Asymmetric Synthesis of Alkyl Fluorides: Hydrogenation of Fluorinated Olefins

Article abstract of DOI:10.1002/anie.201903954

The development of new general methods for the synthesis of chiral fluorine-containing molecules is important for several scientific disciplines. We herein disclose a straightforward method for the preparation of chiral organofluorine molecules that is ba

Full text of DOI:10.1002/anie.201903954

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Accepted Article
Title: Asymmetric Synthesis of Alkyl Fluorides: Hydrogenation of
Fluorinated Olefins
Authors: Sudipta Ponra, Jianping Yang, Sutthichat Kerdphon, and Pher
G. Andersson
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10.1002/anie.201903954
Angewandte Chemie International Edition
RESEARCH ARTICLE
Asymmetric Synthesis of Alkyl Fluorides: Hydrogenation of
Fluorinated Olefins
Sudipta Ponra,!a Jianping Yang,!a Sutthichat Kerdphona and Pher G. Andersson*a,b
Abstract: The development of new general methods for the
synthesis of chiral fluorine-containing molecules is important for
several scientific disciplines. By the Ir-catalyzed asymmetric
hydrogenation of tri-substituted vinyl-fluorides, a straightforward
preparation of chiral organofluorine molecules is disclosed. The
developed method represents a catalytic asymmetric process that
enables the synthesis of chiral fluorine molecules with or without
carbonyl framework. Owing to the tunable steric and electronic
properties of azabicyclo iridium-thiazole-phosphine catalyst, this
stereoselective reaction could be optimized and found compatible
with various aromatic, aliphatic and heterocyclic systems with a
variety of functional groups providing the highly desirable product in
excellent yield and enantioselectivities.
generation of the C-F bond. Despite the availability of a variety
of methods, simple and general asymmetric protocol,
a
irrespective of the presence of a carbonyl group, has remained
comprehensively elusive for a long time. These limitations of
asymmetric fluorination have prompted us to devise a new atom
economical, highly enantioselective synthetic method for
versatile fluorinated molecules.
Asymmetric hydrogenation of alkenes using transition metal
catalysts is one of the most fundamental and atom economical
processes for synthetic organic chemistry.12 Moreover, excellent
chemo-, regio-, and enantioselectivity can be obtained by the
appropriate choice of metal and chiral chelating ligand. The
presence of strongly coordinating functional groups such as
amides and carboxylic acids in close proximity to the double
bond facilitates hydrogenation with the use of Rh, Ru or Ir
catalysts.13 For olefins having no coordinating or only weakly
coordinating groups, Ir complexes are the catalysts of choice.14
Usually, for iridium-catalyzed hydrogenations, the smallest
substituent (hydrogen for a trisubstituted olefin) determines
which enantioface of the olefin preferentially coordinates to Ir in
the enantioselectivity-determining transition state. Having two
small substituents (H and F) in tri-substituted vinyl-F presents a
challenge since more than one orientation of the olefin is
possible, resulting in enantiomeric mixtures of the product. The
electron withdrawing behavior of the fluorine together with
frequent de-fluorination (de-F) that occurs during hydrogenation,
makes tri-substituted vinyl-fluorides even more difficult
substrates to hydrogenate.15
Introduction
Stereo-defined organofluorine compounds possess unique
physical properties and are highly important in agrochemicals,
pharmaceuticals, material sciences1 and medicinal chemistry.2
Despite its widespread use as a pharmacological modulator; the
asymmetric installation of fluorine onto organic molecules
presents challenges. The limited number of asymmetric fluorine
molecules3 in nature makes its availability dependent on organic
synthesis. Hence, the development of new, simple and efficient
methods to access a diverse array of novel chiral fluorinated
derivatives, has become a highly prioritized research area.1b,4
Among the distinct approaches available for the asymmetric
construction of the C(sp3)-F stereogenic center,4c,e is the
commonly exploited technique of α-fluorination of enolate or
enolate-equivalents,5 fluorination of olefins,6 and asymmetric
addition of nucleophilic fluorides to carbon electrophiles.7 α-
Fluorination of carbonyl derivatives is undeniably a viable
strategy5 however it is limited to either aldehyde,5b,c,8 β-keto
esters9 or cyclic ketones10 while simple acyclic ketonic
substrates are met with difficulties. Although a number of
fluorination methods for acyclic ketonic substrates have been
reported,11 the asymmetric version is still very limited.11c-f Most of
the asymmetric methods require multi steps and have a limited
substrate scope.11c-e Negishi cross coupling of racemic α,α-
dihaloketones has been shown to be an effective strategy but is
restricted to only aromatic tertiary alkyl fluorides.11f The
tractability of such reported methods however, are restricted to
substrates containing carbonyl groups. For substrates without a
carbonyl group, other techniques are required for asymmetric
Vinyl fluorides are however relatively easy to prepare and the
development of
a
suitable catalyst for the asymmetric
hydrogenation of tri-substituted vinyl fluorides would enable the
generation of various chiral fluorine molecules with and without
the carbonyl framework, in one simple step.16 With the above-
mentioned limitations in mind, we set out to develop an atom
economical protocol for asymmetric hydrogenation of tri-
substituted vinyl fluorides (Scheme 1).
+
R
R
-
BArF
P
Ir
H
H
L*
X
F
X
F
N
R
R
H2, r.t.
X = C=O, CR
R1
H
H
R1
Scheme 1. Atom economical synthesis of asymmetric fluorine
motifs.
Dr. Sudipta Ponra,! Mr. Jianping Yang,! Dr. Sutthichat Kerdphon and
Prof. Dr. Pher G. Andersson
Results and Discussion
[a]
Department of Organic Chemistry
Stockholm University
Svante Arrhenius väg 16C, SE-10691 Stockholm, Sweden
E-mail: pher.andersson@su.se
School of Chemistry and Physics, University of KwaZulu-Natal,
Durban, South Africa.
Recently, we successfully developed
a
diastereo- and
enantioselective synthesis of fluorine motifs with two contiguous
stereogenic centers by highly selective and efficient
hydrogenation of tetra-substituted vinyl fluorides.16d Motivated by
[b]
[!]
this
accomplishment,
we
selected
(Z)-2-fluoro-1,3-
Authors contributed equally to this work.
diphenylpropenone 1a as an the model substrate and azabicyclo
iridium oxazoline phosphine complex A as the catalyst for this
asymmetric hydrogenation. However, applying our previously
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201903954
Angewandte Chemie International Edition
RESEARCH ARTICLE
optimized catalytic method (1 mol% catalyst, CH2Cl2, 10 bar H2)
to substrate 1a gave only trace amounts (6% conversion) of the
desired product 2a (Table 1). Based on our previous knowledge
of N,P-iridium-catalyzed asymmetric hydrogenation,16a,b we
started to optimize the basic skeleton of the heterocycle of the
N,P-iridium complex. Imidazole B provided a comparable result
of 23% conversion of starting material 1a to 2a but with poor
enantioselectivity (31% ee). Encouragingly, the thiazole N,P-
iridium complex dramatically increased the enantioselectivity
(>99% ee). However, despite their high enantioselectivity, both
catalysts C and D provided moderate conversion (32% and 27%
respectively) of the desired product (entries 3 and 4). Next, the
effect of the substituents on phosphine was studied. Gratifyingly,
replacing the two ortho-tolyl groups with suitable aliphatic
substituents on the bicyclic thiazole N,P-iridium catalyst resulted
in much higher conversion to the desired product 2. Iridium
complexes with cyclohexyl E or isopropyl F on the phosphorus
resulted in the successful hydrogenation of 1a in 99%
conversion with excellent enantiomeric excess (>99%).
in a lower conversion (entry 7). Remarkably, in all cases the
enantioselectivity (>99% ee) was maintained. Hence, the optimal
conditions with regards to conversion and enantioselectivity for
substrate 1a are 0.5 mol% catalyst loading of catalyst F, 5 bar
H2 pressure for 2 hours (entry 6). It should be mentioned that no
defluorinated (de-F) product was detected which is a frequent
problem in hydrogenations of vinyl fluorides.15b
Table 2. Optimization of hydrogenation of vinyl fluoride 1aa
O
O
O
Ph
Ph
Ir-N,P catalyst (F)
Ph
*
+
Ph
F
H2, CH2Cl2, r.t.
Ph
F
Ph
1a
2a
de-F
ee (%)b
de-F
Conversion (%)
Entry
H2 (bar)
Catalyst (mol%)
Time (h)
>99
>99
>99
>99
>99
>99
>99
0
0
0
0
0
0
0
99
99
76
99
95
99
77
1.
2.
3.
4.
5.
6.
7.
10
10
10
10
10
5
F (1.0)
F (0.5)
F (0.3)
F (0.5)
F (0.5)
F (0.5)
F (0.5)
24
24
24
2
Table 1. Evaluation of N,P-iridium catalysts in the asymmetric hydrogenation
of 1aa
1
O
O
O
Ph
2
Ph
Ph
Ir-N,P catalyst
*
+
F
2
F
2
H2 (10 bar)
CH2Cl2, r.t.
1a
de-F
a Reaction conditions: 0.05 mmol of 1a, 0.5 mL CH2Cl2. The conversion was
2a
determined by 1H-NMR. Enantiomeric excess was determined by SFC.
Ph
Ph
N
o-Tol
(o-Et
Ph)2
o-Tol
Me
P
P
P
Ir(COD)
N
Ir(COD)
N
Ir(COD)
BArF
BArF
N
S
With the optimized reaction conditions established, we evaluated
the hydrogenation of various (Z)-3-fluoropent-3-en-2-one
substrates 1 (Table 3) having different substituents. A variety of
phenyl ketones were successfully hydrogenated to generate the
desired products 2a-2h in excellent yield and enantioselectivity.
The (Z)-2-fluoro-1,3-diphenylprop-2-en-1-one substrates with
either electron-donating or electron-withdrawing substituents on
the phenyl rings were well tolerated and provided high isolated
yields and excellent enantioselectivities of the desired products.
Replacing the phenyl with the heterocyclic (3-thienyl) or 2-
naphthyl substituent yielded 2e (99% yield) or 2f (96% yield) in
excellent ee (>99%). Next we examined the effect of replacing
the carbonyl phenyl substituent into various aliphatic side chains.
For these substrates the optimal reaction conditions were 1.0
mol% of catalyst G, 10 bar H2 pressure for 24 hours. Methyl
substituted substrates performed very well irrespective of the
electron-donating and electron-withdrawing substituents in the
aromatic ring with excellent yields and enantioselectivities.
Interestingly, substrates with electron-withdrawing substituents
seem advantageous for higher enantioselectivity. Various
substituted (Z)-3-fluoro-4-(4-(trifluoromethyl)phenyl)but-3-en-2-
ones where Me was replaced with other aliphatic substituent
such as Et, nBu or Bn also reacted smoothly and resulted in
excellent yields (97-98%) and enantiomeric excess (98->99%
ee). Secondary (iPr, Cy) and tertiary aliphatic groups (tBu), all
afforded the desired products 2p, 2q and 2r in exceptional yields
(94-97%) and ee (99->99%). Another significant aspect is that
no de-F was observed in any of these examples, which
underlines the usefulness of this catalytic method.
BArF
N
Ph
Ph
O
N
C
Conv. 32%
>99% ee
B
Conv. 23%
31% ee
A
Conv. 6%
iPr
iPr
P
Cy
Cy
o-Tol
o-Tol
N
P
N
N
Ir(COD)
P
Ir(COD)
Ir(COD)
BArF
N
BArF
N
BArF
N
Ph
Ph
S
Ph
S
S
F
E
D
Conv. 27%
>99% ee
1a: Conv. 99%, >99% ee
7a: Conv. 72%, 86% ee
1a: Conv. 99%, >99% ee
7a: Conv. 93%, 89% ee
a Reaction conditions: 0.05 mmol of 1a, 1 mol% catalyst, 0.5 mL CH2Cl2. The
conversion was determined by 1H-NMR. Enantiomeric excess was determined
by SFC.
After successfully designing the new effective catalyst E and F,
we carried out further optimization of the catalyst loading and
hydrogen pressure (Table 2). A decrease in the catalyst loading
for substrate 1a from 1.0 mol% (entry 1) to 0.5 mol% (entry 2) at
10 bar of H2 pressure did not affect the conversion and
enantioselectivity (99% conversion, >99% ee). However, a
further decrease in the catalyst loading to 0.3 mol% (entry 3)
significantly decreased the conversion (71%). By maintaining the
catalyst loading at 0.5 mol% and decreasing the reaction time to
2 hours, the product was obtained with 99% conversion and
>99% ee (entry 4). Reducing the reaction time to 1 hour gave
95% conversion (entry 5) with 0.5 mol% of catalyst F. A gradual
decrease of the H2 pressure from 10 bar (entry 4) to 5 bar (entry
6) using 0.5 mol% of catalyst F in 2 hours did not change the
conversion. A further decrease in the pressure to 2 bar resulted
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10.1002/anie.201903954
Angewandte Chemie International Edition
RESEARCH ARTICLE
Table 3. Hydrogenation of various fluoro-phenyl-ketone a
(6a-6g), secondary (6h-6n), and tertiary (6o) aliphatic
substituents afforded excellent results. However, the conversion
of the aliphatic substrates occasionally depends on the sterics
around the C=C double bond of the vinyl-F. These steric effects
were easily overcome by using a higher pressure (50 bar), which
led to good yields for bulky aliphatic substituent products such
as 6i, 6l, and 6n as well as the tertiary aliphatic substituted
product 6o. Thus, the challenging aliphatic fluorine molecules
with different substituents were effectively synthesized with good
to excellent yield and ee, which shows the extended scope of
this hydrogenation process.
O
O
R1
R1
Ir-N,P ligand (F)
R
F
H2, CH2Cl2, r.t.
R
F
2
1
O
O
O
O
O
Ph
Ph
Ph
Ph
Ph
F
F
F
F
F
S
F3C
2db
2c
2eb
Me
F
2a
2b
96% yield
>99% ee
97% yield
>99% ee
99% yield
>99% ee
98% yield
>99% ee
97% yield
>99% ee
O
O
O
O
Table 4. Hydrogenation of various polyfluorinated vinyl-fluoride ketonea
OMe
Me
Ph
F
O
O
R1
F
F
R1
F
F
Ir-N,P ligand (F)
F
F
H2 (10 bar)
F3C
F3C
2g
2ic
2h
CH2Cl2, r.t., 24h
2f
3
4
98% yield
>99% ee
98% yield
>99% ee
96% yield
90% ee
R
R
96% yield
>99% ee
O
O
O
O
F
O
Me
F
Et
Me
Me
Me
O
O
O
O
F
O
F
Me
Me
Me
Et
F
F
F
F
F
F
F
F
F
F
F
F3CS
F
F
F
F
F
F
4b
4d
4c
4e
4a
Me
F
F3C
F3C
F3C
2nc
2lc
97% yield
98% ee
2mc
97% yield
96% ee
2kc
2jc
98% yield
94% ee
95% yield
>99% ee
99% yield
93% ee
98% yield
98% ee
95% yield
98% ee
97% yield
96% yield
93% ee
99% yield
90% ee
98% ee
O
O
O
O
Me
F
Me
Me
Me
O
O
F
O
F
O
F
F
CF3
F
F
F
F
F
F3C
F
F3C
F
F3C
4i
4h
4g
4f
96% yield
99% ee
96% yield
>99% ee
98% yield
99% ee
F3C
F3C
97% yield
98% ee
F3C
2rc
2pc
2oc
2qc
F3C
94% yield
>99% ee
97% yield
>99% ee
98% yield
>99% ee
97% yield
99% ee
a
Reaction conditions: 0.05 mmol of substrate, 1 mol% catalyst F, 0.5 mL
a Reaction conditions: 0.05 mmol of substrate, 0.5 mol% catalyst F, 5 bar H2,
CH2Cl2. Yields are isolated hydrogenated product. Enantiomeric excess was
determined by GC/MS using chiral stationary phases.
b
c
0.5 mL CH2Cl2, 2h. Reaction time 6h. 1.0 mol% catalyst F, 10 bar H2, 24h.
Yields are isolated hydrogenated product. Enantiomeric excess was
determined by SFC or GC/MS using chiral stationary phases.
To further study the effectiveness of this developed method for
the catalytic asymmetric synthesis of alkyl fluorides, various vinyl
Considering that polyfluorinated compounds are very useful
molecules in various scientific disciplines17 as well as the fact
that de-F during hydrogenation of vinyl-fluorides presents
potential challenges,15 a further study of polyfluorinated vinyl
fluoride ketones was carried out (Table 4). A number of
polyfluorinated substrates were evaluated under standard
conditions and irrespective of the position of the fluorine or
trifluoromethyl in the aromatic ring, no trace of de-F products
was observed. In all cases, high yields (95-99%) and
enantioselectivities (93->99% ee) were obtained for the
polyfluorinated products.
fluorides without a carbonyl functional group were also
evaluated. For this class of substrates it was found that catalyst
E is most suitable (see Supporting Information for optimization
details). Employing the same conditions as used previously,
catalyst E was found effective for a variety of un-functionalized
vinyl-fluoride substrates and produced no or very small amounts
of de-F product (Table 6). Electron-donating (-Me and -OMe) or
electron-withdrawing (-F, -CF3) substituents on the aromatic ring
were both tolerated however; the electron-donating substituent
on the benzene ring was slightly favorable both in terms of yield
and enantioselectivity. Naphthyl or heterocyclic substituted vinyl-
F also works very effectively. Notably, substrates having bulky
secondary (iPr or Cy) or tertiary (tBu) substituents were
hydrogenated in high levels of stereoselectivity. However, for
substrates containing the tert-butyl substituent the reaction was
slow under standard reaction conditions. This was easily
overcome by either increasing the catalyst loading (8k) and/or
by increasing the H2 pressure (8l). The fruitful examples
presented here emphasizes that this catalytic system is very
general for fluoro-olefins.
The efficacy of this stereoselective hydrogenation process was
further investigated by evaluating various substrates that would
produce completely aliphatic chiral fluorine molecules (Table 5).
It was observed that the developed protocol was not dependent
on the aliphatic or aromatic nature of the substituents and
gratifyingly a number of aliphatic vinyl fluorides were also
efficiently hydrogenated in good to excellent yield with very high
enantioselectivitiy. Interestingly, various acyclic or cyclic primary
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10.1002/anie.201903954
Angewandte Chemie International Edition
RESEARCH ARTICLE
Table 5. Hydrogenation of various aliphatic vinyl-fluorides a
fluorine molecules under mild reaction conditions. A gram-scale
set-up using for 1.0 g of starting material 1a, 0.5 mol% of
catalyst F, 5 bar H2 produced the desired compound 2a in
excellent 96% yield and >99% ee without any de-F products
(Scheme 2).
O
O
R1
R1
Ir-N,P ligand (F)
H2, CH2Cl2, r.t., 24h
R
F
R
O
F
6
5
O
O
O
F
O
O
O
Me
n-C4H9
Me
Me
n-C4H9
Ir-N,P catalyst F (0.5 mol%)
F
Et
F
F
n-C4H9
F
n-C5H11
H2 (5 bar)
F
F
CH2Cl2 (10 mL), r.t., 6h
2a
971 mg
6e
6b
6d
6c
6a
1a
97% yield
88% ee
97% yield
97% ee
93% yield
91% ee
95% yield
95% ee
96% yield
94% ee
96% yield
>99% ee
1.0 g
O
O
O
O
F
Scheme 2. Gram-scale production of chiral fluorine molecule.
n-C4H9
O
n-C4H9
F
F
Computional12e, 18 and experimental studies19 suggests that the
enantioselectivity of Ir-catalyzed asymmetric hydrogenations
depend mainly on the steric interactions between the substrate
olefin and co-ordination environment around the N,P-iridium
catalyst. A quadrant model has been developed12e, 18 to explain
the enantioselectivity. The ligand is positioned as shown in
Scheme 3a, having the iridium atom in the center of the four
quadrants (Scheme 3b). The olefin then coordinates vertically
trans to phosphorous as shown in Scheme 3c. The phenyl on
the thiazole points outward making quadrant i sterically hindered.
One of the cyclohexyl group on the phosphorus also points
slightly outwards, making quadrant iv a semi-hindered quadrant.
Quadrant ii and iii are considered as open quadrants since
there are no obstructions from the ligand here. When the tri-
substituted (Z)-vinylflouride olefin 7a is placed trans to
phosphorus, such that the smallest substituent (H) occupies the
hindered quadrant i and the other small substituent (F) occupies
the semi-hindered quadrant iv, this should result in a favored
arrangement (Scheme 3d). Considering the similar size of H and
F another sterically favorable arrangement is also possible
placing fluorine in the sterically hindered quadrant i (Scheme 3e).
The other two possible arrangements (Scheme 3f, 3g) are
sterically unfavoured. Thus, based on the quadrant model, both
of the sterically favored orientations of the vinylflouride olefin 7a
results in hydrogenation from the same face of the olefin and
the predicted absolute configuration of hydrogenated product 8a
is S which is in agreement with the experimental results (see
F
Et
F
6f
6g
6h
6ib
6j
85% yield
91% ee
90% yield
84% ee
94% yield
95% ee
87% yield
96% ee
93% yield
96% ee
O
F
O
O
F
O
O
Et
Me
Me
F
F
F
6ob
6lb
6k
6m
6nb
51% yield
83% ee
95% yield
94% ee
80% yield
95% ee
79% yield
87% ee
82% yield
91% ee
a
Reaction conditions: 0.05 mmol of substrate, 1 mol% catalyst F, 0.5 mL
b
CH2Cl2, 10 bar H2. 50 bar H2. Yields are isolated hydrogenated product.
Enantiomeric excess was determined by GC/MS using chiral stationary
phases.
Table 6. Hydrogenation of various substituted 2-fluoropropenyl benzene a
R1
R1
R1
Ir-N,P ligand (E)
+
R
F
R
F
H2, CH2Cl2, r.t., 24h
R
8
9 (de-F)
7
Me
Me
Me
F
Me
F
F
F
F
Me
MeO
F
8d
8c
8b
8a
95% yield
0% de-F
95% ee
96% yield
0% de-F
95% ee
95% yield
0% de-F
95% ee
93% yield
2% de-F
89% ee
Et
Me
Me
Me
F
F
F
Me
F
Supporting
Information
for
absolute
configuration
S
F3C
determination).20
8h
8g
8e
8f
96% yield
4% df-F
92% ee
93% yield
3% de-F
92% ee
92% yield
0% de-F
92% ee
96% yield
7% de-F
96% ee
However, in case of the (E)-vinylflouride olefin 7aʹ the two
sterically favored orientations (Scheme 3h and 3i) will take place
from opposite faces which would result in the formation of
mixtures of R and S products. These predictions are in well
agreement with experimental results (Scheme 4) as the (Z)-
vinylflouride olefin (7a) provides product 8a with high
enantioselectvity (89% ee) while the (E)-isomer gives the
corresponding products in enantiomeric mixture of 55% ee.
Me
Me
F
F
F
F
Me
Me
Me
8kb,c
8lb
8i
8j
95% yield
0% de-F
95% ee
92% yield
0% de-F
93% ee
98% yield
0% de-F
98% ee
97% yield
8% de-F
97% ee
a Reaction conditions: 0.05 mmol of substrate, 1 mol% catalyst E, 20 bar H2,
b
c
0.5 mL CH2Cl2.
100 bar H2,
2 mol% catalyst E. Yields are isolated
hydrogenated product, in some cases containing small amount of de-F product.
Enantiomeric excess was determined by SFC or GC/MS using chiral
stationary phases.
This Ir-catalyzed hydrogenation reaction was also found to be
particularly robust for the preparative scale production of chiral
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10.1002/anie.201903954
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RESEARCH ARTICLE
Schematic 3D
quadrant model
Experimental Details are available in Supporting Information section.
(a)
(c)
(b)
H
H
i
i
ii
ii
Hindered
Open
Open
R1
F
P
H
R
Acknowledgements
P
N
R1 Ir
H
N
H
R
N
S
Semi-
hindered
F
iii
iii
The Swedish Research Council (VR), Stiftelsen Olle Engkvist
Byggmästare, Knut and Alice Wallenberg foundation (KAW
2016.0072 and KAW 2018:0066) supported this work. We thank
Dr. Thishana Singh, School of Chemistry and Physics,
University of Kwazulu-Natal, South Africa, for proof reading and
editing the manuscript.
iv
iv
H
H
Me
(Z)-2-fluoropropenyl benzene
Ph
F
(e)
Sterically favored
(d) Sterically favored
i
ii
i
ii
F
Me
H
Me
H
F
H
H
Me
F
Me
F
(S)-(2-fluoropropyl)
benzene
(S)-(2-fluoropropyl)
benzene
Keywords: Asymmetric hydrogenation • vinyl-fluoride • N,P-
iii
iv
iii
iv
iridium catalyst • organofluorine • carbonyl framework
Sterically unfavored
(g)
(f) Sterically unfavored
i
ii
i
ii
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H
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H
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H
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H
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(R)-(2-fluoropropyl)
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iii
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iii
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(i)
(h) Sterically favored
i
ii
i
ii
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H
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F
H
F
Me
H
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(R)-(2-fluoropropyl)
benzene
(S)-(2-fluoropropyl)
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iii
iv
iii
iv
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Scheme 3. Determination of absolute configuration of olefin 7a
Ir-N,P ligand (E, 1 mol%)
Me
Me
Me
+
F
F
H2, CH2Cl2, r.t., 24h
7a
8a
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9 (2%)
93% yield
89% ee
Ir-N,P ligand (E, 1 mol%)
F
Me
Me
Me
+
F
H2, CH2Cl2, r.t., 24h
8a
7a’
9 (6%)
77% yield
55% ee
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Conclusion
In summary, we have developed a new azabicyclo iridium-
thiazole-phosphine-complex, which is very general and efficient
for the stereoselective synthesis of various alkyl fluorides,
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aromatic and aliphatic tri-substituted vinyl-fluorides, providing
chiral fluoro-alkanes in excellent yield and enantioselectivity.
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RESEARCH ARTICLE
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10.1002/anie.201903954
Angewandte Chemie International Edition
RESEARCH ARTICLE
Sudipta Ponra,!a Jianping Yang,!a
Sutthichat Kerdphona and Pher G.
Andersson*a,b
R
R
R1 = Ar, Aliphatic
X = C=O, CR
H
H
P
S
X
F
N
Ir(COD)
X
F
Y
BArF
Y
N
(R = Aliphatic)
Y = Ar, Aliphatic
R1
H
R1
Page No. – Page No.
Ph
H
H2
R = iPr or Cy
Up to >99% ee
>54 examples
Asymmetric Synthesis of Alkyl
Fluorides: Hydrogenation of
Fluorinated Olefins
A new general method for the synthesis of asymmetric alkyl fluorides is
developed. The method relies on Ir-catalyzed asymmetric hydrogenation of
different tri-substituted vinyl-fluorides. It provides the first catalytic asymmetric
process that enables the synthesis of different array of chiral organofluorine
molecules with and without carbonyl framework with different electronic
nature in excellent yield and enantioselectivities.
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