Modified Julia fluoroolefination: Selective preparation of fluoroalkenoates

Article abstract of DOI:10.1021/jo070994c

(Chemical Equation Presented) The modified Julia olefination reaction has been applied to develop a stereoselective synthesis of fluoroalkenoate derivatives from a fluorobenzothiazolyl sulfone and aldehydes or a ketone. The olefination reaction can be ach

Full text of DOI:10.1021/jo070994c

Modified Julia Fluoroolefination: Selective Preparation of
Fluoroalkenoates
Emmanuel Pfund, Cyril Lebargy, Jacques Rouden, and Thierry Lequeux*
Laboratoire de Chimie Mole´culaire et Thio-organique, ENSICAEN, UniVersite´ de Caen Basse-Normandie,
CNRS, 6 bouleVard du Mare´chal Juin, 14050 Caen, France
thierry.lequeux@ensicaen.fr
ReceiVed May 10, 2007
The modified Julia olefination reaction has been applied to develop a stereoselective synthesis of
fluoroalkenoate derivatives from a fluorobenzothiazolyl sulfone and aldehydes or a ketone. The olefination
reaction can be achieved by using a variety of bases. DBU and DBU in the presence of MgBr2 were
found to be the most efficient systems to prepare either (Z)- or (E)-alkenoates in moderate to excellent
stereoselectivity.
Introduction
prepare a variety of fluoroalkenes bearing an alkyl or function-
alized alkyl chain, to obtain enzyme inhibitors or peptide
mimics.3 The most efficient strategies install the carbon-carbon
double bond through a concerted elimination pathway from
fluorosulfoxides, fluorosilylacetates, fluorocarboxylates, or a
chemical modification of fluorovinylsulfones, gem-bromofluo-
roalkenes, or fluoroalkenoates.4 Due to the number of steps
Fluoroolefins are well-known as precursors of biologically
active compounds and have been successfully used to prepare
a new generation of modified pheromones, herbicides, and
medicines.1 The major approach for their preparation is based
on the Wittig or related reactions.2 However, these methods are
often limited to the synthesis of terminal fluoroalkenes, R-fluoro-
R,â-unsaturated esters, or 1-fluoro-1-arylmethylidene deriva-
tives. Some efforts have been made during the past decade to
(3) (a) Hollenstein, M.; Leumann, C. J. J. Org. Chem. 2005, 70, 3205-
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2005, 48, 1768-1780. (d) Moore, W. R.; Schatzman, G. L.; Jarvi, E. T.;
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Lett. 1990, 31, 7301-7304. (g) Welch, J. T.; Lin, J. Tetrahedron 1996, 52,
291-304. (h) Otaka, A.; Wanatabe, J.; Yukimasa, A.; Sasaki, Y.; Wanatabe,
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69, 1634-1645.
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Tetrahedron Lett. 2002, 43, 6099-6102. (b) Asakura, N.; Usuki, Y.; Iio,
H.; Tanaka, T. J. Fluorine Chem. 2006, 127, 800-808. (c) Yoshimatsu,
M.; Murase, Y.; Itoh, A.; Tanabe, G.; Muraoka, O. Chem. Lett. 2005, 34,
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Q.; Strack, N.; McCarthy, J. R. J. Fluorine Chem. 2000, 101, 285-290.
(h) Chen, C.; Wilcoxen, K.; Kyung-il, K.; McCarthy, J. R. Tetrahedron
Lett. 1997, 38, 7677-7680. (i) Petasis, N. A.; Yudin, A. K.; Zavialov, I.
A.; Prakash, G. K.; Olah, G. A. Synlett 1997, 606-608. (j) Kawasaki, T.;
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Okada, M.; Koura, M.; Tojo, M.; Saito, A.; Sato, A.; Taguchi, T. J. Fluorine
Chem. 2006, 127, 627-636. (c) Guan, T.; Yoshida, M.; Ota, D.; Fukuhara,
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Han, H.; Ludwig, R. T. J. Org. Chem. 1994, 59, 2430-2436. (e) Laue, K.
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1985, 448-454. (f) van Steenis, J. H.; van der Gen, A. J. Chem. Soc., Perkin
Trans. 1 2002, 2117-2133. (g) Pfund, E.; Masson, S.; Vazeux, M.; Lequeux,
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10.1021/jo070994c CCC: $37.00 © 2007 American Chemical Society
Published on Web 09/19/2007
J. Org. Chem. 2007, 72, 7871-7877
7871

Pfund et al.
SCHEME 2. Contrasted Reactivity of a Fluorosulfone
SCHEME 1. Fluoroalkylidene Synthesis and Recent
Application
the base and the solvent are important to control the geometry
of the double bond. The use of DBU in DCM at room
temperature appeared to be the most efficient method to prepare
the (E)-alkenoates selectively from ethyl benzothiazolylsulfonyl
acetate and aromatic aldehydes. When extended to the fluo-
robenzothiazolylsulfonyl acetate derivatives this approach showed
a great influence of the fluorine atom on the reactivity of the
sulfone, and on the geometry of the alkenoates.11 Due to the
presence of the fluorine atom the alkenes were formed faster
(20 min vs 16 h) with selectivity opposite to those observed
from nonfluorinated sulfones (Scheme 2).
These observations in connection with our present work
prompted us to report our additional results in this field.
Selective syntheses of both (Z)- and (E)-fluoroalkenoates from
a fluorobenzothiazolylsulfone and aldehydes or ketones are
described in this paper.
involved in the synthesis of fluoroalkenes by using these
strategies, the modified Julia (or Julia-Kocienski) olefination
reaction appeared attractive as an elegant alternative one-step
procedure.5 Indeed, in a preliminary work we have already
described a modified Julia fluoroolefination of carbonyl com-
pounds to prepare fluoroalkylidene derivatives in one step, from
a fluoroalkylbenzothiazolylsulfone and aldehydes or ketones in
the presence of tBuOK or NaHMDS, respectively (Scheme 1).6
This method was applied to the synthesis of an important
intermediate to an insecticide and represents the most direct
route to build fluoroalkylidene derivatives. Other groups have
supported this approach and extended this reaction to the
synthesis of gem-fluoroaryl derivatives from the in situ prepared
fluoroarylbenzothiazolylsulfones.7 Nevertheless, the major limi-
tation of this methodology is the poor control of the double
bond configuration. A mixture of fluoroalkenes was generally
obtained, depending on the nature of the electrophile and the
aromatic sulfone.8 The use of 1-phenyltetrazolylsulfone or bis-
trifluoromethylphenylsulfone instead of benzothiazolylsulfone
to control the formation of the double bond has allowed progress
for the synthesis of natural products,9 but moderate selectivity
was observed with fluorinated derivatives.6
Results and Discussion
Previously we reported the synthesis of fluoroalkylbenzothia-
zolylsulfones by alkylation of the 2-mercaptobenzothiazole with
gem-bromofluoroalkane or by halogen-exchange reaction from
the 2-chloroalkyl-2-mercaptobenzothiazole derivatives. The
electrophilic fluorination of a 2-substituted-2-benzothiazolyl-
sulfone with F-TEDA or NFSI can be used as an alternative
route.6,11 For the synthesis of fluoroalkenoate derivatives, the
preparation of the benzothiazolylsulfone 2 was carried out from
the commercially available ethyl 2-bromo-2-fluoroacetate and
2-mercaptobenzothiazole (Scheme 3).
The alkylation proceeded smoothly at room temperature to
afford the corresponding sulfide 1 in excellent yield (up to 85%).
The slow oxidation of this fluorosulfide with mCPBA (3 equiv
molar) resulted in a mixture of sulfoxides and sulfone even after
stirring the mixture for over 60 h at room temperature. Better
results were obtained when the oxidation was performed with
a stronger oxidant (H2O2, 5% (NH4)6Mo7O24).12 The corre-
sponding fluorosulfone 2 was isolated in 72-75% yield as a
white crystalline compound.11 This procedure was reproducibly
and efficiently scaled-up to 5 g. With a large amount of
fluorobenzothiazolylsulfone in hand, the study was then focused
on the selective synthesis of either (Z)- or (E)-fluoroalkenoates
from the sulfone 2 (Scheme 4, Table 1). To control the geometry
of the carbon-carbon double bond, a variety of experimental
conditions were screened. THF was selected as a suitable
solvent, and the reactions were performed from benzaldehyde
and nonanal as model electrophiles. The Barbier-type conditions
as originally reported by Julia and co-workers5a were applied:
the base (1.4 equiv neat or in solution in THF) was added to a
mixture of sulfone (1 equiv) and electrophile (1.2 equiv) in THF.
The reaction was performed at -78, -17, or 20 °C with or
without additive. Results are reported in Table 1.
The synthesis of R,â-unsaturated esters from heteroaromatic
sulfones and carbonyl compounds has been recently reported
as an alternative route to the Horner-Wadworth-Emmons
reaction.10 It has been shown that the influence of the nature of
R.; Gouverneur, V.; Miokowski, C. J. Org. Chem. 2000, 65, 1235-1238.
(l) Dutheuil, G.; Lei, X.; Pannecoucke, X.; Quirion, J-C. J. Org. Chem.
2005, 70, 1911-1914. (m) Lei, X.; Dutheuil, G.; Pannecoucke, X.; Quirion,
J-C. Org. Lett. 2004, 6, 2101-2104. (n) Allmendinger, T. Tetrahedron 1991,
47, 4905-4914. (o) Wang, Y.; Xu, J.; Burton, D. J. Org. Chem. 2006, 71,
7780-7784.
(5) (a) Baudin, J. B.; Hareau, G.; Julia, S. A.; Lorne, R.; Ruel, O. Bull.
Soc. Chim. Fr 1993, 130, 856-878. (b) Blakemore, P. R. J. Chem. Soc.,
Perkin Trans. 1 2002, 2563-2585. (c) Najera, C.; Yus, M. Tetrahedron
1999, 55, 10547-10658.
(6) (a) Chevrie, D.; Lequeux, T.; Pazenok, S.; Demoute, J. P. Tetrahedron
Lett. 2003, 44, 8127-8130. (b) Pazenok, S.; Demoute, J. P.; Zard, S.;
Lequeux, T. PCT Int. Appl. WO 0240459 A1, 2002; Chem. Abstr. 2002,
136, 386131.
(7) Ghosh, A. K.; Zajc, B. Org. Lett. 2006, 8, 1553-1556.
(8) (a) Bellingham, R.; Jarowicki, K.; Kocienski, P.; Martin, V. Synthesis
1996, 285-296. (b) Charette, A. B.; Lebel, H. J. Am. Chem. Soc. 1996,
118, 10327-10328. (c) Hilpert, H.; Wirz, B. Tetrahedron 2001, 57, 681-
684. (d) Comostella, F.; Franchini, L.; Panza, L.; Prosperi, D.; Ronchetti,
F. Tetrahedron 2002, 58, 4425-4428. (e) Trost, B. M.; Chisholm, J. D.;
Wrobleski, S. T.; Jung, M. J. Am. Chem. Soc. 2002, 124, 12420-12421.
(f) Sorg, A.; Bru¨ckner, R. Synlett 2005, 289-293.
(9) (a) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett
1998, 26-28. (b) Kocienski, P. J.; Bell, A.; Blakemore, P. R. Synlett 2000,
365-366. (c) Alonso, D. A.; Fuensanta, M.; Najera, C. Eur. J. Org. Chem.
2006, 4747-4754.
(10) Blakemore, P. R.; Ho, D. K. H.; Nap, W. M. Org. Biomol. Chem.
2005, 3, 1365-1368.
(11) Zajc, B.; Kake, S. Org. Lett. 2006, 8, 4457-4460.
(12) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Bull. Soc. Chim.
Fr 1993, 130, 336-357.
7872 J. Org. Chem., Vol. 72, No. 21, 2007

SelectiVe Preparation of Fluoroalkenoates
SCHEME 3. Synthesis of a Fluorobenzothiazolysulfone
SCHEME 4. Synthesis of Fluoroalkenoates
and 15). From DBU the best results were obtained when the
reaction was conducted from -78 to 20 °C (entries 16 and 17),
and E-alkene was formed as the major product in a 24:76 Z/E
ratio. After purification a mixture of alkenes 3b was isolated in
moderate yield. Quinuclidine afforded the expected alkene in
59% yield as a Z/E mixture after 48 h at 20 °C (entry 18). In
contrast, the addition of MgBr2 allowed control of the formation
of the Z-alkene. After 2 h at 20 °C, the alkenes 3b were formed
in a 88:12 Z/E ratio and isolated in good yield (87%, entry 19).
The scope and the limitation of this reaction were explored by
using other aldehydes and NaHMDS, DBU, or DBU/MgBr2 as
bases (Table 2).
From NaHMDS and benzaldehyde the (Z)-fluoroalkenoate
3a was formed as the major product in a Z/E ratio up to 85:15
(entries 1-3) when the reaction was performed at -78, -17 °C,
or room temperature. After flash chromatography, the alkenes
were isolated in 53-69% yield. Changing the nature of the
metalated base slightly modified the observed selectivity as
exemplified by the experiment realized with KHMDS (entries
4 and 5). In contrast, the replacement of a metal amide by a
milder base such as DBU10,11 resulted in reverse selectivity.
When the reaction was performed from -78 to 20 °C, the (E)-
fluoroalkenoate 3a was formed as the major product in a 24:76
Z/E ratio (entry 6), and isolated in good yield (70%). The
polarity of the solvent and the temperature of the medium
appeared crucial to control the formation of alkenes. High
E-selectivity was observed when the reaction was run in the
presence of DBU in THF from -78 to 20 °C (entry 6), while
similar results were obtained in DCM at 20 °C.11 This ratio
decreased with the reaction temperature and an equimolar
mixture of isomers was obtained at reflux (entries 7-9). The
trans olefin (Z-alkene) appeared as the thermodynamic product.
Indeed, a reverse selectivity in favor of the Z-alkene was
observed by stirring the mixture over 48 h at 20 °C. Similar
observations were made when the reaction was carried out with
quinuclidine. In this case, the reaction was slower and needed
at least 47 h at room temperature to reach completion affording
the (Z)-alkenoate as the major product (entry 10). This reaction
can be performed under phase-transfer conditions in the presence
of KOH and the alkenes were isolated in 75% yield after 27 h
at room temperature (entry 11) though with modest stereose-
lectivity. It is still difficult to rationalize the selectivity observed
in the modified Julia reaction; however, the presence of the metal
is highly important,13 as shown by the reverse selectivity
obtained when the reaction was performed in the presence of
DBU or NaHMDS. To confirm these observations an alternative
method was attempted by using DBU in the presence of a
chelating metal such as magnesium(II). A THF solution of
benzaldehyde and the fluorosulfone 2 containing MgBr2 (1.4
equiv) was exposed to DBU (1.4 equiv) at room temperature
or at reflux. At these two temperatures the (Z)-alkenoate 3a was
formed in an excellent selectivity (Z/E ) 92:8) and 72% isolated
yield (entries 12 and 13). During these experiments, we noticed
that the most reproducible results were obtained when MgBr2
was prepared in situ from Mg0 and 1,2-dibromoethane, instead
of using the commercially available MgBr2-Et2O.
With all aromatic aldehydes tested, DBU was the most
efficient base affording the (E)-alkenoates 3c-g preferentially,
while NaHMDS was the most effective for the preparation of
the (Z)-alkenoates. The observed yields ranged from 71% to
91%. The selectivity depended on the nature of the base. The
(E)-alkenoates can be obtained in a 85:15 to 98:2 E/Z ratio when
the reaction was performed in the presence of DBU, while (Z)-
alkenoates were obtained in a 71:29 to 85:15 Z/E ratio in the
presence of NaHMDS. The reaction performed with 4-nitroben-
zaldehyde and DBU (1.4 equiv) in the presence of MgBr2 (1.4
equiv) afforded the expected alkenes 3c accompanied by at least
24% of other products (19F NMR δ: -171.5 (d, J ) 26 Hz)
and -160.5 (d, J ) 16 Hz)) suspected to be the two intermediate
â-hydroxysulfones. Indeed, the addition of an excess of DBU
to the crude mixture allowed their complete conversion and the
alkenes were obtained as the sole products. By working in the
presence of an excess of DBU (3 equiv instead of 1.4 equiv)
no traces of the intermediate â-hydroxysulfones were observed,
and the alkenes were isolated in 66% yield and excellent Z
selectivity. From the other aromatic aldehydes a good Z
selectivity was still observed except for the reaction with
furfuraldehyde. However, the yields were lower than those
obtained when the experiment was conducted in the presence
of NaHMDS.
From aliphatic aldehydes a reverse of stereoselectivity was
also observed when the reaction was performed in the presence
of NaHMDS or DBU. However, a modest selectivity was
observed, especially from sterically hindered aliphatic aldehydes
(Table 2). From these aldehydes, the alkenes 3h-j were isolated
in good yield (up to 81%) but in a low E or Z selectivity
depending on the base used to perform the reaction. The best
results were obtained in the presence of MgBr2. In this case,
the (Z)-alkenoates 3h-j were obtained in excellent Z/E ratios
(up to 94:6) even from a D-galacto-dialdopyranose derivative.
It is worthy of note that during the preparation of alkenes 3i
and 3j no epimerization of the stereogenic center was observed,
even under refluxed solvent. In contrast, the same reaction
performed with Garner’s aldehyde afforded an equimolar
mixture of epimeric Z/E alkenes in 87% yield.
Low selectivity in favor of the E-alkene 3b was observed
from nonanal and NaHMDS at either -78 or 20 °C (entries 14
As mentioned in a recent review on the modified Julia
olefination, it is difficult to predict the selectivity in the alkene
formation.5b However, some points of the mechanism have been
clarified: (a) in major cases the E/Z ratio of the product olefins
(13) Lebrun, M. E.; Le Marquant, P.; Berthelette, C. J. Org. Chem. 2006,
71, 2009-2013.
J. Org. Chem, Vol. 72, No. 21, 2007 7873

Pfund et al.
TABLE 1. Influence of the Nature of the Base and the Temperature on the Z/E Ratio
product,
entry
aldehyde
PhCHO
base (additive)
NaHMDS
temp (°C)
time
2 h
2 h
2 h
Z/Ea (%)
yieldb (%)
1
2
3
-78 to 20
-17 to 20
20
85:15
83:17
85:15
70:30
78:22
24:76
36:64
44:56c
50:50
86:14
63:37
92:8
3a, 53
3a, 61
3a, 69
3a, 64
3a, 59
3a, 70
3a, 78
3a, 72
3a, 75
3a, 58
3a, 75
3a, 71
3a, 72
3b, 76
3b, 74
3b, 66
3b, 57
3b, 59
3b, 87
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
KHMDS
DBU
-78 to 20
-17 to 20
-78 to 20
-17 to 20
20
2 h
2 h
2 h
2 h
2 h
reflux
20
10 min
47 h
27 h
2 h
10 min
2 h
2 h
2 h
2 h
48 h
2 h
quinuclidine
KOH (Bu4NBr)
DBU (MgBr2)d
DBU (MgBr2)d
NaHMDS
20
20
reflux
20
-78 to 20
-78 to 20
20
93:7
n-C8H17CHO
52:48
34:66
24:76
31:69
48:52
88:12
DBU
quinuclidine
20
20
DBU (MgBr2)d
a Relative ratio of the crude determined by 19F NMR. b Isolated yield. c Stirring over 48 h at 20 °C, leading to alkenes in a 66:34 Z/E ratio. d In situ
prepared in THF from Mg0 and 1,2-dibromoethane.
reflects the anti/syn ratio of the intermediate â-alkoxysulfones;
(b) retroaddition in the reaction of metalated sulfones with
aldehydes could occur; (c) the energy barrier to Smiles rear-
rangement is higher for the anti â-alkoxysulfone; and (d) in
some cases aromatic aldehydes undergo formation of zwitteri-
onic betaine more easily providing the trans alkene as the major
product. In the present case, assuming a nonchelated transition
state by using DBU (Figure 1), two different pathways were
proposed going through the formation of the syn (I) and anti
(II) â-alkoxysulfones. After a Smiles rearrangement followed
by an antiperiplanar elimination, these sulfones afforded the cis
and trans alkenes, respectively. The presence of the fluorine
atom destabilizes the carbanion issued from the sulfone,14 and
no retroaddition could occur. In the presence of DBU at -78 °C,
kinetic control was expected and the syn â-alkoxysulfone (I)
was formed as the major intermediate, the cis olefin (E-alkene)
was then obtained selectively (entry 6, Table 1). However, as
mentioned recently,11 the E-selectivity decreased with bulky
aldehydes as exemplified for the preparation of the alkenes 3h-j
(Table 2). Raising the temperature favored the equilibration
between the â-alkoxysulfones (I) and (II), and the proportion
of the thermodynamic trans olefin (Z-alkene) rose concomitantly
(entries 7-9, Table 1).
The transition state differed when the olefination was
performed in the presence of metal as exemplified by the
experiments carried out with NaHMDS, or DBU/MgBr2. In
these cases, we assume that the reaction goes through a
metalated or closed chairlike transition state. The two pathways
leading to the cis and the trans olefins go through the formation
of the â-alkoxysulfones (III) and (IV), respectively (Figure 2).
From aryl aldehydes, the anti â-alkoxysulfone (IV), where the
alkyl chain opposes the benzothiazolyl group, appeared as the
most stable intermediate. This preferred pathway was observed
when the reaction was performed from -78 to 20 °C or at 20 °C
from aromatic aldehydes only, and was exclusive at 20 °C by
using DBU in the presence of MgBr2 either from aromatic or
aliphatic aldehydes. This mechanism led to the trans olefin (Z-
alkene) preferentially (Tables 1 and 2).
It is noteworthy that in both cases the formation of the trans
olefins could result from a zwitterionic intermediate, as postu-
lated originally by Julia and co-workers.5a,b
The olefination of ketones was more difficult under these
experimental conditions and only preliminary results are reported
here. From aromatic ketones such as benzophenone and ac-
etophenone no reaction occurred even at reflux over 24 h (the
starting material was recovered). From aliphatic ketone such
as the 4-tert-butylcyclohexanone the reaction was slower and
needed at least 6 h at room temperature to reach completion. In
the presence of DBU at 20 °C the expected alkenoate 4 was
obtained in 83% isolated yield (Scheme 5).
These preliminary results showed that it might be possible
to extend this reaction to other aliphatic ketones after optimiza-
tion of the experimental conditions. The fact that the reaction
failed from aromatic ketones is not clearly understood but was
probably due to a retroreaction. Current work seeks to under-
stand this limitation and to generalize this reaction to other
aliphatic and aromatic functionalized ketones.
Conclusion
In summary, we have shown that the modified Julia olefi-
nation is an efficient strategy for the selective preparation of
the (E)- or (Z)-R-fluoro-R,â-unsaturated esters from a ben-
zothiazolyl fluorosulfone. Depending on the base and the
additive used to perform the reaction, it is possible to prepare
selectively both the (Z)- and the (E)-alkenoates in good yields,
from aromatic and aliphatic aldehydes. Several bases can be
used with or without a metal and it has been observed that the
role of the metal is crucial in controlling the double bond
geometry. In most cases the chelation with MgBr2 allowed the
(Z)-alkenoates to be obtained from either aromatic or aliphatic
aldehydes. The (Z)-alkenoates appeared as the thermodynamic
product of the reaction, and its formation can be exclusive under
refluxed solvent. In the absence of metal, the reaction was
selective from aromatic aldehydes to afford the (E)-alkenoates.
This method has been extended to a ketone, and appeared to
be limited to aliphatic ketones under the present experimental
conditions. Efforts are underway to extend the scope of the
modified Julia fluoroolefination to ketones and to apply this
(14) (a) Burton, D. J.; Yang, Z. Y. Tetrahedron 1992, 48, 189-275. (b)
Farnham, W. B. Chem. ReV. 1996, 96, 1633-1640.
7874 J. Org. Chem., Vol. 72, No. 21, 2007

SelectiVe Preparation of Fluoroalkenoates
TABLE 2. Preparation of Fluoroalkenoates from Aromatic and Aliphatic Aldehydes
a Relative ratio of the crude determined by 19F NMR. b Isolated yield. c Prepared in situ in THF from Mg0 and 1,2-dibromoethane. d Experiment run in
the presence of DBU (3 equiv) and MgBr2 (1.4 equiv). e Experiment run in the presence of DBU (1.4 equiv) and MgBr2 (1.4 equiv).
7.44 (m, 2H), 7.71 (d, 3JHH ) 6.5 Hz, 1H), 7.85 (d, 3JHH ) 7.8 Hz,
1H); 19F NMR (235 MHz, CDCl3) δ -161.10 (d, 2JHF ) 49.4 Hz);
approach to the preparation of fluoroalkenes such as peptidyl
peptidase (IV) inhibitors.
1
13C NMR (100 MHz, CDCl3) δ 14.3, 63.5, 92.4 (d, JCF ) 237.4
Hz), 121.6, 123.0, 125.8, 126.9, 136.6, 153.0, 159.9, 165.3 (d, 2JCF
) 27.2 Hz); HRMS (ESI) m/z [M + H]+ calcd for C11H11FNO2S2
272.0215, found 272.0215.
Experimental Section
2-(1-Ethylfluoroacetate)sulfanyl-1,3-benzothiazole (1). A solu-
tion of tBuOK (3.15 g, 0.0281 mol) in THF (20 mL) was added
dropwise via a canula to a solution of 2-mercaptobenzothiazole
(3.98 g, 0.0237 mol) in THF (30 mL) at -17 °C under N2. After
30 min ethyl bromofluoroacetate (4 g, 0.0216 mol) was added
dropwise. The mixture was stirred for 1 h 30 at 20 °C, then
quenched with a saturated solution of NH4Cl (20 mL) and extracted
with Et2O/CH2Cl2 (1:1, 100 mL). The organic layer was washed
with brine, dried over MgSO4, filtered, and evaporated under
reduced pressure. The crude product was purified by column
chromatography (silica, pentane/EtOAc, 9:1) to afford 2-(1-eth-
ylfluoroacetate)sulfanyl-1,3-benzothiazole (1) (4.77 g, 0.0176 mol,
81%). 1H NMR (250 MHz, CDCl3) δ 1.22 (t, 3JHH ) 7.2 Hz, 3H),
4.24 (q, 3JHH ) 7.1 Hz, 2H), 6.82 (d, 2JHF ) 51.2 Hz, 1H), 7.19-
2-(1-Ethylfluoroacetate)sulfonyl-1,3-benzothiazole (2). A solu-
tion of 1 (4 g, 0.0147 mol) in ethanol (24 mL) was added dropwise
to a solution of (NH4)6Mo7O24‚4H2O (3.64 g, 0.00295 mol) in 30%
H2O2 (46 mL, 0.441 mol) at 0 °C under N2. The mixture was stirred
for 48 h at room temperature, then quenched with H2SO4 (10%,
10 mL). The ethanol was removed by evaporation under reduced
pressure and NaCl (5 g) was added. The resulting solution was
extracted twice with CH2Cl2/Et2O (1:1, 100 mL). The organic layers
were washed with brine, dried over MgSO4, filtered, and evaporated
under reduced pressure. The crude product was purified by column
chromatography (silica, CH2Cl2/pentane 8:2) to afford 3.22 g of 2
as a white solid (3.22 g, 0.0106 mol, 72%). Mp 76 °C; registry
number 910803-66-6; 1H NMR (250 MHz, CDCl3) δ 1.23 (t, 3JHH
J. Org. Chem, Vol. 72, No. 21, 2007 7875

Pfund et al.
FIGURE 1. Plausible mechanism for a nonchelated transition state (opened transition state).
FIGURE 2. Plausible mechanism for a metalated chairlike transition state (closed transition state).
3
SCHEME 5. Fluoroolefination of a Ketone
E), 7.25-7.55 (m, 5H), 7.57 (d, JHH ) 1.6 Hz, 2H); 19F NMR
(235 MHz, CDCl3) δ -125.75 (d, 3JHF ) 37.7 Hz, Z), -117.66 (d,
3JHF ) 22.6 Hz, E); 13C NMR (100 MHz, CDCl3) δ 14.2 (E), 14.5
3
3
(Z), 61.9 (E), 62.2 (Z), 117.8 (d, JCF ) 4.6 Hz), 121.8 (d, JCF
)
3
25.7 Hz), 128.3, 129.0 (E), 129.1 (Z), 129.9 (d, JCF ) 3.0 Hz),
3
2
130.0 (d, JCF ) 2.8 Hz), 130.6 (d, JCF ) 8.3 Hz), 131.3, 131.4
(d, 2JCF ) 4.5 Hz), 147.3 (d, 1JCF ) 267.6 Hz, Z), 161.7 (d, 3JCF
)
34.4 Hz); HRMS (ESI) m/z [M + H] calcd for C11H12FO2 195.0821,
found 195.0815.
) 7.2 Hz, 3H), 4.32 (m, 2H), 5.98 (d, 2JHF ) 47.5 Hz, 1H), 7.53-
Representative Procedure for Olefination with DBU: Ethyl
3-Cyclohexyl-2-fluoroacrylate (3h, Table 2). DBU (0.21 mL, 1.38
mmol, 1.4 equiv) was added dropwise to a solution of sulfone 2
(300 mg, 0.989 mmol, 1 equiv) and cyclohexylcarboxaldehyde (132
mg, 1.18 mmol) in THF (5 mL) at -78 °C under N2. After addition
the mixture was stirred for 30 min at -78 °C and then 1 h and 30
min at 20 °C. The reaction was quenched with a saturated solution
of NH4Cl (1 mL) and brine (2 mL), then extracted with CH2Cl2/
Et2O (1:1, 20 mL). The organic layer was washed with brine, dried
over MgSO4, filtered, and evaporated under reduced pressure. The
crude product was purified by chromatography (silica, pentane/
AcOEt, 95:5) to afford 3h (170 mg, 0.85 mmol, 86%) (Z:E ) 29:
7.58 (m, 2H), 7.95 (m, 1H), 8.16 (m, 1H); 19F NMR (235 MHz,
2
CDCl3) δ -180.90 (d, JHF ) 47.3 Hz); 13C NMR (62.9 MHz,
CDCl3) δ 14.1, 64.3, 96.7 (d, 1JCF ) 234.9 Hz), 122.6, 126.1, 128.3,
129.1, 137.8, 152.8, 160.2 (d, 2JCF ) 23.3 Hz), 161.2; HRMS (ESI)
m/z [M + H]+ calcd for C11H11FNO4S2 304.0114, found 304.0100.
Representative Procedure for Olefination with NaHMDS:
Ethyl 2-Fluoro-3-phenylacrylate (3a) (Table 1, Entry 3). NaH-
MDS (1.7 mL, 1.38 mmol, 1.4 equiv, 0.8 M) was added dropwise
to a solution of sulfone 2 (300 mg, 0.989 mmol, 1 equiv) and
benzaldehyde (126 mg, 1.18 mmol, 1.2 equiv) in THF (5 mL) at
room temperature under N2. The mixture was stirred for 2 h at
20 °C, then was quenched with a saturated solution of NH4Cl (1
mL) and brine (2 mL) and extracted with CH2Cl2/Et2O (1:1, 20
mL). The organic layer was washed with brine, dried over MgSO4,
filtered, and evaporated under reduced pressure to give 200 mg of
crude product. The crude product was purified by chromatography
(silica, pentane/AcOEt 95:5) to afford ethyl 2-fluoro-3-phenylacry-
late (132 mg, 0.68 mmol, 69%) (Z:E ) 85:15). Registry number
1
71). H NMR (400 MHz, CDCl3) δ 1.01-1.29 (m, 9H), 1.57-
1.65 (m, 4H), 2.49 (m, 1H, Z), 2.95 (m, 1H, E), 4.16-4.27 (m,
2H), 5.73 (dd, 3JHF ) 22.00 Hz, 3JHH ) 10.4 Hz, 1H, E), 5.90 (dd,
3
3JHF ) 33.6 Hz, JHH ) 9.6 Hz, 1H, Z); 19F NMR (235 MHz,
3
3
CDCl3) δ -125.03 (d, JHF ) 22.4 Hz, E), -131.82 (d, JHF
)
33.9 Hz, Z); 13C NMR (100 MHz, CDCl3) δ 14.2 (E), 14.3 (Z),
25.6, 25.7, 25.9, 26.0, 32.2 (Z), 33.0 (E), 34.1 (Z), 34.8 (d, 3JCF
4.6 Hz, E), 61.4 (E), 61.6 (Z), 125.8 (d, 2JCF ) 11.2 Hz, E), 129.0
)
1
3
350-99-2; H NMR (400 MHz, CDCl3) δ 1.17 (t, JHH ) 7.1 Hz,
2
1
3H, E), 1.30 (t, 3JHH ) 7.2 Hz, 3H, Z), 4.16 (q, 3JHH ) 7.1 Hz, 2H,
E), 4.27 (q, JHH ) 7.2 Hz, 2H, Z), 6.85 (d, JHF ) 22.3 Hz, 1H,
(d, JCF ) 15.3 Hz, Z), 146.3 (d, JCF ) 251.7 Hz, E), 147.1 (d,
1JCF ) 255.2 Hz, Z), 161,1 (d, JCF ) 36.2 Hz, E), 161.4 (d, JCF
3
3
2
2
7876 J. Org. Chem., Vol. 72, No. 21, 2007

SelectiVe Preparation of Fluoroalkenoates
1
) 36.1 Hz, Z); HRMS (ESI) m/z [M + H]+ calcd for C11H18FO2
201.1291, found 201.1275.
6). Registry number 18238-98-7; H NMR (400 MHz, CDCl3) δ
1.16 (t, 3JHH ) 7.2 Hz, 3H, E), 1.31 (t, 3JHH ) 7.2 Hz, 3H, Z), 4.17
(q, 3JHH ) 8.0 Hz, 2H, E), 4.30 (q, 3JHH ) 8.0 Hz, 2H, Z), 6.86 (d,
3JHF ) 20.3 Hz, 1H, E), 7.52 (d, 3JHH ) 12.0 Hz, 2H, E), 7.71 (d,
Representative Procedure for Olefination with DBU (1.4
equiv) and MgBr2 in Situ: Ethyl 2-Fluoro-3-(2,2,7,7-
tetramethyltetrahydrobis[1,3]dioxolo[4,5-b;4′,5′-d]pyran-5-yl)-
acrylate (3j). Dibromoethane (0.128 mL, 1.48 mmol, 1.5 equiv)
was added dropwise to a suspension of Mg0 (34 mg, 1.38 mmol,
1.4 equiv) in THF (5 mL) at 20 °C under N2. After disappearance
of all magnesium (1 h of stirring), a solution containing galac-
tosaldehyde (305 mg, 1.18 mmol, 1.2 equiv) and sulfone 2 (300
mg, 0.989 mmol, 1 equiv) in THF (1 mL) was added. After 10
min, DBU (0.21 mL, 1.38 mmol, 1.4 equiv) was added dropwise,
and the solution was stirred for 2 h at 20 °C. The reaction was
quenched with a saturated solution of NH4Cl (1 mL) and brine (2
mL), then extracted with CH2Cl2/Et2O (1:1, 20 mL). The organic
layer was washed with brine, dried over MgSO4, filtered, and
evaporated under reduced pressure. The crude product was purified
by chromatography (silica, pentane/AcOEt 92:8) to afford 3j (246
mg, 0.71 mmol, 72%) (Z:E ) 94:6). 1H NMR (250 MHz, CDCl3)
δ 1.31 (m, 15 H), 1.46 (m, 4H), 1.55 (m, 4H), 4.29 (m, 5H), 4.64
3JHH ) 8.0 Hz 2H, Z), 8.11 (d, JHH ) 12.0 Hz, 2H, E), 8.15 (d,
3
3JHH ) 8.0 Hz, 2H, Z); 19F NMR (235 MHz, CDCl3) δ -120.15
(d, 3JHF ) 34.5 Hz, Z), -112.98 (d, 3JHF ) 23.1 Hz, E); 13C NMR
(100 MHz, CDCl3) δ 14.0 (E), 14.3 (Z), 62.3 (E), 62.6 (Z), 115.1
3
2
(d, JCF ) 4.5 Hz, E), 119.3 (d, JCF ) 27.3 Hz), 123.4, 124.1,
130.7 (d, 3JCF ) 3.2 Hz, E), 131.0 (d, 3JCF ) 9.1 Hz, Z), 137.5 (d,
3JCF ) 8.7 Hz), 138.1 (d, 3JCF ) 10.2 Hz), 147.3, 149.0 (d, 1JCF
)
222.8 Hz, E), 149.4 (d, 1JCF ) 251.0 Hz, Z), 160.0 (d, 2JCF ) 35.7
Hz, E), 160.7 (d, 2JCF ) 34.2 Hz, Z); HRMS m/z [M + H]+ calcd
for C11H11FNO4 240.0672, found 240.0677.
Representative Procedure for Olefination with DBU and
Ketone: (4-tert-Butylcyclohexylidene)fluoroacetic Acid Ethyl
Ester (4). DBU (0.21 mL, 1.38 mmol, 1.4 equiv) was added
dropwise to a solution of sulfone 2 (300 mg, 0.989 mmol, 1 equiv)
and 4-tert-butylcyclohexanone (182 mg, 1.18 mmol, 1.2 equiv) in
THF (5 mL) at 20 °C under N2. After 6 h of stirring at 20 °C, the
reaction mixture was quenched with a saturated solution of NH4Cl
(1 mL) and brine (2 mL), then extracted with CH2Cl2/Et2O (1:1,
20 mL). The organic layer was washed with brine, dried over
MgSO4, filtered, and evaporated under reduced pressure. The crude
product was purified by chromatography (silica, pentane/AcOEt
98:2) to afford 4 (198 mg, 0.82 mmol, 83%). Registry number
3
2
3
(dd, JHH ) 3.1 Hz, JHH ) 8.5 Hz, 1H), 4.83 (dt, JHH ) 4.1 Hz,
2JHH ) 16.2 Hz, 1H, Z), 5.33 (m, 1H), 5.52 (d, JHH ) 5.3 Hz,
3
3
3
1H), 5.98 (dd, JHH ) 11.2 Hz, JHF ) 20.4 Hz, 1H, E), 6.23 (dd,
3JHH ) 8.5 Hz, JHF ) 34.2 Hz, 1H, Z); 19F NMR (235 MHz,
3
CDCl3) δ -123.78 (dd, 3JHF ) 34.5 Hz, 4JHF ) 2.0 Hz, Z), -120.13
(d, JHF ) 20.2 Hz, E); 13C NMR (100 MHz, CDCl3) δ 14.4 (E),
3
1
23.0 (E), 24.6 (Z), 24.7 (E), 25.2 (Z), 25.3 (m), 26.3, 29.7 (Z), 30.0
425407-78-9; H NMR (250 MHz, CDCl3) δ 0.83 (s, 9H), 1.03-
3
3
3
(E), 30.1, 32.2, 62.1, 63.9 (d, JHH ) 1.9 Hz), 64.0 (d, JHH ) 9
1.21 (m, 3H), 1.26 (t, JHH ) 7.2 Hz, 3H), 1.58-1.88 (m, 4H),
Hz), 70.4 (Z), 70.6 (E), 71.0 (Z), 71.3 (E), 72.9 (d, 3JCF ) 1.2 Hz),
2.92 (m, 1H), 3.55 (m, 1H), 4.19 (q, 3JHH ) 7.2 Hz, 2H); 19F NMR
(235 MHz, CDCl3) δ -131.78; 13C NMR (100 MHz, CDCl3) δ
3
73.4 (d, JCF ) 2.5 Hz), 96.6 (Z), 96.7 (E), 109.3 (E), 109.4 (Z),
3
2
3
3
109.8, 110.0 (m), 116.5 (d, JCF ) 8.0 Hz, E), 120.6 (d, JCF
)
14.4, 26.4, 26.6, 26.7 (d, JCF ) 1.9 Hz), 27.1 (d, JCF ) 2.4 Hz),
21.5 Hz, Z), 147.1 (d, 1JCF ) 262.3 Hz, Z), 148.2 (d, 1JCF ) 259.9
Hz, E), 160.4 (d, 2JCF ) 36.2 Hz, E), 160.8 (d, 2JCF ) 35.3 Hz, Z);
HRMS (ESI) m/z [M + Na]+ calcd for C16H23FNaO7 369.1326,
found 369.1330.
28.3, 28.6, 28.7, 30.9, 31.4, 46.5, 61.2, 135.3 (d, 2JCF ) 12.3 Hz),
1
2
139.7 (d, JCF ) 246.6 Hz), 161.8 (d, JCF ) 36.4 Hz); HRMS
(ESI) m/z [M + H]+ calcd for C14H24FO2 243.1760, found
243.1770.
Representative Procedure for Olefination with DBU (3 equiv)
and MgBr2 in Situ: Ethyl 2-Fluoro-3-(4-nitrophenyl)acrylate
(3c). Dibromoethane (0.128 mL, 1.48 mmol, 1.5 equiv) was added
dropwise to a suspension of Mg0 (35 mg, 1.38 mmol, 1.4 equiv) in
THF (5 mL) at 20 °C under N2. After disappearance of the
magnesium (1 h of stirring), a solution of 4-nitrobenzaldehyde (180
mg, 1.18 mmol, 1.2 equiv) and sulfone 2 (300 mg, 0.989 mmoles,
1 equiv) in THF (1 mL) was added. After 10 min DBU (0.44 mL,
2.96 mmol, 3 equiv) was added dropwise. The reaction mixture
was stirred for 2 h at 20 °C, then quenched with a saturated solution
of NH4Cl (1 mL) and brine (2 mL) and extracted with CH2Cl2/
Et2O (1:1, 20 mL). The organic layer was washed with brine, dried
over MgSO4, filtered, and evaporated under reduced pressure. The
crude product was purified by chromatography (silica, pentane/
AcOEt 95:5) to afford 3c (156 mg, 0.65 mmol, 66%) (Z:E ) 94:
Acknowledgment. This work has been performed within
the PUNCHOrga network (Poˆle Universitaire de Chimie Or-
ganique). “Le Ministe`re de la Recherche et des Nouvelles
Technologies”, the CNRS (Centre National de la Recherche
Scientifique), the “Re´gion Basse-Normandie”, and the European
Union (FEDER funding) are gratefully thanked for their
financial support.
Supporting Information Available: Additional experimental
1
procedures for the preparation of 3b, 3d-g, and 3i and 19F, H,
13C NMR spectra of the compounds 1, 2, and 3a-j. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO070994C
J. Org. Chem, Vol. 72, No. 21, 2007 7877