Catalytic asymmetric synthesis of cyclic α-allylated α-fluoroketones

Article abstract of DOI:10.1055/s-2006-950265

This manuscript details the development of an asymmetric, palladium-catalyzed, decarboxylative coupling of fluoroenolates with allyl electrophiles. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950265

2
824
LETTER
Catalytic Asymmetric Synthesis of Cyclic a-Allylated a-Fluoroketones
C
E
atalytic
A
symm
.
etric Synth
C
e
sis of Cyclic
a
-A
.
llylated
a
-F
B
luoroketones urger, B. R. Barron, J. A. Tunge*
Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045-7582, USA
Fax +1(785)8645396; E-mail: tunge@ku.edu
Received 12 June 2006
kinetic bases often fail, and the generation of boron
enolates results in enolization at the non-fluorinated car-
bon. A noteworthy exception was reported by Shimizu
in which palladium-catalyzed decarboxylation is used to
access fluorinated ketone enolates under mild condi-
tions.12
Abstract: This manuscript details the development of an asym-
metric, palladium-catalyzed, decarboxylative coupling of fluoro-
enolates with allyl electrophiles.
1
1
Key words: fluorine, enolate, decarboxylation, palladium
During the course of our studies13 on the asymmetric
palladium-catalyzed decarboxylative allylation of allyl b-
keto carboxylates,1 we became interested in developing
a catalytic system capable of inducing high levels of enan-
tioenrichment at the stereogenic a-carbon formed in the
g,d-unsaturated ketone product. More specifically, we
envisioned a route which would take advantage of the
ease with which b-keto esters can be fluorinated, followed
by the Pd-catalyzed decarboxylative allylation reaction to
yield products of high enantiopurity at the fluorinated
carbon center (Scheme 2).
The synthesis of organofluorine compounds is an area of
widespread interest due to the utility of fluoro-organic
compounds in pharmaceuticals, material science, and
4,15
1
agricultural chemistry. The development of relatively
non-hazardous, commercially available, and easily
handled electrophilic fluorinating reagents such as Select-
fluor has made a significant impact in the preparation of
2
,3
fluoro-organic compounds. Recently, particular atten-
tion has been directed toward development of catalysts for
the asymmetric electrophilic fluorination of enolates to
produce enantioenriched a-fluoro carbonyl compounds
4
a
4b
(
Scheme 1). While chiral, non-racemic zinc, nickel,
4
c
4d
O
O
O
O
O
copper, and palladium catalysts have been successfully
developed for the enantioselective fluorination of easily
enolizable b-keto esters, catalytic methods for the enan-
tioselective synthesis of simple a-fluoro ketones are not
F
F
Pd(0)/L*
O
Selectfluor
O
*
2
a
3a
well developed. Procedures employing Selectfluor with Scheme 2
catalytic amounts of various proline derivatives have only
recently been disclosed for the enantioselective fluorina-
Encouraged by reports on the asymmetric alkylation of
5
a
5b
tion of aldehydes and ketones, however, the enantio-
15b,c
allyl enol carbonates,
an extensive survey of various
6
selectivities obtained are moderate. Until recently,
chiral ligands was conducted for the transformation of
fluorinated b-keto ester 2a to ketone 3a (Table 1). It was
found that chiral P,N ligands provided the highest levels
of reactivity as well as selectivity. In contrast, the use of
bidentate nitrogenous ligands led to a catalytically inac-
tive species. More surprisingly, the Trost ligand-modified
palladium complex, which is known to be effective for the
published methods for the asymmetric fluorination of
ketone enolates relied on the stoichiometric addition of
enantioenriched N-fluorosultams or cinchona alkaloids to
7
,8
enolates, or diastereoselective fluorination of enantio-
enriched ketones.9
–
–
O
O
O
rearrangement of allyl-b-keto esters and enol carbon-
R3N*F+
R3
F
R X
3
R3
F
13a,15c
R1
R1
R1
ates,
failed to catalyze the reaction. In the course of
common
rare
R2
R2
R2
these studies Nakamura reported the use of PHOX ligands
for the asymmetric allylation of fluoro-enolates,1 thus
QUINAP was selected for further studies.
5a
Scheme 1
With the optimized reaction conditions in hand, the scope
of the reaction was briefly examined. Various fluorinated,
cyclic enolates were allylated with good enantioselectivi-
ty and good to excellent yields (Table 2). In all cases the
enolate was regiospecifically generated and byproducts
resulting from equilibration of enolate regioisomers were
not observed. For several saturated monocyclic b-keto
esters that were not previously investigated, we have com-
pared the enantioselectivities of the reaction utilizing the
tert-butyl PHOX ligand (Table 2 in parentheses) with
Asymmetric alkylation of fluorinated enolates is an alter-
native approach toward the synthesis of enantioenriched
a-fluoro ketones that remains relatively unexplored
1
0
(
Scheme 1). Perhaps this is because the generation of
fluorinated ketone enolates is unexpectedly difficult. For
instance, aldol reactions of fluoro ketones using typical
SYNLETT 2006, No. 17, pp 2824–2826
1
7
.1
0
.2
0
0
6
Advanced online publication: 09.10.2006
DOI: 10.1055/s-2006-950265; Art ID: S12806ST
©
Georg Thieme Verlag Stuttgart · New York

LETTER
Catalytic Asymmetric Synthesis of Cyclic a-Allylated a-Fluoroketones
2825
Table 1 Ligand Screen for Conversion of 2a to 3aa
Table 2 Yields and Enantioselectivities for Decarboxylative Ally-
lation of Fluoroenolates with the QUINAP Ligand
Substrate
Time (h) Yield (%)a era
O
O
N
O
NH HN
PPh2
O
O
N
PPh2
PPh2 Ph2P
O
8
92 (91)
84 (73)
82:18 (94:6)
84:16 (91:9)
R
F
Trost Ligand
PHOX
QUINAP
Ligand
% ee
Ligand
% ee
76 (S)
NR
2a
O
O
(
(
(
(
S)-QUINAP
85.5 (S)
88 (R)
38 (S)
8 (R)
(R)-i-PrPHOX
O
3.5
F
S)-t-BuPHOX P
R,M)-PINAP
S)-PhanPhos
R)-MOP
(1S,2S)-Trost ligand
(R,R)-MeDuPhos
(R,S)-JosiPhos
2
b
13 (S)
2 (S)
7 (S)
O
O
O
8
83 (94)
88:12 (90:10)
F
(
30 (S)
(R)-MonoPhos
a
Reactions were ran with Pd (dba) (2.5 mol%) and ligand (5.5
2c
2
3
mol%) at 40 °C in C D .
O
O
6
6
O
O
O
5
3
2
97
86:14
F
those obtained using the QUINAP ligand. While the
PHOX ligand performed somewhat better for substrates
2
2
d
O
2
a–c, QUINAP was much more effective for substrate 2g.
83
89:11
Furthermonre, the (S)-t-BuPHOX ligand provided the R
fluoro ketone while (S)-QUNIAP affored the S product.
We are currently working on models that will help explain
the origin of the enantioselectivity.
F
e
O
O
O
1
82 (64)
94:6 (73:27)
The mechanism of the decarboxylative allylation reaction
has been investigated and is commonly thought to begin
with the oxidative additon of substrates to Pd(0),1
producing cationic p-allyl palladium intermediates
F
3–15
2g
O
O
(
Scheme 3). Decarboxylation of the resulting b-keto car-
O
5
6
87
58
88:12
94:6
boxylates leads to the in situ generation of non-stabilized,
fluorinated palladium enolates. To maintain the preferred
F
2
h
1
6-electron configuration for palladium, this requires ei-
O
O
ther dissociation of one of the arms of the bidentate ligand
or formation of a s-allyl complex. Reductive elimination
from the allyl(enolato)palladium complex would result in
product formation and regenerate the Pd(0) catalyst.
O
F
2i
a
Results for t-Bu-PHOX ligand are shown in the parentheses.
O
O
O
F
F
O
LnPd0
reactions take advantage of the ease with which b-keto
esters are derivatized, which is a distinct advantage over
related decarboxylative couplings of enol carbonates.13
O
O
F
+
–
PdL
O
O
O
F
PdL
F
PdL
Catalytic Decarboxylative Allylation Reactions
In a Schlenk tube under Ar, Pd (dba) (2.5 mol%) and QUINAP (5.5
2
3
mol%) were dissolved in anhyd benzene (2 mL) and stirred for 1–2
min at 40 °C. The solution of catalyst was then cannula-transferred
to a Schenk tube containing the allyl-b-keto ester (4 mmol) in ben-
zene (2 mL). The reaction was stirred in a 40 °C oil bath for the re-
ported time (Table 2). Following solvent evaporation, the crude
CO2
Scheme 3
In conclusion, decarboxylative coupling of allyl b-keto product was purified by flash chromatography (SiO
, 3% Et O–
2 2
hex). Enantiomeric excesses were determined by GC utilizing a
chiral stationary phase (Chiraldex B-TA).
esters is an atom economical approach to the synthesis of
chiral non-racemic a-fluoro and a-alkyl ketones. These
Synlett 2006, No. 17, 2824–2826 © Thieme Stuttgart · New York

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826
E. C. Burger et al.
LETTER
2
-Allyl-2-fluorocycloheptanone (3a)
GC: Chiraldex B-TA: Hold 50 °C for 5 min, ramp 1 °C/min to
5 °C; t = 43.4, 44.8 min.
References
(
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9
R
–
1
IR (CD Cl ): 1712, 1606, 1433 cm .
2
2
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3
CH=CH ), 5.01 [d, J = 10 Hz, 1 H, CH=CH(H) ], 5.00 [d, J = 18
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3
C NMR (125 MHz, CDCl ): d = 210.82 (d, J = 24.0 Hz, C=O),
3
1
30.85 (=CH), 119.40 (=CH ), 101.70 (d, J = 185.22 Hz, CF), 41.11
2
(
(
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(
d, J = 22.6 Hz, allylic CH ), 39.94 (CH ), 35.18 (d, J = 23.9 Hz,
2 2
CH ), 27.80 (CH ), 24.29 (d, J = 2.5 Hz, CH ), 24.02 (d, J = 2.5 Hz,
2
2
2
(
b) Shibata N., Kohno J., Takai K., Ishimauru T., Nakamura
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1
9
F NMR (376 MHz, CDCl ): d = –161.66 (m).
3
1
5, 1007. (d) Hamashima, Y.; Yagi, K.; Takano, H.; Tamás,
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1
0
15
L.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124, 14530.
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71.1184.
(
(
2
-Allyl-2-fluorocyclohexanone (3b)
991.
GC: Chiraldex B-TA: Hold 50 °C for 5 min, ramp 1 °C/min to
6) NFSI provides much higher ee values: (a) Beeson, T. D.;
9
5 °C; t = 37.9, 43.6 min.
R
MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 8826.
–
1
IR (CD Cl ): 1728, 1604, 1413 cm .
2
2
(b) Marigo, M.; Fielenbach, D.; Braunton, A.; Kjaersgaard,
1
H NMR (500 MHz, CDCl ): d = 5.73 (ddt, J = 7, 10, 18 Hz, 1 H,
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3
CH=CH ), 5.09 [d, J = 10 Hz, 1 H, CH=CH(H) ], 5.08 [d, J = 18
2
cis
Hz, 1 H, CH=CH(H)trans], 2.60 (m, 2 H), 2.43 (m, 1 H), 2.30 (m, 1
H), 2.03 (m, 1 H), 1.82 (overlapping m, 4 H), 1.62 (m, 1 H).
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3
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3
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1
30.77 (=CH), 119.26 (=CH ), 97.71 (d, J = 183.78 Hz, CF), 39.36
2
(
8) (a) Davis, F.; Zhou, P.; Murphy, C. Tetrahedron Lett. 1993,
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(
allylic CH ), 38.76 (d, J = 2.5 Hz, CH ), 37.19 (d, J = 2.5 Hz, CH ),
2
2
2
3
2
7.18 (CH ), 21.42 (CH ).
2
2
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1
9
F NMR (376 MHz, CDCl ): d = –156.44 (m).
3
HRMS: m/z [M + H] calcd for C H OF: 157.1029; found:
9
13
(
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1
57.1034.
2
-Allyl-2-fluorocyclooctanone (3c)
(
(
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R
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–
1
IR (CD Cl ): 1712, 1606, 1465 cm .
2
2
1
H NMR (500 MHz, CDCl ): d = 5.67 (ddt, J = 7, 10, 17 Hz, 1 H,
3
CH=CH ), 5.05 [d, J = 10, 1 H, CH=CH(H) ], 5.03 [d, J = 17 Hz,
2
cis
1
H, CH=CH(H)trans], 2.63 (m, 1 H), 2.55 (ddd, J = 7, 14, 20 Hz, 1
H), 2.37 (ddd, J = 7, 14, 19 Hz, 1 H), 2.23 (m, 1 H), 2.10 (m, 1 H),
1
1
.98 (m, 1 H), 1.87 (m, 1 H), 1.71 (m, 1 H), 1.55 (m, 5 H), 1.17 (m,
H).
1
3
C NMR (125 MHz, CDCl ): d = 215.97 (d, J = 25.0 Hz, C=O),
3
1
31.10 (=CH), 119.49 (=CH ), 101.93 (d, J = 188.1 Hz, CF), 42.12
2
(
(
d, J = 22.6 Hz, allylic CH ), 39.70 (CH ), 37.68 (d, J = 22.6 Hz,
2 2
CH ), 27.41 (CH ), 26.00 (CH ), 24.85 (CH ), 21.37 (CH ).
2
2
2
2
2
1
9
F NMR (376 MHz, CDCl ): d = –167.59 (m).
3
HRMS: m/z [M + H] calcd for C H OF: 185.1342; found:
1
1
17
1
85.1353.
Acknowledgment
We thank the Petroleum Research Fund (44453-AC) and the
National Science Foundation (CHE-0548081) for financial support.
ECB thanks the Madison and Lila Self foundation for support.
Synlett 2006, No. 17, 2824–2826 © Thieme Stuttgart · New York