Enolizable β-Fluoroenones: Synthesis and Asymmetric 1,2-Reduction

Article abstract of DOI:10.1021/acs.orglett.8b02435

The hydrofluorination of enolizable ynones with AgF in t-BuOH/DMF is reported. The formation of furans as side products can be suppressed using 2,2′-biphenol. The corresponding β-fluoroenones were obtained with good Z-selectivity. A variety of functional groups are tolerated. β-Fluoroenones are vinylogous acid fluorides whose hydrolysis to vinylogous acids can be avoided under the reported reaction conditions. The asymmetric 1,2-reduction of β-fluoroenones to 3-fluoroallylic alcohols is possible with pinacolborane and a Ni(0) catalyst prepared from a pyrimidyloxazoline ligand.

Full text of DOI:10.1021/acs.orglett.8b02435

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enolizable β‑Fluoroenones: Synthesis and Asymmetric
1,2‑Reduction
Lukas Zygalski, Christoph Middel, Klaus Harms, and Ulrich Koert*
Fachbereich Chemie, Philipps-University Marburg, Hans-Meerwein-Strasse 4, D-35043 Marburg, Germany
S
* Supporting Information
ABSTRACT: The hydrofluorination of enolizable ynones with AgF in t-BuOH/DMF is reported. The formation of furans as
side products can be suppressed using 2,2′-biphenol. The corresponding β-fluoroenones were obtained with good Z-selectivity.
A variety of functional groups are tolerated. β-Fluoroenones are vinylogous acid fluorides whose hydrolysis to vinylogous acids
can be avoided under the reported reaction conditions. The asymmetric 1,2-reduction of β-fluoroenones to 3-fluoroallylic
alcohols is possible with pinacolborane and a Ni(0) catalyst prepared from a pyrimidyloxazoline ligand.
he establishment of methods for the selective introduc-
tion of C−F bonds in organic molecules is an important
Scheme 1. Synthetic Routes to Fluoroenones
T
task and constitutes a significant synthetic challenge due to the
numerous applications of organofluorine compounds in life
and material sciences.1−3 Fluoroolefins are used as monomers
in polymer chemistry and peptide mimics4 and can be
synthesized by olefin metathesis5 or by olefination6 of a
carbonyl precursor. Methods for the synthesis of fluoroolefins
as peptide mimetics require stereoselectivity (E,Z) and
functional group tolerance (e.g., protected amines).
Fluoroenones such as 1 and 4 are valuable building blocks
for the synthesis of fluoroorganics (Scheme 1). While α-
fluoroenones 1 are readily available, e.g., by Julia−Kocienski
olefination6 from sulfone 2 and aldehyde 3, the synthesis of β-
fluoroenones 4 is less well developed. The addition of HF
(hydrofluorination) to ynones 5 is a promising solution to this
problem. The use of a 1,3 dicarbonyl precursor 6 is limited to
symmetrical 1,3-dicarbonyl compounds or at least monoaryl
ketones in order to avoid the formation of regioisomers.7 Aryl
β-fluoroenones have been prepared from 1,2-allenic ketones
using TBAF.8 The reaction of β-fluoroacroyl chlorides with
organo cuprates9a and the copper-catalyzed fluoroolefination of
silyl enol ethers9b are other entries to β-fluoroenones. The
addition of DMPU/HF to triple bonds has been reported for
propiolic esters to generate β-fluoroacrylates.10 The gold-
catalyzed hydrofluorination of arylalkylalkynes11 has not been
Ynone 7a was chosen as an enolizable test substrate to
optimize the reaction conditions for the hydrofluorination. All
ynones used within this study were synthesized from the
corresponding Weinreb amides (Supporting Information
(SI)). For ynone 7a, the carboxylic acid 8 was converted
into the Weinreb amide 9, which upon treatment with the
lithiated 1-octyne gave the desired ynone 7a (Scheme 2).
12
reported for ynones. Hydrofluorinations using Bu4NH2F3 or
Au(I)−NHC catalysis13 have been limited to the preparation
of diaryl β-fluoroenones 4a. Recently, the gold-catalyzed
hydrofluorination of electron-deficient alkynes using RuPhos-
AuCl and Et3N·3HF has been reported.14 Here, a more general
method to synthesize enolizable dialkyl-β-fluoroenones 4b is
presented.
Received: July 31, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02435
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Synthesis of Ynone 7a
Scheme 3. Formation of the Furan Side Product 11
The starting point for our hydrofluorination study was
Jiang’s observation that AgF in CH3CN/H2O leads to diaryl-β-
fluoroenones 4a.15 With these conditions, the hydrofluorina-
tion of ynone 7a led to a mixture of the (Z)-β-fluoro enone
10a (3JαHF = 40 Hz), the furan 11, and the β-hydroxy enone 12
(Table 1, entry 1).
a Ag-mediated cyclization to form the 2,5-disubstituted
furan.16,17 The absence of an enolizable position in diaryl β-
fluoroenones 4a prohibits furan formation for these cases.
The scope and limitations of the optimized hydrofluorina-
tion conditions were studied for a series of ynones with
different aliphatic substitution patterns and functional groups
present (Scheme 4). Good to excellent Z/E selectivites were
Table 1. Optimizing Reaction Conditions for the
Hydrofluorination of Ynone 7a
Scheme 4. Scope and Limitations for Hydrofluorination of
Ynones (7 → 10) Using Optimized Conditions
yield
of 11
(%)
yield
of 12
(%)
yield of 10a
(%) (Z/E)
entry
1
conditions
2 equiv of AgF, H2O, DMF, 80
52 (7:1)
23
19
55
18
°C, 3.5 h
2
3
2 equiv of AgF, t-BuOH, DMF,
80 °C, 3.5 h
2 equiv of AgF, 2 equiv of
DTBPy t-BuOH, CH3CN, 80
51 (5.4:1)
18 (1:1.2)
a
°C, 2.5 h
4
5
6
7
2 equiv of AgF, 0.1 equiv of
BINOL t-BuOH, DMF, 80 °C,
5 h
2 equiv of AgF, 2 equiv of
BINOL t-BuOH, DMF, 80 °C,
5 h
3 equiv of AgF, 0.45 equiv of
2,2′-biphenol, t-BuOH, DMF,
70 °C, 5 h
74 (6.4:1)
2
75 (10.0:1)
2
RuPhosAuCl, AgBF4, Et3N·3HF,
60 (19:1)
2
b
p-Cl benzoic acid
a
b
DTBPy = 6,6′-di-tert-butylbipyridine. MeCN/CH2Cl2 4:1, 24 h,
rt.14
The formation of the vinylogous acid 12 by partial
hydrolysis of the vinylogous acid fluoride with water as
cosolvent is not surprising. Remarkably, the hydrolysis was not
complete under Jiang’s conditions. Substitution of water by t-
BuOH suppresses the hydrolysis side reaction (entry 2).
Attempts to improve the reaction by addition of chelating
ligands were undertaken next. For 6,6′-di-t-Bu-bipyridine the
furan 11 was formed as the main product (entry 3). With 10%
BINOL, the desired β-fluoroenone 10a was produced in good
yield and only with traces of side product (entry 4). The use of
2 equiv of BINOL, however, blocked the reaction (entry 5).
With 2,2′-biphenol, the best yield was obtained (entry 6).
Hydrofluorination using Toste’s conditions14 (entry 7)
resulted in the formation of the desired product in moderate
yield and good stereoselectivity. BINOL and 2,2′-biphenol can
act as ligand and proton source.
observed for all cases, except for 7b where no hydro-
fluorination product 10b could be obtained. A variety of
functional groups were tolerated under the hydrofluorination
conditions (10i, 10j, 10k, 10l, 10m, 10n). Noteworthy is the
excellent Z-selectivity for the case of the hydroxy-substituted
substrate (7m → 10m).
β-Fluoroenones could be valuable building blocks, e.g., as
peptide mimetics, if a stereocontrolled functionalization could
be achieved. In this context, a stereocontrolled 1,2-reduction of
β-fluoroenones is of interest. This reaction is challenged by the
competing 1,4-reduction, defluorination, and potential double
bond Z/E isomerization. The stereocontrolled 1,2-reduction
The formation of furan 11 can be rationalized by
rearrangement of the ynone 7a to the allenone 13 under the
reaction conditions (Scheme 3). The latter can undergo via 14
B
DOI: 10.1021/acs.orglett.8b02435
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
was studied and optimized for the case of the β-fluoroenone
10a (Table 2). DIBAL-H was a suitable reagent for the racemic
Scheme 5. Scope and Limitations for Asymmetric 1,2-
Reduction of β-Fluoroenones(10 → 15) Using Optimized
Conditions
Table 2. Optimizing Reaction Conditions for the
Stereocontrolled 1,2-Reduction of β-Fluoroenone 10a
yield of 15a
(%) (ee)
yield of yield of
entry
conditions
16 (%)
17 (%)
a
1
1 equiv of DIBAH
0.05 equiv of RuCl2[(S)-DM-
BINAP][(S)-DAIPEN]
0.05 equiv of RuCl(p-cymene)
[Ts-DPEN]
75 (rac)
b
2
c
3
d
4
1 equiv of (S)-(−)-o-Tol-CBS
99 (37)
32 (−)
20 (83)
72 (97)
catalyst
e
5
3.6 equiv of (+)-N-
methylephedrine
were obtained for the 3-fluoroallylic alcohols 15 for different
aliphatic substitution patterns in the α′-position of the ketone,
while an aromatic substituent in β-position (15d) resulted in
low yield and no significant ee. A variety of functional groups
were tolerated under the hydrofluorination conditions (15i,
15j, 15k, 15l, 15m, 15n).
f g
6 ,
0.02 equiv of Ni(COD)2,
26
6
j
0.024 equiv of L
f h
7 ,
0.04 equiv of Ni(COD)2, 0.10
3
j
equiv of L
h,i
8
0.04 equiv of Ni(COD)2, 0.10
j
equiv of L
Chiral 3-fluoroallylic alcohols 15 offer a variety of synthetic
applications in fluoroorganics. One example is the stereo-
controlled cyclopropanation (15g → 18), which exhibits a
remarkably high diastereoselectivity (Scheme 6).
The relative configuration of the cyclopropanation product
18 was secured by X-ray crystallography of its 3,5-
dinitrobenzoate (SI). While no stereoselective cyclopropana-
tion of 3-fluoroallylic alcohols has been reported, the
stereochemical outcome for (15g → 18) is in agreement
a
b
c
Et2O, −10 °C. 0.05 equiv of KOtBu, H2 (5 bar), iPrOH, 25 °C. 1.5
d
equiv of HCO2H/NEt3, CH3CN, 25 °C. 1 equiv of BH3·SMe2, THF,
e
0 °C. 3.3 equiv of LAH, 7.2 equiv pf 1,2,3,4-tetrahydrochinoline,
f
Et2O, −78 to +50 °C. 1.2 equiv of HBpin, 1.5 equiv of DABCO,
g
h
i
j
toluene. −25 °C. 0 °C. 1.5 equiv of DABCO, toluene. L = (S)-t-
Bu-PMROX.
1,2-reduction (entry 1).18 Ru-catalyzed hydrogenation of β-
fluoroenone 10a under various conditions gave no conversion
of the starting material (entries 2 and 3).19
Scheme 6. Diastereoselective Cyclopropanation of
Fluoroallylic Alcohol 15g and X-ray Crystal Structure of the
3,5-Dinitrobenzoate of 18
The CBS reduction provided the desired fluoroallylic
alcohol 15a in very good yield, however, with only low
enantioselectivity (entry 4).20 A LiAlH4 reduction using N-
methylephedrine as chiral ligand was less effective (entry 5).21
The NiH/PMROX-catalyzed 1,2-reduction of 10a using Zhu’s
conditions22 gave the desired product 15a in low yield and
good enantioselectivity (entry 6). Under these conditions, the
defluorinated allylic alcohol 16 was formed as side product in
nearly equal amounts. It was found that changing the catalyst
loading to 4% Ni(COD)2 and 10% (S)-t-Bu-PMROX resulted
in a very good yield and excellent enantioselectivity (entry 7).
Only traces of side products 16 and 17 were observed in this
case. Without borane, no conversion of the starting material
was observed (entry 8). The absolute configuration of 15a was
determined using Mosher-NMR analysis23 (SI) and is in
accordance with the prediction made by Zhu.22
The scope and limitations of the optimized conditions for
the asymmetric 1,2-reduction were studied for a series of β-
fluoroenones 10 (Scheme 5). Excellent enantioselectivities
C
DOI: 10.1021/acs.orglett.8b02435
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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pinacolborane as hydride donor and a Ni(0)catalyst prepared
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ASSOCIATED CONTENT
* Supporting Information
■
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Experimental details; spectroscopic and analytical data of
all new compounds (PDF)
Accession Codes
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CCDC 1824992 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: + 44 1223 336033.
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AUTHOR INFORMATION
(24) (a) Piers, E.; Coish, P. D. Synthesis 1995, 1995, 47−55.
(b) Lebel, H.; Marcoux, J. F.; Molinaro, C.; Charette, A. B. Chem. Rev.
2003, 103, 977−1050.
■
Corresponding Author
*E-mail: koert@chemie.uni-marburg.de.
ORCID
Ulrich Koert: 0000-0002-4776-8549
Author Contributions
Experimental work was done by L.Z. and C.M.; X-ray
crystallography was done by K.H.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support by the Deutsche Forschungsgemeinschaft is
gratefully acknowledged. The authors thank Christian Mu
(Fachbereich Chemie, Philipps-University Marburg) for GC
analysis.
■
̈
ller
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DOI: 10.1021/acs.orglett.8b02435
Org. Lett. XXXX, XXX, XXX−XXX