Chelation-controlled diastereoselective reduction of α-fluoroketones

Article abstract of DOI:10.1021/ja052546x

The effect of Ti-based Lewis acids on the reduction of α-fluoropropiophenone was examined to determine whether chelation control could be used to direct the diastereoselectivity of conversion to an α-fluoro alcohol. Pretreatment of α-fluoropropiophenone with TiCl₄ followed by reduction with LiBH₄ in diethyl ether or methylene chloride provided the syn diastereomer predominantly, while use of Ti(OⁱPr)₄ under identical conditions provided the anti diastereomer as the major product. The products are consistent with a chelation-controlled mechanistic pathway in the former reduction and a nonchelation pathway in the latter case. Detailed ¹H, ¹³C, and ¹⁹F NMR studies were consistent with chelation between TiCl₄ and α-fluoropropiophenone under the reaction conditions utilized in this study. Reduction of other α-fluoroketones in the presence of TiCl₄ also provided a high degree of diastereoselectivity in the conversion to α-fluoro alcohols, showing the generality of this approach. Copyright

Full text of DOI:10.1021/ja052546x

Published on Web 08/06/2005
Chelation-Controlled Diastereoselective Reduction of r-Fluoroketones
Pramod K. Mohanta,† Todd A. Davis,‡ Jeremy R. Gooch,‡ and Robert A. Flowers, II*,†
Department of Chemistry, Lehigh UniVersity, Bethlehem, PennsylVania 18015, and Department of Chemistry and
Biochemistry, Texas Tech UniVersity, Lubbock, Texas 79409-1061
Received April 19, 2005; E-mail: rof2@lehigh.edu
Table 1. Data for Reduction of R-Fluoropropiophenone in the
The replacement of hydrogen or heteroatoms with fluorine can
provide an enormous impact on the biological activity of substrates.1
There is currently great demand for the development of new
synthetic methodologies to obtain optically active pure isomers of
fluorine-containing substrates, and in particular, stereoselective
approaches to R-fluoro alcohols are important in numerous drug
targets.2 In recent decades, considerable progress has been made
in controlling the stereochemistry of newly formed chiral centers
by aid of interactions between carbonyls and polar neighboring
groups (e.g., alkoxy, amine, etc.) with Lewis acids (LA) through
chelation.3 While there are a number of approaches to the
stereoselective synthesis of R-fluoro alcohols, to the best of our
knowledge, none utilize chelation with Lewis acids to control
stereoselectivity.4,5 To examine the use of chelation control, a series
of R-fluoroketones were synthesized and reduced with common
reductants in the presence of TiCl4 and Ti(OiPr)4. The data described
herein show two important features: (1) The identity of the Ti-
based Lewis acid has a large impact on the diastereoselectivity of
reduction, and (2) NMR (1H, 13C, 19F) data are consistent with the
presence of chelation between TiCl4 and R-fluoroketones under
conditions utilized in synthetic studies.
Salts of titanium(IV) are known to be effective Lewis acids for
chelation-controlled reactions of R- and â-alkoxyketones,3 and since
fluorine is a relatively hard, electron-rich atom, analogous ap-
proaches should work for R- and â-fluoroketones. A mechanistic
pathway for chelation-controlled reduction of R-fluoroketones
requires a relatively strong interaction between Ti-based Lewis acids
and fluorine. Examination of the bond strengths of diatomic
titanium-fluorides (Ti-F, 136 ( 8 kcal/mol) shows that there is
a strong interaction between fluorine and titanium.6 Further evidence
supporting the interaction of Lewis acids with fluoro substituents
is found in the recent work of Hessen and co-workers who have
shown that the titanocene cation has a high affinity for fluorine.7
Another potential advantage of using Ti(IV) Lewis acids is their
solubility in a range of organic solvents.
Presence and Absence of Ti-Based Lewis Acidsa
entry
Lewis acid
reducing agent
solvent
syn:anti
yield (%)
1
2
3
4
5
6
7
8
9
none
none
none
none
TiCl4
TiCl4
TiCl4
TiCl4
Ti(OiPr)4
Ti(OiPr)4
NaBH4
NaBH4
LiBH4
LiBH4
NaBH4
NaBH4
LiBH4
LiBH4
LiBH4
LiBH4
Et2O
CH2Cl2
Et2O
CH2Cl2
Et2O
CH2Cl2
Et2O
CH2Cl2
Et2O
CH2Cl2
1:2
1:4
3:1
2:1
9:1
6:1
24:1
7:1
1:3
1:2
qb
qc
qb
qc
88b
83c
96b
76d
99b
98c
10
a Experimental conditions: 1 equiv of substrate is treated with 1.25-
2.5 equiv of LA at -78 °C; 2 equiv of metal hydrides with respect to
substrate is used. b Reaction time ) 6 h. c Reaction time ) 7 h. d Reaction
time ) 4 h.
higher in the presence of this Lewis acid with higher diastereo-
selectivities in Et2O.8 In particular, the combination of TiCl4 with
LiBH4 in Et2O produces very high syn selectivity of 24:1.
Conversely, the addition of Ti(OiPr)4 to the substrate prior to
reduction by LiBH4 provides the anti diastereomer predominantly.
The stereochemical results of the reactions shown in Table 1
can be explained using Cram’s chelation9 and the Felkin-Ahn10
models. In the absence of chelation, the dipoles of the carbonyl
and C-F bond align to minimize repulsion.11 Attack on this
conformation by reductant would be expected to provide the anti
product predominantly. Conversely, the presence of a Lewis acid
capable of interacting with the carbonyl oxygen and fluorine would
provide a chelated intermediate, and attack on the less hindered
side of this conformation would lead to the syn fluoro alcohol. The
anti product reduction is observed when NaBH4 is used alone or
when Ti(OiPr)4 is used as the LA in concert with LiBH4, indicating
that the Na+ or the sterically encumbered LA are incapable of
providing a chelated intermediate. When LiBH4 is used alone or
when TiCl4 is used as the LA with either reductant, the syn
diastereomer is the major product, a finding consistent with
chelation.
To examine the likelihood of chelation in detail, NMR experi-
ments were initiated to explore the influence of the Ti-based Lewis
acid on R-fluoropropiophenone. The seminal work of Keck has
shown the utility of this approach in exploring the extent of
chelation in â-alkoxyketones.12 Figure 1 contains the 1H, 13C, and
19F NMR spectra of R-fluoropropiophenone in the presence and
absence of 1.25 equiv of Ti(IV)-based Lewis acids in CD2Cl2 at
-78 °C. Further addition of up to 2.5 equiv of Lewis acid showed
no change in the NMR spectrum. In the absence of LA, the proton
signals of -CH3 and -CHF- appear at δ 1.58 (dd, JHH ) 6.7 Hz,
JHF ) 24.4 Hz) and δ 5.96 (dq, JHH ) 6.7 Hz, JHF ) 49.0 Hz)
(Figure 1A), respectively. A significant downfield shift of the
To examine the concept of chelation control in detail, R-fluoro-
propiophenone was prepared using standard methods. Reductions
were examined in CH2Cl2 and Et2O using the mild reductants
NaBH4 and LiBH4 in the presence and absence of TiCl4 and
Ti(OiPr)4. When the Lewis acids were used, they were premixed
with substrate for 15 min at -78 °C before addition of reductant.
Diastereomers were determined by 1H and 19F NMR coupling
constants, and the selectivity was determined by GC. The results
of these experiments are shown in Table 1. In the absence of a
Lewis acid, NaBH4 provides the anti diastereomer predominantly,
whereas LiBH4 provides the syn isomer, but overall, the selectivity
was modest. The addition of TiCl4 produced the syn diastereomer
regardless of the solvent or reductant used, and the selectivity is
corresponding proton signals to δ 2.15 (dd, JHH ) 6.4 Hz, JHF
28.8 Hz, CH3) and δ 6.82 (bdd, JHH ) 5.8 Hz, JHF ) 50.4 Hz,
)
† Lehigh University.
‡ Texas Tech University.
9
11896
J. AM. CHEM. SOC. 2005, 127, 11896-11897
10.1021/ja052546x CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Reduction of R-Fluoroketones by LiBH4 in Et2O in the
a
Presence of TiCl4
entry
substrate
LA
syn:anti
yield (%)
1
2
3
4
5
6
7
8
9
R-fluorotetralone
none
TiCl4
none
TiCl4
none
TiCl4
none
TiCl4
none
TiCl4
8:1
27:1
3:1
32:1
1:1
5:1
1:1
6:1
2:1
q
q
R-fluorotetralone
R-fluoroindanone
R-fluoroindanone
3-fluoro-2-butanone
3-fluoro-2-butanone
3-fluoro-2-octanone
3-fluoro-2-octanone
4-fluoro-5-nonanone
4-fluoro-5-nonanone
98
87
91
85
93
88
96
89
10
5:1
a Experimental conditions: 1 equiv of substrate is treated with 1.25-
2.5 equiv of LA at -78 °C, followed by addition of 2 equiv of LiBH4.
Reaction times were 5-7 h.
(Table 2). In each case, pretreatment with TiCl4 substantially
increased the diastereoselectivity of the reduction, providing a
selectivity consistent with chelation. Detailed mechanistic studies
on the use of other Lewis acids and the role of solvent on the
diastereoselectivity of reductions and bond-forming reactions are
currently being examined. The results of these studies will be
reported in due course.
Figure 1. All spectra are recorded at -78 °C in CD2Cl2.1H, 13C, and 19F
NMR spectra of 2-fluoropropiophenone are shown in A, D, and G,
respectively. Spectra B, E, H and C, F, I are the 1H, 13C, and 19F NMR
spectra of 2-fluoropropiophenone-TiCl4 complex and 2-fluoropropio-
phenone-Ti(OiPr)4 complex, respectively. In all 1H NMR spectra, the peak
at δ 5.32 is due to trace amounts of CHDCl2 in CD2Cl2, whereas the
additional peaks at δ 1.41 and 4.67 in spectrum C are due to isopropoxide.
In all 13C NMR spectra, the peak at δ 54.0 is due to CD2Cl2, and the peaks
at δ 76.59 and 26.71 in spectrum F are due to isopropoxide. The peak at δ
25.54 in F is due to 2-propanol impurity.
Acknowledgment. R.A.F. is grateful to the National Science
Foundation (CHE-0413845) and Lehigh University for support of
this work. We thank the reviewers for their insightful comments
on the manuscript.
1
CHF) are observed when H NMR is recorded in the presence of
TiCl4 under similar conditions (Figure 1B).
Supporting Information Available: General experimental condi-
tions, synthetic procedures, and spectral data (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
In the presence of TiCl4, the 13C spectrum shows that the carbonyl
carbon, CH3CFH- and CH3 appear at δ 205.8 (bs), δ 98.36 (d),
and δ 20.12 (d) (Figure 1E), whereas the respective 13C signals of
R-fluoropropiophenone in the absence of Lewis acid appear at δ
196.17 (d), δ 90.93 (d), and δ18.11 (d) (Figure 1D). Addition of
TiCl4 also results in a downfield shift of the aromatic 13C signals
[δ 129.0, 130.7, 132.23, 140.33] with respect to original aromatic
13C signals [δ 129.0, 129.12, 134.07, 134.47]. In addition, 19F NMR
spectra of R-fluoropropiophenone in the presence and absence of
TiCl4 display the 19F signal at δ -174.82 (m) and δ -187.0 (m),
respectively. Interaction of Ti with the fluorine and the carbonyl,
as shown by the concomitant shift of the 19F signal and 13C, provides
compelling evidence for the formation of TiCl4-R-fluoropropio-
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1
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