First stereospecific synthesis of (E)- or (Z)-α-fluoroenones via a kinetically controlled Negishi coupling reaction

Article abstract of DOI:10.1021/jo0604787

A highly stereospecific synthesis of (E)- or (Z)-α-fluoro-α, β-unsaturated ketones 4, via a kinetically controlled Negishi palladium-catalyzed coupling reaction, was developed, providing an easy and general access to valuable fluorinated intermediates (pharmaceutical, peptide mimic, and so on). The synthesis involved a reaction between E/Z gem-bromofluoroolefins 2 and alkoxyvinylzinc species 6 under controlled reaction temperature. At 10 °C, (Z)-4 (70 to 99% yields) was obtained along with unreacted (Z)-2 (66 to 99% yields). At THF reflux, the recovered olefin was transformed into (E)-4 (up to 98% yield).

Full text of DOI:10.1021/jo0604787

(sCOsNHs) as a result of steric and electronic similarities.3
Fluoroolefins have been used in peptide chemistry as hydro-
lytically stable mimics of peptidic bonds.4 Depending on the
initial configuration of the double bond (E or Z), an access to
blocked cisoide or transoide peptidic bond conformation mimics
is made possible. Since the pioneering study in the peptide area
by Allmendinger et al.,4a some useful methods for the synthesis
of fluoroalkenes have been reported.5,6 Nevertheless, despite
these methods, several problems remain to be tackled, in
particular with respect to the control of the Z or E configuration
of the double bond, the stereochemistry of the chiral center R
to the double bond, and the versatility of the syntheses.
Our initial project aimed to propose a stereospecific and mild
method to obtain both isomers of dipeptide mimics 5. Our
strategy was based on the reaction of easily accessible bromo-
fluoroalkenes 27 to set up the carbon skeleton, followed by a
Nozaki-Hiyama-Kishi reaction (Scheme 1).8 Unfortunately,
under these conditions, we were unable to access to the E
isomer, probably because of the instability of the chromium
intermediate derived from (Z)-bromofluoroalkenes 2.
First Stereospecific Synthesis of (E)- or
(Z)-r-Fluoroenones via a Kinetically Controlled
Negishi Coupling Reaction
Guillaume Dutheuil, Clotilde Paturel, Xinsheng Lei,
Samuel Couve-Bonnaire, and Xavier Pannecoucke*
IRCOF-ECOFH, UMR CNRS 6014, INSA de ROUEN, rue
Tesnie`re, 76131 Mont-Saint-Aignan, France
xaVier.pannecoucke@insa-rouen.fr.
ReceiVed March 6, 2006
To provide straightforward access to both isomers from the
same precursor 2, we decided to investigate the palladium-
catalyzed coupling reactions, which are known to react with
hindered Z vinylhalides.9 Another advantage of these methods
is the potential difference in reactivity between E and Z isomers,
which allows a selective coupling of the E isomer in the presence
of the Z isomer by kinetic control.10 To anticipate further
A highly stereospecific synthesis of (E)- or (Z)-R-fluoro-
R,â-unsaturated ketones 4, via a kinetically controlled
Negishi palladium-catalyzed coupling reaction, was devel-
oped, providing an easy and general access to valuable
fluorinated intermediates (pharmaceutical, peptide mimic, and
so on). The synthesis involved a reaction between E/Z gem-
bromofluoroolefins 2 and alkoxyvinylzinc species 6 under
controlled reaction temperature. At 10 °C, (Z)-4 (70 to 99%
yields) was obtained along with unreacted (Z)-2 (66 to 99%
yields). At THF reflux, the recovered olefin was transformed
into (E)-4 (up to 98% yield).
(3) (a) Welch, J. T.; Lin, J.; Boros, L. G.; De Corte, B.; Bergmann, K.;
Gimi, R. H. In Biomedical Frontiers of Fluorine Chemistry; The American
Chemical Society: Washington, DC, 1996; Chaper 10, pp 129-142. (b)
Cieplak, P.; Kollman, P. A.; Radomski, J. P. In Biomedical Frontiers of
Fluorine Chemistry; The American Chemical Society: Washington, DC,
1996; Chapter 11, pp 143-156 (c) Abraham, R. J.; Ellison, S. L. R.;
Schonholzer, P.; Thomas W. A. Tetrahedron 1986, 42, 2101-2110.
(4) (a) Allmendiger, T.; Furet, P.; Hungerbu¨hler, E. Tetrahedron Lett.
1990, 31, 7297-7300 and 7301-7304. (b) Boros, L. G.; De Corte, B.;
Gimi, R. H.; Welch, J. T.; Wu, Y.; Handschumacher, R. E. Tetrahedron
Lett. 1994, 35, 6033-6036. (c) Zhao, K.; Lim, D. S.; Funaki, T.; Welch, J.
T. Bioorg. Med. Chem. 2003, 11, 207-215. (d) Van der Veken, P.; Senten,
K.; Kerte`sz, I.; De Meester, I.; Lambeir, A.-M.; Maes, M.-B.; Scharpe´, S.;
Haemers, A.; Augustyns, K. J. Med. Chem. 2005, 48, 1768-1780.
(5) (a) Welch, J. T.; Lin, J. Tetrahedron 1996, 52, 291-304. (b) Van
der Veken, P.; Kerte`sz, I.; Senten, K.; Haemers, A.; Augustyns, K.
Tetrahedron Lett. 2003, 44, 6231-6234. (c) Veenstra, S. J.; Hauser, K.;
Felber, P. Bioorg. Med. Chem. Lett. 1997, 7, 351-354. (d) Hollenstein,
M.; Leumann, C. J. J. Org. Chem. 2005, 70, 3205-3217. (e) Bartlett, P.
A.; Otake, A. J. Org. Chem. 1995, 60, 3107-3111.
(6) (a) Nakamura, Y.; Okada, M.; Sato, A.; Horikawa, H.; Koura, M.;
Saito, A.; Taguchi, T. Tetrahedron 2005, 61, 5741-5753. (b) Otaka, A.;
Watanabe, H.; Mitsuyama, E.; Yukimasa, A.; Tamamura, H.; Fujii, N.
Tetrahedron Lett. 2002, 43, 5845-5847. (c) Otaka, A.; Watanabe, H.;
Yukimasa, A.; Sasaki, Y.; Watanabe, H.; Kinoshita, T.; Oishi, S.; Tamamura,
H.; Fujii, N. J. Org. Chem. 2004, 69, 1634-1645.
(7) (a) Lei, X.; Dutheuil, G.; Pannecoucke, X.; Quirion, J.-C. Org. Lett.
2004, 6, 2101-2104. (b) Burton, D. J.; Yang, Z.-Y.; Qiu, W. Chem. ReV.
1996, 96, 1641-1715.
(8) Dutheuil, G.; Lei, X.; Pannecoucke, X.; Quirion, J.-C. J. Org. Chem.
2005, 70, 1911-1914.
The development of efficient and mild methods for the
synthesis of organofluorine compounds represents a broad area
in organic chemistry, because the incorporation of a fluorine-
containing group into an organic molecule dramatically alters
its physical, chemical, and biological properties.1 Among them,
monofluorinated olefins have attracted a great deal of attention
because of their wide range of applications.1,2 Especially,
fluoroolefins (sCFdCHs) can act as ideal amide bond mimics
* Corresponding author. Fax: (33) 2.35.52.29.59. Tel.: (33) 2.35.52.24.27.
(1) (a) Kirsch, P., Ed. Modern Fluoroorganic Chemistry; Wiley-VCH:
Weinheim, Germany, 2004. (b) Chambers, R. D., Ed. Fluorine in Organic
Chemistry; Blackwell Publishing CRC Press: Boca Raton, FL, 2004. (c)
Banks, R. E., Smart, B. E., Tatlow, J. C., Eds. Organofluorine Chemistry:
Principle and Principal Applications; Plenum Press: New York, 1994.
(2) (a) Fieler, R.; Kobayashi, Y. Biomedical Aspects of Fluorine
Chemistry; Elsevier: Amsterdam, 1982. (b) Ojima, I. ChemBioChem 2004,
5, 628-635. (c) Jeschke, P. ChemBioChem 2004, 5, 570-579. (d) Resnati,
G., Soloshnok, V. A., Eds.; Fluoroorganic Chemistry: Synthetic Challenges
and Biomedical Rewards; Tetrahedron Symposia-in-print No. 58 Tetrahe-
dron 1996, 52, 1-330.
(9) (a) Andrei, D.; Wnuk, S. F. J. Org. Chem. 2006, 71, 405-408. (b)
Eddarir, S.; Francesh, C.; Mestdagh, H.; Rolando, C. Tetrahedron Lett. 1990,
31, 4449-4452. (c) Chen, C.; Wilcoxen, K.; Strack, N.; McCarthy, J. R.
Tetrahedron Lett. 1999, 40, 827-830. (d) Xu, J.; Burton, D. J. Tetrahedron
Lett. 2002, 43, 2877-2879.
(10) (a) Xu, J.; Burton, D. J. J. Org. Chem. 2005, 70, 4346-4353. (b)
Shimizu, M.; Nakamaki, C.; Shimono, K.; Schelper, M.; Kurahashi, T.;
Hiyama, T. J. Am. Chem. Soc. 2005, 127, 12506-12507. (c) Tan, Z.;
Negishi, E. Angew. Chem., Int. Ed. 2006, 45, 762-765. (d) Zeng, X.; Quian,
M.; Hu, Q.; Negishi, E. Angew. Chem., Int. Ed. 2004, 43, 2259-2263.
10.1021/jo0604787 CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/04/2006
4316
J. Org. Chem. 2006, 71, 4316-4319

SCHEME 1. Fluoroolefins as Amide Mimics; General Method Envisioned
SCHEME 2. Stereospecific Synthesis of (Z)-r-Fluoroenones
from an E/Z Mixture of Bromofluoroolefins 2a
of (E)- or (Z)-R-fluoro-R,â-unsaturated ketones 4 via a kineti-
cally controlled palladium-catalyzed coupling reaction.
Stereospecific Preparation of (Z)-r-Fluoro-r,â-unsatur-
ated Ketones. We reasoned that 1-bromo-1-fluoroolefins 2 (E/Z
≈ 1/1),7 could serve as precursors for the preparation of both
E- and Z-R-fluoroenones, provided sufficient kinetic differences
can be exploited. Based on the Hegedus and Russel13a and
Negishi and Luo13b procedure, we first optimized the preparation
of the R-ethoxyvinylzinc chloride 6a. The best results were
obtained reacting ethoxyethene with 1 equiv of the Lochmann-
Schlosser superbase (n-BuLi/t-BuOK) and 2 equiv of zinc
chloride in THF from -78 °C to rt. After optimization of the
reaction conditions (temperature, palladium catalyst, and reaction
time), the E/Z mixture of bromofluoroalkenes 2 was reacted
under Negishi coupling conditions with 0.85 equiv of R-ethoxy-
vinylzinc chloride 6a, 2.5% of Pd(OAc)2, and 5% of PPh3 in
THF at 10 °C, yielding the enolether intermediates (Scheme
2). After hydrolysis, the R-fluoro-R,â-unsaturated ketones 4a
were isolated in high yields. Aldehyde-derived bromofluoroole-
fins led to a totally stereospecific coupling; at 10 °C, only
bromofluoroolefins (E)-2 reacted, affording ketones (Z)-4a along
with the unreacted (Z)-2. The reaction was versatile and mild
enough to be compatible with various substituents: aromatic,
aliphatic, functionalized (ester, nitrile, halogen, protected alco-
hol). The coupling product and the recovered bromofluoroolefins
(Z)-2 were isolated in excellent yields (79 to 99% and 66 to
98%, respectively; Table 1 entries 1-8). Actually, temperature
was revealed to play a crucial role: rising the medium above
10 °C led to an E/Z mixture of ketones 4a.
At this stage, we had only considered R-ethoxyvinylzinc
chloride 6a in the Negishi coupling reaction. To probe the scope
and limitations of the reaction, we extended our investigation
to â-substituted R-ethoxyvinylzinc derivatives, both in aromatic
and in aliphatic series. The access to phenylalanine-type mimics
required coupling substrates such as 6b (R2dPh).14 A convenient
introduction of various aliphatic chains, aimed to build common
amino acid moiety, was also desired. Accordingly, we first
attempted to prepare â-methyl-R-ethoxyvinylzinc derivatives 6
(R2)Me). However, the addition of 1 equiv of the Lochmann-
Schlosser base and 2 equiv of zinc chloride to 1-ethoxypropene
in THF led exclusively to the more stable allylic zinc deriva-
a Reagents and conditions: (a) 6a-d (0.85 equiv), Pd(OAc)2 2.5%/PPh3
5%, THF, 10 °C; (b) 1 N HCl, rt; (c) i. mCPBA, CH2Cl2, MeOH; ii. NaBH4,
EtOH; iii. pTsOH in 1% aq acetone (R1 ) 4-MeOPh 38%).
transformations into dipeptide mimics, a functionalized carbon
is to be introduced R to the fluorovinyl moiety. Only a few
examples of palladium-catalyzed coupling reactions with bro-
mofluoroolefins affording R-functionalized fluoroalkenes have
been described to date: the carbonylation, affording the
corresponding conjugated esters or amides10a (transformation
into chiral amines 5 appeared to be rather complicated as shown
by Allmendinger et al.4a and Welch and Lin5a) and the reaction
with aromatic acyl chloride, affording fluoroenones 4.11 Surpris-
ingly, and despite their interest in organic synthesis (Michael
addition, Diels-Alder reaction) and the fact that these ketones
should be easily converted into dipeptide mimics, only a few
routes to R-fluoro-R,â-enones were described.11,12 These ones
revealed to be inadapted to our peptidomimetic program in terms
of substrate diversity, yields or reaction conditions. To overcome
these limitations we, therefore, turned our attention toward the
Negishi-type coupling reaction (Scheme 2). Additionally, the
good availability of zinc derivatives makes this approach highly
attractive.13 Herein, we report the first stereospecific synthesis
(11) (a) Chen, C.; Wilcoxen, K.; Zhu, Y. F.; Kim, K.; McCarthy, J. R.
J. Org. Chem. 1999, 64, 3476-3482. (b) Chen, C.; Wilcixen, K.; Huang,
C. Q.; Strack, N.; McCarthy, J. R. J. Fluorine Chem. 2000, 101, 285-290.
(12) (a) Bainbridge, J. M.; Corr, S.; Kanai, M.; Percy, J. M. Tetrahedron
Lett. 2000, 41, 971-974. (b) Kanai, M.; Percy, J. M. Tetrahedron Lett.
2000, 41, 2453-2455.
(13) (a) Russel, C. E.; Hegedus, L. S. J. Am. Chem. Soc. 1983, 105,
943-949. (b) Negishi, E.-I.; Luo, F.-T. J. Org. Chem. 1983, 48, 1560-
1562. (c) Su, M.; Kang, Y.; Yu, W.; Hua, Z.; Jin, Z. Org. Lett. 2002, 4,
691-694.
(14) (a) Tzalis, D.; Koradin, C.; Knochel, P. Tetrahedron Lett. 1999,
40, 6193-6195. (b) Soderquist, J. A.; Hsu, G. J.-H. Organometallics 1982,
1, 830-833.
J. Org. Chem, Vol. 71, No. 11, 2006 4317

TABLE 1. Reaction of an E/Z Mixture of Bromofluoroolefins 2
under Negishi Coupling Conditions
TABLE 2. Reaction of (Z)-Bromofluoroolefins under Negishi
Coupling Conditions
substrate:
organo- product: (Z)-2 yieldb
substrate:
organo-
zinc
product:
yield (%)
entry
R1 (E/Z ratio)
zinc
yielda (%)
(%)
entry
R1 (E/Z ratio)
1
2
3
4
5
6
7
8
9
21: 4-MeO-C6H4 (51/49)
22: 2-naphthyl (48/52)
6a
6a
6a
6a
6a
6a
6a
6a
6b
6b
6c
6c
6d
6d
(Z)-4a1: 85
(Z)-4a2: 86
(Z)-4a3: 85
(Z)-4a4: 92
(Z)-4a5: 99
(Z)-4a6: 91
(Z)-4a7: 79
(Z)-4a8: 94
(Z)-4b1: 93c
(Z)-4b2: 95c
(Z)-4c1: 75c
(Z)-4c2: 70c
(Z)-71: 95
86
85
70
90
88
66
98
93
99
71
84
69
90
85
1
2
3
4
5
6
7
8
9
10
11
12
13
14
21: 4-MeO-C6H4
22: 2-naphthyl
6a
6a
6a
6a
6a
6a
6a
6a
(E)-4a1: 72
(E)-4a2: 81
(E)-4a3: 83
(E)-4a4: 17a
(E)-4a5: 51a
0
(E)-4a7: 70
(E)-4a8: 77
(Z)-4b1: 98c
(E)-4b2: 79
(E)-4c1: 90d
(E)-4c2: 88d
(E)-71: 71
(E)-72: 78
23: 4-NC-C6H4 (45/55)
24: 4-MeO2C-C6H4 (45/55)
25: 4-O2N-C6H4 (42/58)
26: 4-Br-C6H4 (45/55)
27: PhCH2CH2 (51/49)
28: TBDPSOCH2CH2 (47/53)
21: 4-MeO-C6H4 (51/49)
23: 4-NC-C6H4
24: 4-MeO2C-C6H4
25: 4-O2N-C6H4
26: 4-Br-C6H4
27: PhCH2CH2
28: TBDPSOCH2CH2
21: 4-MeO-C6H4
27: PhCH2CH2
21: 4-MeO-C6H4
27: PhCH2CH2
6bb
6bb
6cb
6cb
6d
6d
10 27: PhCH2CH2 (51/49)
11 21: 4-MeO-C6H4 (51/49)
12 27: PhCH2CH2(51/49)
13 21: 4-MeO-C6H4 (51/49)
14 27: PhCH2CH2(51/49)
21: 4-MeO-C6H4
27: PhCH2CH2
(Z)-72: 79
a Based on starting (E)-2 isomer. b Based on starting (Z)-2 isomer. c Zinc
derivatives 6 are needed in the amount of 2 equiv.
a Along with (Z)-4a (entry 4, 58%; entry 5, 27%). b Zinc derivatives 6
are needed in the amount of 4 equiv. c Enoletherhydrolysis conditions: 6
N HCl, 70 °C. d The coupling reactions were performed at 55 °C.
SCHEME 3. Stereospecific Synthesis of
(E)-r-Fluoro-r,â-unsaturated Ketones from (Z)-2a
2, entries 1-3, 7-8, and 10-14). Note that to prevent coupling
of the allylic zinc reagent present in the mixture with 6c and to
get higher yields, the palladium-catalyzed Negishi reaction had
to be run at 55 °C, with 4 equiv of the zinc mixture.
These higher temperature conditions (reflux of THF) led
bromoaromatic derivatives to decompose, probably due to side
coupling reactions at the aromatic site (Table 2, entry 6). With
good electron-withdrawing substituents (CO2Me and NO2), a
partial isomerization was observed, yielding a chromatographi-
cally separable E/Z mixture of compounds 4 (Table 2, entries
4-5). With aromatic (Z)-2 and 6b (Table 2, entry 9), ketone
(Z)-4b was even obtained in 98% yield instead of (E)-4b,
probably because of the harsh conditions needed to hydrolyze
the conjugated enolether intermediates.18 In all cases, the
isomerization occurred during the enolether hydrolysis, as the
enolether intermediates were only present under the E config-
uration (3JH-F ) 17 Hz).
We could use this feature to obtain exclusively (Z)-4 from
an E/Z mixture of bromofluoroolefins 2. Indeed, running the
Negishi reaction under reflux of THF led to an E/Z mixture of
enolether intermediates, which could then be transformed under
strong acidic conditions to the pure (Z)-4 isomer. Unfortunately,
because of the acidic instability of some conjugated ketones 4
(especially 4a and 4c), this improved route was applicable to
only a few cases.19
a Reagents and conditions: (a) 6 (2 equiv), Pd(OAc)2 5%/PPh3 10%,
THF, reflux; (b) 1 N HCl, rt (c) i. mCPBA, CH2Cl2, MeOH; ii. NaBH4,
EtOH; iii. pTsOH in 1% aq acetone (R1 ) 4-MeOPh, 42%).
tive.15 We then tried to prepare 6c (R2 ) Et). As predicted from
the work of Sebastian and Power,15 in the case of 6c, due to
the presence of an allylic methylene group, a mixture of allylic
and vinylic zinc chlorides was recovered. Two equivalents of
this mixture were coupled in the condition described above with
olefins 2. Only the more reactive vinylic zinc derivatives 6c
gave rise to the coupling product 4c. We also tried the
functionalized coupling reagent 6d16 (2,3-dihydro-1,4-dioxine
zinc chloride) en route to serine-type peptide mimics.
With these three organozinc derivatives, 6b-d, the coupling
reactions proceeded smoothly and stereospecifically with the
isomeric mixture of trisubstituted bromofluoroolefins 2 (aliphatic
or aromatic); at 10 °C, only bromofluoroolefins (E)-2 reacted,
providing in high yields (Z)-7 (from 6d) or after hydrolysis (Z)-
4b, (Z)-4c (from 6b and c, respectively). In all cases, the
recovery of the unreacted isomers (Z)-2 was achieved in high
yield (Table 1, entries 9-14). A known, purification-free, three-
step procedure17 allowed us to transform coupling products (Z)-7
into the desired functionalized R-fluoro-R,â-unsaturated ketone
(Z)-4d (38% overall yield, 72% per step).
Synthesis of Chiral Nonracemic (E)- and (Z)-r-Fluoro-
r,â-unsaturated Ketones. The application of the above strategy
to the synthesis of peptidomimetic derivatives required that our
coupling reaction did not racemize the stereogenic center borne
by the substrates (Scheme 1). To control the mildness of the
procedure, enantiomerically pure bromofluoroolefin (R)-97a was
prepared from chiral nonracemic aldehyde (S)-8.20 The E/Z
mixture (R)-9 was then subjected to our standard Negishi
Stereospecific Preparation of (E)-r-Fluoro-r,â-unsatur-
ated Ketones. The recovered bromofluoroolefins (Z)-2 were
submitted, at higher temperature (reflux of THF), to similar
Negishi reaction conditions. Thus, 6a-d (Scheme 3) afforded,
stereospecifically and after hydrolysis, R-fluoro-R,â-unsaturated
ketones (E)-4 in very good coupling yields (70 to 90%, Table
(18) Strongly acidic conditions such as H2SO4, 6 N HCl, and pTsOH
were required and led to totally isomerized ketone (Z)-4b, while milder
conditions such as amberlyst 15, HClO4, HCO2H, 1 N HCl were ineffective.
TMSI deprotection led to the decomposition of the enolether intermediates.
(19) 4b (hydrolysis conditions; 6 N HCl, 70 °C, up to 99% yield based
on (E)-2 + (Z)-2) and 4a,c with R1 ) 4-NO2-Ph and 4-MeO2C-Ph
(hydrolysis conditions; 1 N HCl, rt, 12h, up to 75% yield based on (E)-2
+ (Z)-2).
(15) Power, T. D.; Sebastian, J. F. Tetrahedron 1998, 54, 8371-8392.
(16) Fetizon, M.; Goulaouic, P.; Hanna, I. Tetrahedron Lett. 1985, 26,
4925-4928.
(17) Fetizon, M.; Goulaouic, P.; Hanna, I. J. Chem. Soc., Perkin Trans.
1 1990, 1107-1110.
(20) Konno, K.; Fujishima, T.; Maki, S.; Liu, Z.; Miura, D.; Chokki,
M.; Ishizuka, S.; Yamaguchi, K.; Kan, Y.; Kurihara, M.; Miyata, N.; Smith,
C.; DeLuca, H. F.; Takayama, H. J. Med. Chem. 2000, 43, 4247-4265.
4318 J. Org. Chem., Vol. 71, No. 11, 2006

SCHEME 4. Stereospecific Synthesis of Nonracemic (E)-
and (Z)-r-Fluoro-r,â-unsaturated Ketone from Chiral
Nonracemic Aldehydea
mmol), and a mixture of bromofluoroolefins 21 (4.7 g, 20.3 mmol)
in anhydrous THF (200 mL) at 10 °C under argon. The mixture
was stirred for 1 h. HCl aq (1N, 200 mL) was added, and the
solution was stirred for 15 min. The mixture was then extracted
with Et2O (200 mL x 3), washed with brine, and the combined
organic layers were dried over MgSO4. After filtration and
concentration under reduced pressure, the residue was purified by
chromatography on silica gel (eluent: 5% AcOEt in cyclohexane),
affording fluorenones (Z)-4a1 (1.72 g, 8.82 mmol, yield ) 85%)
and unreacted bromofluoroolefin (Z)-21 (1.98 g, 8.57 mmol, yield
) 86%).
(Z)-2-1: (Z)-1-(2-Bromo-2-fluorovinyl)-4-methoxybenzene.7a
(Z)-4a-1: (Z)-3-Fluoro-4-(4-methoxyphenyl)but-3-en-2-one. Yel-
low powder (mp ) 72-74 °C), Rf 0.2 (5% AcOEt in cyclohexane).
1H NMR (300 MHz, CDCl3) δ 7.6 (d, J ) 8.9 Hz, 2H, H4), 6.9 (d,
J ) 8.9 Hz, 2H, H5), 6.7 (d, 3JH-F ) 36.9 Hz, 1H, H2), 3.7 (s, 3H,
H7), 2.3 (d, 4JH-F ) 3.3 Hz, 3H, H9). 19F NMR (282.5 MHz, CDCl3)
δ -127.1 (dq, 3JH-F ) 36.9 Hz, 4JH-F ) 3.3 Hz). 13C NMR (75.5
MHz, CDCl3) δ 192.2 (d, 2JC-F ) 32 Hz, C8), 161.2 (d, J ) 4 Hz,
C6), 153.5 (d, 1JC-F ) 267 Hz, C1), 135.5 (d, J ) 6 Hz, C4), 124.0
a Reagents and conditions: (a) CFBr3, PPh3, ZnEt2, THF, rt, 85%; (b) i.
6a (1.5 equiv), Pd(OAc)2 5%/PPh3 10%, THF, 10 °C or reflux; ii. 1 N
HCl, rt, (R,Z)-10 81% based on (E)-bromofluoroolefin, (R,E)-10 62% based
on (Z)-bromofluoroolefin.
coupling conditions with 6a, affording separately after hydrolysis
(R,Z)-10 (81%) and (R,E)-10 (62%; Scheme 4).
3
2
(d, JC-F ) 4 Hz, C3), 116.4 (d, JC-F ) 6 Hz, C2), 114.5 (d, J )
18 Hz, C5), 55.7 (C7), 25.9 (C9). MS (EI) 194 (M+), 179 (M+
-
CH3), 159, 43 (CH3CO+). IR (KBr) 3037, 2970, 2937, 2898, 2837,
1672, 1643, 1605, 1570, 1513, 1424, 1343, 1264, 1185, 1177, 1069,
1022, 869, 808, 539 cm-1. Anal. Calcd for C11H11FO2: C, 68.03;
H, 5.71. Found: C, 68.06; H, 5.63.
After various unsuccessful attempts to determine the enan-
tiomeric purities of (R,Z)-10 and (R,E)-10 (Chiral GC or
HPLC), the excesses could finally be measured by 19F NMR
studies of the crude chiral imines resulting from the condensation
of 10 with a chiral nonracemic amine. By comparison with the
19F NMR chemical shift of the imine derived from racemic 10,
the enantiomeric purities were determined to be more than 95%
for (R,Z)-10 and (R,E)-10 (see spectra in the Supporting
Information).
In summary, we report the first stereospecific synthesis of
(E)- or (Z)-R-fluoro-R,â-unsaturated ketones 4 via a kinetically
controlled Negishi palladium-catalyzed coupling reaction. The
method is high yielding, mild, versatile, and nonracemizing.
Varying the starting aldehydes and the substituted R-ethoxyvi-
nylzinc derivatives (including one with allylic hydrogen atom),
a large number of fluoroenones 4 are accessible. These
compounds 4 could be relevant intermediates in agro and
pharmaceutical chemistry and could also act as peptide bond
mimics. In our ongoing chemical-biology program, we are
currently concentrating our effort toward the transformation of
fluoroolefins 4 into dipeptide analogues (Z)-5 or (E)-5.
Representative procedure for the obtention of (E)-fluorinated
methyl ketones (E)-4 from (Z)-2. Same protocol was used as for
(Z)-4a1, preparing 2 equiv of vinylzinc derivatives 6a and letting
the coupling reaction occur at the reflux of THF with 0.05 equiv
of palladiumdiacetate and 0.1 equiv of PPh3. Bromofluoroolefin
(Z)-2 afforded, after purification by chromatography on silica gel
(eluent: 5% AcOEt in cyclohexane), (E)-methyl ketone (E)-4a1
(1.2 g, 6.17 mmol, yield ) 72%).
(E)-4a1: (E)-3-Fluoro-4-(4-methoxyphenyl)but-3-en-2-one. Yel-
1
low solid (mp < 44°C), Rf 0.2 (5% AcOEt in cyclohexane). H
NMR (300 MHz, CDCl3) δ 7.6 (d, J ) 8.9 Hz, 2H, H4), 6.9 (d, J
3
) 8.9 Hz, 2H, H5), 6.7 (d, JH-F ) 26.1 Hz, 1H, H2), 3.7 (s, 3H,
H7), 2.3 (d, 4JH-F ) 5.1 Hz, 3H, H9). 19F NMR (282.5 MHz, CDCl3)
3
4
δ -115.2 (d, JH-F ) 26.1 Hz, JH-F ) 5.1 Hz). 13C NMR (75.5
MHz, CDCl3) δ 193.4 (d, 2JC-F ) 39 Hz, C8), 161.2 (d, J ) 2 Hz,
C6), 152.6 (d, 1JC-F ) 252 Hz, C1), 132.6 (d, J ) 3 Hz, C4), 123.5
3
2
(d, JC-F ) 10 Hz, C3), 121.0 (d, JC-F ) 29 Hz, C2), 114.1 (C5),
55.7 (C7), 28.6 (d, 3JC-F ) 4 Hz, C9). MS (EI) 194 (M+), 179 (M+
- CH3), 159, 43 (CH3CO+). IR (KBr) 3005, 2937, 2839, 1729,
1681, 1601, 1513, 1462, 1423, 1371, 1304, 1257, 1177, 1031, 832,
599, 533. Anal. Calcd for C11H11FO2: C, 68.03; H, 5.71. Found:
C, 68.09; H, 5.54.
Experimental Section
Representative Procedure for the Obtention of (Z)-Fluori-
nated Methyl Ketones (Z)-4 from an E/Z Mixture of Bromo-
fluoroolefins 2: Preparation of (Z)-4a1. To a mixture of potassium
tert-butoxide (1.94 g, 17.3 mmol) ethylvinyl ether (1.65 mL, 17.3
mmol) in anhydrous THF (85 mL) at -78 °C was added n-BuLi
in hexanes (1.6M, 10.8 mL, 17.3 mmol) dropwise under argon.
The mixture was stirred for 30 min at -78 °C, and then a solution
of dry zinc chloride (4.7 g, 34.6 mmol) in THF (135 mL) was added
dropwise. After 10 min, the cooling bath was removed, and the
solution was allowed to warm to room temperature for 30 min.
The mixture was then added slowly to a solution of palladiumdi-
acetate (115 mg, 0.51 mmol), triphenylphosphine (265 mg, 1.02
Acknowledgment. The authors want to thank the ministry
of Education and Research (doctoral fellowship to G.D.) and
the region Haute-Normandie (PunchOrga fellowship to C.P.)
for financial support.
Supporting Information Available: Complete experimental
1
section and H, 13C, and 19F NMR spectra with atom numbers for
the NMR spectra attribution. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO0604787
J. Org. Chem, Vol. 71, No. 11, 2006 4319