-1-en-2-yl
1) oxidatio
) hydrolysis
3) crystallizatio
n
0
.4 mol% [Rh(acac)(CO) 2]
2
H
[
16]
acetate
0.6 mol% (R,R,S,S)-Du Phos
a
n
n
OH
F3C OAc
Me
F3C
Me
O
P
P
H
tBu
R,R,S,S)-Duanphos
Employing a rhodium(ꢀ) catalyst in the
presence of the chiral phosphine ligands
F3C
OAc
C
O
O
H
C
O/H 2 (1:1), 31 bar
tBu
tolu e, 110°C, 18h
en
9
2
% e
e
5
2
% (over 2steps)
(
3
,3,3-trifluoroprop-1-en-2-yl acetate could
>
9
9
% e
e
be hydroformylated with good regio- and
enantioselectivity. Among the different Scheme 10. Enantioselective hydroformylation of 3,3,3-trifluoropropenyl acetate.
chiral ligands screened, DuanPhos provid-
ed the best results for branched aldehyde
in terms of regioselectivity and enantio-
selectivity.
Scheme 11.
Hydroformylation of
α-CF -styrene-type
3
substrates.
3
.3 α-CF -Styrene-type Substrates
3
First we decided to study the regiose-
lectivity of hydroformylation of a variety
of α-CF styrene substrates by screening a
3
series of different phosphine ligands with
Rh(acac)(CO) as the precatalyst (Scheme
Regioselectivities were in general high monodentate triphenylphosphine afforded
2
1
1, Ta ble 3). Th e best results are summa-
for the linear aldehyde when Xantphos was low regioselectivities for most substrates.
rized in Ta ble 3.
chosen as the rhodium ligand. In contrast, Only the 3,5-dichlorophenyl substrate 6

374 CHIMIA 2014, 68, Nr. 6
Fluorine Chemistry
gave high regioselectivity in favor of the Table 3. Results of hydroformylation of α-CF -styrene-type substrates.
3
branched aldehyde. Accordingly, it is now
possible to produce both aldehydes start-
ing from 6 in a regiocomplementary man-
ner ( Ta ble 3, entries 2 and 3). Encouraged
by the results obtained, an asymmetric
version of the reaction was investigated
for this substrate. From a screening of
a
a
Entry
Substrate
Ligand
Conv. [%]
l/b
b
1
5
Xantphos
33
100/0
2
6
6
7
7
8
8
9
PPh
100
100
66
9/91
85/15
50/50
96/4
3
c
3
4
5
6
7
8
9
0
Xantphos
PPh3
2
1 commercially available chiral ligands
Xantphos
PPh3
54
(
R,R)-Ph-BPE turned out to be best both
in terms of conversion, regio- and enantio-
selectivity (Scheme 12).
86
40/60
92/8
Xantphos
Xantphos
80
61
92/8
3
.4 (E)-4,4,4-Trifluorobut-2-en-1-ol
α- Tr ifluoromethyl-γ-butyrolactones
10
PPh
88
40/60
3
are particularly interesting building blocks
for the synthesis of compounds having bio-
1
10
Xantphos
88
92/8
[17]
[18]
Conditions: Rh(acac)(CO) 1 mol%, PPh : 10 mol%, Xantphos: 5 mol%, CO/H (1:1) 40 bar, toluene,
2 3 2
0 °C, 24h. determined by H or F NMR analysis. CO/H (1:1) 65 bar, 120°C. 0.15mol % [Rh].
logical activity and for material ap-
plications. Several reports have described
the synthesis of 2-(trifluoromethyl)buty-
rolactone (12),[ but all of these required
multiple steps or afforded the product in
low yield. Here we report an efficient two-
step preparation of 12 starting from the
a
1
19
b
c
9
2
19]
Scheme 12.
Enantioselective
hydroformylation of
α-CF -styrene-type
3
substrates.
CF -substituted allylic alcohol (Scheme
3
1
3). Hence, a completely regioselective
hydroformylation furnished the lactol 11.
A subsequent oxidation furnished lactone
1
2 in a high overall yield.
Scheme 13.
3
.5 (E)-Ethyl-4,4,4-trifluorobut-2-
enoate
In(E)-ethyl-4,4,4-trifluorobut-2-enoate
Regioselective hy-
droformylation of
(E)-4,4,4-trifluorobut-
2-en-1-ol.
two electron-withdrawing groups (CF3
and ester) compete to direct the aldehyde
installation in the direct neighbourhood.
Interestingly and unexpectedly, good re-
gioselectivity for the 2-position was found
employing a rhodium(ꢀ)/Biphephos cata-
lyst to furnish aldehyde 13 which exists
preferentially in its enolic form stabilized
[
20]
by the intramolecular hydrogen bond
Scheme 14). Th is result suggests that an
(
ester group has a stronger directing effect
than a CF substituent for the rhodium-
3
catalyzed hydroformylation.
4. Conclusion and Outlook
It is well recognized that the introduc- Scheme 14. Regioselective hydroformylation of (E)-ethyl-4,4,4-trifluorobut-2-enoate.
tion of fluorine into organic substrates of-
ten brings about unique properties in biol-
ogy. Th e same is true for the reactivity of
5. Experimental
coated with silica gel (MERCK, 60F254),
which were visualized by the quenching of
All reactions were carried out in ov- UV fluorescence (λmax = 254 nm), and/
fluorinated substrates in transition-metal
catalysis. In this article we have illustrated,
how the replacement of H with F in a close en-dried glassware under an argon atmo- or by KMnO solution. Hydroformylation
4
distance to the reaction site influences both sphere (Argon 5.0 from Sauerstoffwerke reactions for ligand screening were per-
the regio- and stereoselectivity of hydro- Friedrichshafen) using standard Schlenk formed in an Endeavor parallel autoclave
formylation reactions and how this effect techniques. All reagents were purchased with eight reaction vessels from Argonaut
may be used for the selective preparation from commercial sources and used as re- Te chnologies. Hydroformylation reactions
of fluorinated compounds. In the future we ceived.All solvents were dried and distilled were performed in stainless steel auto-
expect to see more applications of hydro- by standard procedures. Chromatographic claves (autoclave volume: 100 ml) from
formylation in the synthesis of enantiopure purification of products was accomplished Roth using a glass inlet. Gases: carbon
®
fluorinated building blocks and as a key using Machery-Nagel silica gel 60 (230– monoxide 3.7, hydrogen 4.3 (1:1, Messer-
synthetic step toward more complex mo- 400 mesh). Th in layer chromatography
lecular targets.
was performed on aluminium plates pre- (NMR) spectra were acquired on a Bruker
Griesheim). Nuclear magnetic resonance

Fluorine Chemistry
CHIMIA 2014, 68, Nr. 6 375
Avance 400 spectrometer (400 MHz and 1:1, 20–60 bar), moved to the aluminium propyl)thiazole-4-carboxylate (3): To 200
1
13
1
00.6 MHz for H and C respectively), block and heated (25–150 °C) under stir- mg of 3- TF MPA (1.58 mmol) dissolved
on a Varian Mercury (300 MHz and 75.5 ring for 24 h. After reaction the autoclave in Et O, NaOMe (298 mg, 5.53 mmol)
2
1
13
MHz for H and C respectively) and on a was cooled to –90 °C and then depressur- and ethyl-dichloroacetate (220 µL, 1.80
Bruker DXR 250 (125 MHz and 235 MHz ized.A sample of the crude mixture was di- mmol) were added at 0 °C. Th e mixture
for H and F respectively). All H NMR luted with C D in a NMR tube and directly was stirred at 0 °C and after 2 h quenched
spectra are reported in parts per million analyzed by F NMR. All the NMR tubes by addition of saturated NaCl. Th e aque-
ppm) downfield of TM S and were mea- were carried and stored into a dry-ice box ous phase was extracted with Et O, then
sured relative to the signals at 7.26 ppm before F NMR analysis. In the most cases the combined organic phases were dried
CDCl ) or 7.16 ppm (C D ). All C NMR the hydroformylation was not regioselec- over MgSO and evaporated. Th e residue
1
19
1
6
6
1
9
(
2
19
13
(
3 6 6
4
spectra were reported in ppm relative to re- tive resulting in a mixture of linear and was dissolved in MeOH and thiourea (120
sidual CDCl (77.16 ppm) or C D (128.06 branched aldehyde, hydrogenated product mg,1.58 mmol) was added, the reaction
3
6
6
1
3
ppm). All C NMR spectra were reported and linear hydrate derived from water ad- mixture was refluxed for 4 h then stirred
in ppm relative to the internal standard dition to the linear aldehyde.
at r.t. over night. Th e product was purified
3,3-Difluoropropanal (linear alde- by crystallization from EtOH/H O. Yield
1
C F (-164.9 ppm). Data for H NMR are
described as follow: chemical shift (ppm), hyde): F NMR (C D ): δ –118.40 (m, 40%. H NMR (CDCl ): δ 1.89 (m, 1H,
multiplicity (s, singlet; d, doublet; t, triplet; J = 2.9 Hz, J = 16 Hz, J = 55 Hz).
6
6
2
19
1
6
6
3
4
3
2
-CH CF ), 2.18 (m, 1H, -CH CF ), 2.39 (m,
HF
HF
HF
2
3
2
3
q, quartet; quint, quintet; m, multiplet; b,
1,1-Difluoroethane
(hydrogenated 2H, -CH CH -), 3.83 (s, 3H, -OCH ), 5.86
2
2
3
19
broad signal; pseudo-q, pseudo quartet), prod.): F NMR (C D ): δ –111.09 (dq, (b, 2H, -NH2).
6
6
3
2
integration, coupling constant (Hz), attri- J = 18 Hz, J = 45 Hz).
Ethyl-2-amino-5-(1,1,1-trifluoropran-
HF
HF
1
3
bution. Data for C NMR spectra are de-
2,2-Difluoropropanal (branched al- 2-yl)thiazole-4-carboxylate (4): To a so-
19
scribed in terms of chemical shift (ppm). dehyde): F NMR (C D ): δ –105.74 (q, lution of ethyl-dichloroacetate (220 µL,
6
6
3
High resolution mass spectra (HRMS) JHF= 15 Hz).
8200
1.80 mmol) in TH F at –78 °C, LDA (850
ture stirred at 0 °C for 15 min. 200 mg of
were obtained on a Finnigan MAT
3,3-Difluoropropane-1,1-diol (hydrat- µL, 6.32 mmol) was added and the mix-
19
instrument (EI: 70 eV; CI/NH : 110 eV). ed): F NMR (C D ): δ –103.20 (m).
3
6
6
Chiral HPLC was performed on a MERCK
3,3-Difluoropropane-1,1-diol was ob- 2- TF MPA (1.58 mmol) was then added to
tained regioselectively in 10% conversion the solution and the mixture stirred for 1.5
HI TA CHIHPLCapparatus(pump:L-7100,
UV detector: D-7400, oven: L-7360; col- ( TO F = 0.22 h , TO N = 5.23). Conditions
umns: Chiralpak AD-3, OD-3, AD-H and 1,1-difluoroethene/Rh/P(4-OMe-Ph)3 Et O and washed with NaCl. Th e organic
–
1
h at 0 °C. Th e reaction was diluted with
2
OD-H 25 cm 4.6 cm, DAICEL).
50/1/10.
phase was dried over MgSO and evapo-
4
rated. Th e residue was dissolved in MeOH
and thiourea (150 mg,1.89 mmol) was add-
ed, the reaction mixture was refluxed for 2
5
.1 General Procedure
5.2 General Procedure
for Hydroformylation of
3,3,3-Trifluoropropene
for Hydroformylation of
1
,1-Difluoroethene
Stock solutions of 1,1-difluoroethene
h then stirred at r.t. over night. Th e product
Th e autoclave was closed and purged
was purified by crystallization from EtOH/
1
were prepared using a particular gradu- with argon. In an oven-dried Schlenk-flask H O. Yield 30%. H NMR (CDCl ): δ 1.32
2
3
ated Schlenk flask and bubbling the fluo- a solution of the ligand in freshly dried sol- (d, 3H, J= 7 Hz, -CHCH ), 1.35 (t, 3H, J=
3
rinated gas into 10 mL of distilled toluene vent was prepared underAr atmosphere.T o
7.1 Hz, -CH CH ), 4.31 (m, 1H, -CHCH ),
2
3
3
or TH F at –90 °C (bp: 1,1-difluoroethene
this solution the metal complex was added 4.35 (q, 2H, J= 7.1 Hz, -CH CH ).
–85°C). C F (0.1 M) was used as in- and the mixture was stirred for 5 min. 2
2 3
=
6 6
ternal standard both for determining the mL of TF P were condensed in a flask at
5.3 General Procedure for the
concentration of the gas within the stock –78 °C and added to the cooled precata- Preparation of the α-CF -Styrene-
3
solution and the conversion of the sub- lyst solution (–78 °C) via cooled cannula type Substrate 7, 8, 10 from the
1
9
[21]
strate after hydroformylation by F NMR and Ar flux. Th e whole reaction mixture
Parental Aryl Ketones
technique. Th e final concentration of the
was transferred under Ar into the cooled
In a dry schlenk flask under Ar, to a
substrate stock solution was between 0.5 autoclave and pressurized with CO/H gas- suspension of KF (227 mg, 3.9 mmol) and
2
and 1.2 molar and remained constant dur- mixture (1:1) and placed into a pre-heated 18-crown-6 (13 mg, 0.05 mmol) in dry
ing at least 5 days at low temperature (–80 metal block. At the end of the reaction the DMF (1 mL), MsCl (200 µL, 2.5 mmol)
°
C) storage. Hydroformylation reactions crude mixture was analyzed by CG and was added dropwise under stirring. After
were carried out by using 1 mL of the sub- NMR analysis (internal standard 1,3,5-tri- 30 min the aryl ketone (1 mmol) was slow-
strate stock solution, [Rh(acac)(CO) ](1–2 methylbenzene). Distillation at ambient ly added and the mixture heated to 110 °C
2
mol%) as catalyst precursor and a series pressure gave the pure aldehydes.
of 16 different monodentate, bidentate and 4,4,4-Trifluorobutanal (3-TFMPA): the mixture between H O (2 mL) and
for 5 h. Workup consisted in portioning
2
self-assembling ligands typically used in Th e linear product was obtained in 96%
Et O (3 mL), after extraction of the aque-
2
hydroformylation reactions. Rhodium/car- regioselectivity (bp 94–95 °C, 1 atm). ous phase twice with Et O, the combined
2
bene systems and different metal complex- Conditions TF P/Pt(COD)Cl /Xantphos/
organic phases were washed with satu-
2
es such as [Ru (CO) ], [Pt(COD)Cl ] and SnCl 100/1/2/2, CO/H (1:1) 96 bar, tolu- rated NaHCO and dried over MgSO . Th e
3
12
2
2
2
3
4
Co (CO) were also tested as precatalyst.
ene (5 M), 80 °C, 48 h.
Th e rhodium precatalyst was prepared 3,3,3-Trifluoro-2-methylpropanal separated by column chromatography (PE/
by mixing the precursor and the modify- (2-TFMPA): Th e branched product was
Et O 99:1, 1% gradient Et O).
product and the unreacted aryl ketone were
2
8
2
2
ing ligand in an oven-dried Schlenk flask obtained in 95% regioselectivity (bp 66 °C,
under Ar. Th e mixture was transferred into 1 atm). Conditions TF P/Rh(acac)(CO) /6-
1-(1,1,1-Trifluoroprop-2-en-2-yl)-4-
methoxybenzene (7): 62% yield (125 mg,
an autoclave under Ar. Th e autoclave was DPPon1000/1/5, CO/H (1:1) 20 bar, tolu- 0.62 mmol) from 2,2,2-trifluo-1-(4-me-
2
2
then cooled to –90 °C with a EtOH/N2liq ene (4 M), 70 °C, 24 h.
bath and before adding 1 mL of the stock Analytical data of the aldehydes match H NMR (C D ): δ 3.23 (s, 3H, -OCH ),
thoxyphenyl)ethanone (200 mg, 1 mmol).
1
6
6
3
[7]
solution theAr flux was stopped. Th e auto-
those reported previously.
5.20 (q, 1H, J= 1.7 Hz, =CH ), 5.55 (q, 1H,
2
clave was pressurized with syngas (CO/H2
Methyl-2-amino-5-(3,3,3-trifluoro- J= 1.3 Hz, =CH ), 6.64 (m, 2H, mH-Ph),
2

376 CHIMIA 2014, 68, Nr. 6
Fluorine Chemistry
1
9
7
.23 (md, 2H, oH-Ph). F NMR (C D ): 71% yield after column chromatography mmol): 80% conversion, the linear prod-
6 6
δ -64.38 (s). MS-CI (m/z): [M] 202.1, (PE/Et O). Conditions: 6/Rh/Xantphos uct was obtained in 92% regioselectivity.
2
[
M+H] 203.1.
600/1/7, CO/H (1:1) 40 bar, toluene (1.2 Conditions: 8/Rh/Xantphos 100/1/5, CO/
2
1 1
1
-Chloro-4-(1,1,1-trifluoroprop-2-en- M), 90 °C. H NMR (C D ): δ 1.90 (m, H (1:1) 40 bar, toluene, 90 °C. H NMR
6
6
2
2
-yl)benzene (8): 60% yield (117 mg, 0.57 1H,-CH -),2.11 (ddd, 1H, J= 0.68, 8.9, (C D ): δ 2.44 (ddd, J= 1.05, 9.1, 18.1 Hz,
2
6
6
mmol) from 1-(4-chlorophenyl)-2,2,2-tri- 18.2 Hz, -CH -), 3.45 (dd, 1H, J= 4.6, 18.7 1H,-CH -),2.29 (dd, J= 4.7, 18.3 Hz, 1H,
2
2
1
fluoethanone (208 mg, 1 mmol). H NMR Hz, -CHCF ), 6.87 (m, 2H, oH- Ph), 6.94 -CH ), 3.57 (m, 1H,-CHCF ), 6.69 (m, 2H,
3
2
3
(
(
C D ): δ 5.02 (q, 1H, J= 2 Hz, =CH ), 5.47 (t, 1H, J= 1,9 Hz pH- Ph), 8.71 (m, 1H, mH-Ph),7.11 (m, 2H, oH-Ph), 8.84 (m,1H,
6
6
2
13
q, 1H, J= 1.6 Hz, =CH ), 6.64 (m, 2H, -CHO). C NMR (C D ): δ 42.3 (m), 42.7 -CHO).
2
6
6
13
mH-Ph), 6.86 (m, 2H, oH-Ph). C NMR (q, J= 29 Hz), 127.7, 129.1, 135.6, 137.6
2-(4-Chlorophenyl)-3,3,3-trifluoro-
1
9
(
1
C D ): δ 120.4, 120.8 (q, J= 6 Hz), 128.3, (q, J= 2 X Hz), 195.0. F NMR (C D ): δ 2-methylpropanal (branched aldehyde):
6
6
6
6
19
28.9, 129.0, 130.3, 131.1, 132.9. F NMR -69.7 (d, J= 7.05 Hz). MS-CI (m/z): [M-H] Starting from 1-chloro-4-(1,1,1-trifluoro-
(
2
C D ): δ -64.52 (s). MS-CI (m/z): [M+H] 270, 272.
prop-2-en-2-yl)benzene (8) (86 mg, 0.2
2-(3,5-Dichlorophenyl)-3,3,3- mmol): 86% conversion, the branched
6
6
07.1, [M-F] 188.1.
1
-Fluoro-3-(1,1,1-trifluoroprop-2-en- trifluoro-2-methylpropanal
(branched product was obtained in 60% regioselectiv-
2
-yl)benzene (10): 30% yield (59 mg, 0.31 aldehyde): Starting from 1,3-dichloro- ity. Conditions: 8/Rh/ PPh 100/1/10, CO/
3
1
mmol) from 1-(4-chlorophenyl)-2,2,2-tri- 5-(1,1,1-trifluoroprop-2-en-2-yl)benzene H (1:1) 40 bar, toluene, 90 °C. H NMR
2
1
fluoethanone (200 mg, 1 mmol). H NMR (6) (144 mg, 0.6 mmol): 100% conversion, (C D ): δ 1.13 (s, 3H,-CH ), 6.70 (m, 2H,
6
6
3
(
5
C D ): δ 5.04 (q, 1H, J= 1.7 Hz, =CH ), the branched product was obtained in 91% mH-Ph), 6.94 (m, 2H, oH-Ph), 9.04 (q,1H,
6
6
2
.47 (q, 1H, J= 1.3 Hz, =CH ), 6.72 (m, 2H, regioselectivityand80%yieldaftercolumn J= 2.5 Hz, -CHO).
2
Ph), 6.94 (m, 2H, Ph).
4,4,4-trifluoro-3-(3-(trifluoromethyl)
2
5
.4 General Procedure for
toluene, 90 °C. Under the same condition from 1-(trifluoromethyl)-3-(1,1,1-trifluo-
the up-scaled reaction starting from 1g of roprop-2-en-2-yl)benzene (9) (100 mg, 0.4
6 (4.14 mmol) gave the branched aldehyde mmol): 61% conversion, the linear prod-
Hydroformylation Reactions
Th e autoclave was closed and purged
with argon. In an oven-dried Schlenk flask in 75% regioselectivity and 70% yield. uct was obtained in 92% regioselectivity.
a solution of the ligand (10 mol% in case Th e branched product was also ob- Conditions: 9/Rh/Xantphos 100/1/5, CO/
1
of monodentate ligands, 5 mol% in cases tained regioselectivity and with ee% = H (1:1) 40 bar, toluene, 90 °C. H NMR
2
of bidentate ligands) in freshly dried tolu- 59% by using the asymmetric ligand (R,R)- (C D ): δ 2.05 (ddd, 1H, J= 0.69, 8.9, 18.8
6
6
ene or TH F (0.2 M) was prepared under
Ph-BPE. Conditions: 6/Rh/(R,R)-Ph-BPE Hz, -CH -), 2.24 (dd, 1H, J= 4.7, 18.5 Hz,
2
Ar atmosphere. To this solution [Rh(acac)
100/1/5, CO/H (1:1) 40 bar, toluene, 90 -CH ), 3.62 (m, 1H,-CHCF ), 6.78 (pseu-
2
2
3
1
5
6
(
CO) ] (1.0 mol%) was added and the mix- °C. H NMR (C D ): δ 0.95 (s, 3H,-CH ), do-t, 1H, H -Ph),7.05 (pseudo-d, 1H, H -
4 2
2
6
6
3
ture was stirred for 5 min. Th e substrate
6.95 (t, 1H, J= 1.8 Hz, pH-Ph), 6.99 (m, Ph), 7.19 (m, 1H, H -Ph), 7.40 (s, 1H, H -
1
9
was then added to the catalytic mixture and 2H, oH-Ph), 8.85 (q,1H, J=2.4 Hz, -CHO). Ph), 8.73 (m, 1H, -CHO). F NMR (C D ):
6
6
1
3
stirred for another 2–3 min. Th e whole re- C NMR (C D ): δ 14.4 (m), 58.7 (q, J= 24 δ -69.8 (d, J= 9.4 Hz,-CHCF ), -62.1 (s,
6
6
3
action mixture was transferred under Ar Hz), 127 (m), 129.6, 132.4, 132.5, 135.9 -Ph-CF ).
into a glass vial containing a stirring bar, (m), 136.1, 192.1 (m). F NMR (C D ): δ
3
1
9
3,3,3-trifluoro-2-(3-(trifluoromethyl)
phenyl)-2-methylpropanal (branched alde-
6
6
then the vial was closed with a septum and -70.6 (s). MS-CI (m/z): [M-H] 270, 272.
equipped with a needle to allow for gas
exchange. Th e glass vial was put into the
steel autoclave. Th e autoclave was sealed 1-(1,1,1-trifluoroprop-2-en-2-yl)-4-me- (9) (100 mg, 0.4 mmol): 37% conversion,
4,4,4-Trifluoro-3-(4-methoxyphenyl) hyde): Starting from 1-(trifluoromethyl)-
butanal (linear aldehyde): Starting from 3-(1,1,1-trifluoroprop-2-en-2-yl)benzene
and purged three times with 5 bar of the thoxybenzene (7) (70 mg, 0.34 mmol): the branched product was obtained regi-
CO/H gas-mixture (1:1), then pressurized 54% conversion, the linear product was ob- oselectivity and with ee = 49% by using
2
(20–65 bar) and placed into a pre-heated tained in 96% regioselectivity. Conditions: the asymmetric ligand (R,R)-Ph-BPE .
metal block (80–90 °C). Th e reaction mix- 7/Rh/Xantphos 100/1/5, CO/H (1:1) 40 Conditions: 9/Rh/(R,R)-Ph-BPE 100/1/5,
2
1
1
ture was stirred at the given temperature bar, toluene, 90 °C. H NMR (C D ): δ CO/H (1:1) 40 bar, toluene, 90 °C. H
6
6
2
for 24 h, then evaporated and directly ana- 2.49 (m, 2H,-CH -), 3.25 (s, 3H, -OCH ), NMR (C D ): δ 1.07 (s, 3H,-CH ), 6.74
2
3
6
6
3
1
19
5
lyzed via H or F NMR without further 3.68 (m, 1H,-CHCF ), 6.89 (m, 2H, mH- (pseudo-t, 1H, H -Ph),6,98 (pseudo-d, 1H,
3
6
4
purifications.
Ph),7.12 (m, 2H, oH-Ph), 8.95 (m,1H, H -Ph), 7.20 (m, 1H, H -Ph), 7.52 (s, 1H,
,4,4-Trifluoro-3-phenylbutanal (lin- -CHO). F NMR (C D ): δ -70.2 (d, J= H -Ph) 8.95 (q,1H, J= 4 Hz, -CHO). F
19
2
19
4
6
6
ear aldehyde): Starting from 1-(1,1,1-tri- 11.7 Hz).
fluoroprop-2-en-2-yl)benzene (5) (33.3
NMR (C D ): δ -70.01 (s,-CHCF ), -62.4
6
6
3
3,3,3-Trifluoro-2-(4-methoxyphenyl)- (s, -Ph-CF3).
mg, 0.2 mmol): 33% conversion, the lin- 2-methylpropanal (branched aldehyde):
4,4,4-trifluoro-3-(3-fluorophenyl)bu-
ear product was obtained regioselectively. Starting from 1-(1,1,1-trifluoroprop-2-en- tanal (linear aldehyde): Starting from
Conditions: 5/Rh/Xantphos 100/1/5, CO/ 2-yl)-4-methoxybenzene (7) (70 mg, 0.34 1-fluoromethyl-3-(1,1,1-trifluoroprop-
1
H (1:1) 65 bar, toluene, 120 °C. H NMR mmol): 66% conversion, the branched 2-en-2-yl)benzene (10) (30 mg, 0.26
2
(
1
(
CDCl ): δ 3.12 (m, 2H,-CH -), 4.03 (m, product was obtained in 50% regioselectiv- mmol): 88% conversion, the linear prod-
3
2
H,-CHCF ), 7.10-7.24 (m, 5H, Ph), 9.69 ity. Conditions: 7/Rh/PPh 100/1/10, CO/ uct was obtained in 92% regioselectivity.
3 3
13 1
pseudo-q,1H, -CHO). C NMR (CDCl ): H (1:1) 40 bar, toluene, 90 °C. H NMR Conditions: 10/Rh/Xantphos 100/1/5, CO/
3 2
19 1
δ 43.3, 43.5, 120.5 (q, J= 6 Hz), 197.4. F (C D 400MHz): δ 1.30 (s, 3H,-CH ), 3.23 H (1:1) 40 bar, toluene, 90 °C. H NMR
NMR (CDCl ): δ -70.1 (d, J= 13.2 Hz).
6
6,
3
2
(s, 3H, -OCH ), 6.99 (m, 2H, mH- Ph), (C D ): δ 2.19 (m,2H,-CH -), 3.60 (m,
3
3
6
6
2
3
-(3,5-Dichlorophenyl)-4,4,4- 7.12 (m, 2H, oH-Ph), 9.19 (q,1H, J= 2.6 1H,-CHCF ), 6.70-7-15 (m, 4H, Ph), 8.80
3
19
trifluorobutanal(linearaldehyde): Starting Hz, -CHO). F NMR (C D ): δ -70.2 (s).
from 1,3-dichloro-5-(1,1,1-trifluoroprop-
2
1
(m,1H, -CHO).
6
6
3 - ( 4 - C h l o r o p h e n y l ) - 4 , 4 , 4 -
-en-2-yl)benzene (6) (4 g, 16.5 mmol): trifluorobutanal (linear
00% conversion, the linear product was Starting from 1-chloro-4-(1,1,1-trifluoro- Starting from 1-fluoromethyl-3-(1,1,1-
3,3,3-trifluoro-2-(3-fluorophenyl)-
aldehyde): 2-methylpropanal (branched aldehyde):
obtained in 85% regioselectivity and prop-2-en-2-yl)benzene (8) (86 mg, 0.2 trifluoroprop-2-en-2-yl)benzene (10) (30

Fluorine Chemistry
CHIMIA 2014, 68, Nr. 6 377
mg, 0.26 mmol): 88% conversion, the finic proton), 12.3 (q,1H, J= 18.7 Hz, OH).
Mol. Catal. 1994, 93, 1; b) I. Ojima, J. Org.
Chem. 2013, 78, 6358.
19
branched product was obtained in 60%
regioselectivity. Conditions: 10/Rh/ PPh3 Data in agreement with those previously
00/1/10, CO/H (1:1) 40 bar, toluene, 90 reported in ref. [21].
F NMR (C D ): δ -69.4 (t, J= 16.2 Hz).
6
6
[
[
7] I. Ojima, K. Kato, M. Okabe, T. Fuchikami, J.
Am. Chem. Soc. 1987, 109, 7714.
8] H. Bestian, K. Rehn, DE1007771, 1953.
1
2
1
°
C. H NMR (C D ): δ 1.13 (s, 3H,-CH ),
[9] U. Gellrich, D. Himmel, M. Meuwly, B. Breit,
6
6
3
Received: March 25, 2014
Chem. Eur. J. 2013, 19, 16272.
6
.70-7-15 (m, 4H, Ph), 9.04 (q,1H, J= 3
[
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3
2
1
9
0 °C. H NMR (C D ): δ 1.58 (m, 2H,- [2] a) T. Furuya1, A. S. Kamlet, T. Ritter, Nature
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6
2
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2
2
3
S. Pazenok, J.-P. Vors, F. R. Leroux, Beilstein [13] S. C. Webster, J. R. Seckl, B. R. Walker, P.
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5
(
2
b,1H, -OH), 3.60 (m, 2H,-CH CH O),
.43 (d,1H, J= 1.8 Hz -CHOH). C NMR
2 2
J. Org. Chem. 2013, 9, 2476; c) V. V. Grushin,
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13
C D ): δ 25.0 (q, J= 2.1 Hz), 51.3 (q, J=
Watson, M. Su, G. Te verovskiy, Y. Zhang, J.
6
6
1
9
6.8 Hz), 66.6, 97.9 (q, J= 3.7 Hz ). F
NMR (C D ): δ -72.1 (d, J= 9.4 Hz).
6
6
3
-(trifluoromethyl)-3,4,5-trihydrofu-
ran-2-one (12): Without further purifica-
tion after hydroformylation, the crude lac-
tol 7 was oxidized following the procedure
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1
0
.34 mmol) over 2 steps. H NMR (C D ):
6
6
δ 1.26 (m, 1H,-CH CH O), 1.50 (m, 1H,-
2004, 104, 1; d) M. Engman, J. S. Diesen, A. [15] a) A. I. M. Keuelemans, A. Kwantes, T. van
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2
CH CH O), 2.36 (m, 1H,-CHCF ), 3.14
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2
2
3
(
-
pseudo-q, 1H,-CH CH O), 3.37 (m,1H,
2 2
1
9
CH CH O). F NMR (C D ): δ -68.5 (d,
2
2
6
6
Seifert, U. Siegrist, H. Steiner, ‘Studies in [16] X. Wang, S. L. Buchwald, J. Org. Chem. 2013,
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00% conversion, the β-isomer 9 was ob-
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H (1:1) 40 bar, toluene, 90 °C. Enolic
2
Hydroformylation’
(Catalysis
1
form: H NMR (C D ): δ 0.84 (t, 3H, J=
6
6
by Metal Complexes), Kluwer Academic
1
0.7 Hz, CH CH O-), 2.37 (q, 2H, J= 15.7
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Powell, J. Org. Chem. 1994, 59, 2898.
3 2
Hz, -CH CF ), 3.81 (q, 2H, J= 10.7 Hz,
2
3
[
CH CH O-), 6.65 (d, 1H, J= 18.7 Hz, ole-
3
2