Syntheses of α-fluoro-α,β-unsaturated thioamides and thiazolines from a fluorophosphonodithioacetate

Article abstract of DOI:10.1021/jo049560x

A high-yielding synthesis of methyl fluoro(diethoxyphosphono)dithioacetate starting from its difluorinated analogue is reported. Fluorophosphonothioacetamides and -methylthiazolines, prepared from this new dithioester, have been successfully transformed i

Full text of DOI:10.1021/jo049560x

Syn th eses of r-F lu or o-r,â-u n sa tu r a ted Th ioa m id es a n d Th ia zolin es
fr om a F lu or op h osp h on od ith ioa ceta te
Emmanuel Pfund, Serge Masson, Michel Vazeux, and Thierry Lequeux*
Laboratoire de Chimie Mole´culaire et Thioorganique UMR CNRS 6507,
ENSICAEN-Universite´ de Caen 6 Bd du Mare´chal J uin, F14050 Caen Cedex, France
thierry.lequeux@ismra.fr
Received March 17, 2004
A high-yielding synthesis of methyl fluoro(diethoxyphosphono)dithioacetate starting from its
difluorinated analogue is reported. Fluorophosphonothioacetamides and -methylthiazolines, pre-
pared from this new dithioester, have been successfully transformed into highly functionalized
fluoroalkenes. Good stereoselectivity in favor of the E isomer was observed from the fluorophospho-
nomethylthiazolines. The potential of these new fluorinated olefinating reagents for the synthesis
of modified peptides and glycosides is also disclosed.
In tr od u ction
fluoromethylphosphonates appended with a dithioester,
a thioamide, or a thiazoline function and the use of the
two latter derivatives in the olefination of carbonyl
compounds. These new monofluorinated phosphonates
open a convergent access to thiopeptides and glycopep-
tides analogues,7,8 possessing a fluorovinylic linkage.
The incorporation of amide isosteres is a common
approach to achieve the synthesis of non-hydrolyzable
peptides as therapeutic agents. Such structural modifica-
tions are often used to prepare conformationally con-
strained peptidomimetics.1 For example, the introduction
of a carbon-carbon double bond or a heterocycle as a
mimic of the peptidic bond can stabilize or probe the
bioactive conformation of peptides.2 In the field of vi-
nylpeptides, the monofluorovinyl moiety has been de-
scribed as the best isoelectronic and isosteric analogue
of the peptidic bond.3 Since the first syntheses of fluoro-
alkenes through a Horner-Wadworth-Emmons (HWE)
reaction by using the easily available triethyl fluoro-
phosphonoacetate,4 an increasing number of alternative
methods were reported.5 Applied to the synthesis of
dipeptides isosteres, most of these methods are based on
divergent strategy and no one offers the flexibility to
connect in one-step two amino acids by a fluorovinylic
linkage. In contrast to the synthesis of alkenes, the
preparation of nonterminal monofluoro olefins by HWE
or Wittig reactions is limited to phosphonates or ylides
bearing an electron-withdrawing group or an aromatic
group.6 In this paper, we report the synthesis of mono-
Resu lts a n d Discu ssion
Dithioesters are excellent N-thioacylating reagents,
and recently we applied this property to the one-step
synthesis of gem-difluorophosphonothioacetamides such
as 2 from the methyl difluoro(diethoxyphosphono)-
dithioacetate 1 and R-aminoesters (Scheme 1).9 However,
competing formation of the monofluorinated dithioester
3 (5-15%) was noticed during the course of this reaction.
Our study is here extended to the preparation of parent
monofluorophosphonates as fluoroalkene precursors to
open a facile and flexible route to new classes of fluo-
rovinyl peptides and glycosides. However, no preparation
of the needed methyl fluorophosphonodithioacetate 3 is
mentioned in the literature. Blackburn et al. attempted
to prepare dithioester 3 (by a method similar to that
used for the synthesis of 1) from the diethoxyphos-
phinyldifluoromethyllithium, carbon disulfide, and io-
domethane.10 Due to the high acidity of the proton R to
(1) Gante, J . Angew. Chem., Int. Ed. Engl. 1994, 33, 1699-1720.
(2) Boeglin, D.; Heitz, A.; Martinez, J .; Fehrentz, J . A. Eur. J . Org.
Chem. 2003, 3139-3146.
(6) (a) Blackburn, G. M.; Rashid, A. J . Chem. Soc., Chem. Commun.
1989, 40-41. (b) McCarthy, J . R.; Matthews, D. P.; Stemerick, D. M.;
Huber, E. W.; Bey, P.; Lippert, B. J .; Snyder, R. D.; Sunkara, P. S. J .
Am. Chem. Soc. 1991, 113, 7439-7740. (c) Xu, Z.; DesMarteau, D. D.
J . Chem. Soc., Perkin Trans 1 1992, 313-315. (d) Burton, D. J .; Yang,
Z.; Qui, W. Chem. Rev. 1996, 96, 1641-1715. (e) Veenstra, S. J .;
Hauser, K.; Felber, P. Bioorg. Med. Chem. Lett. 1997, 7, 351-354. (f)
Boumendjel, A., Nuzillard, J . M.; Massiot, G. Tetrahedron Lett. 1999,
40, 9033-9036. (g) Van Steenis, J . H.; Boer, P. W. S.; Van der Hoeven,
H. A.; Van der Gen, A. Eur. J . Org. Chem. 2001, 911-918.
(7) Miwa, J . H.; Pallivathucal, L.; Gowda, S.; Lee, K. E. Org. Lett.
2002, 4, 4655-4657.
(8) Dondoni, A.; Marra, A. Chem. Rev. 2000, 100, 4395-4422.
(9) Pfund, E.; Lequeux, T.; Masson, S.; Vazeux, M. Org. Lett. 2002,
4, 843-846.
(10) Blackburn, G. M.; Brown, D.; Martin, S. F. J . Chem. Res.,
Synop. 1985, 92-93.
(3) (a) Allmendinger, T.; Furet, P.; Hungerbu¨hler, E. Tetrahedron
Lett. 1990, 7297-7300. (b) Otaka, A.; Wanatabe, H.; Mitsuyama, E.;
Yukimasa, A.; Tamamura, M.; Fujii, N. Tetrahedron Lett. 2001, 42,
285-287. (c) Okada, M.; Nakamura, Y.; Saito, A.; Sato, A.; Horikawa,
H.; Taguchi, T. Tetrahedron Lett. 2002, 43, 5845-5847.
(4) (a) Machleidt, H.; Wessendorf, R. J ustus Liebigs Ann. Chem.
1964, 674, 1-10. (b) Etemad-Moghadam, G.; Seyden-Penne, J . Bull.
Soc. Chim. Fr. 1985, 448-454.
(5) (a) Allmendinger, T. Tetrahedron 1991, 47, 4905-4914. (b) Satoh,
T.; Itoh, N.; Onda, K.; Kitoh, Y.; Yamakawa, K. Bull. Chem. Soc. J pn
1992, 65, 2800-2806. (c) Bartlett, P. A.; Otake, A. J . Org. Chem. 1995,
60, 3107-3111. (d) Welch, J . T.; Lin, J . Tetrahedron 1996, 52, 291-
304. (e) Kawasaki, T.; Ichige, T.; Kitazume, T. J . Org. Chem. 1998,
63, 7525-7528. (f) Xu, J .; Burton, D. J . Org. Lett. 2002, 4, 831-833.
(g) Chevrie, D.; Lequeux, T.; Pommelet, J . C. Tetrahedron 2002, 58,
4759-4767.
10.1021/jo049560x CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/09/2004
4670
J . Org. Chem. 2004, 69, 4670-4676

Syntheses of R-Fluoro-R,â-unsaturated Thioamides and Thiazolines
SCHEME 1
SCHEME 2
SCHEME 3
SCHEME 4
the fluorine and phosphorus atoms, a ketene dithioacetal
was isolated instead of the expected dithioester 3.
Therefore, we studied the monodefluorination of 1 as a
preparative method of 3. The magnesium-promoted R-de-
fluorination of trifluoromethyl ketones, esters, or imines
is well documented to prepare gem-difluoromethylated
parent compounds.11 Besides, compared to esters, dithio-
esters are known, through their reactions with organo-
metallics, as good examples of umpolung addition of
nucleophiles.12-14 The thiophilic addition is favored by the
presence of an electronwithdrawing group R to the
thiocarbonyl function which stabilizes the carbanion.
Therefore, the reactivity of the difluorophosphonodithio-
acetate 1 toward organometallic reagents was investi-
gated with the aim to create a carbanion R to the
difluoromethylene group, which will be able to undergo
defluorination (Scheme 2). As expected, the addition of
Grignard reagents, in THF at -78 °C, proceeds via a
thiophilic addition and induces the elimination a fluoride
anion leading to ketene dithioacetals 4a -c. These com-
pounds were isolated by flash column chromatography
in 85-88% yields. The elimination was selective and the
Z isomer was obtained as the major product (Z/E > 9/1).15
This selectivity presumes a chelation of the metallic
center by the phosphoryl and the thiocarbonyl moieties
which control through a concerted anti-elimination the
formation of the (Z)-ketene dithioacetals.
Previous studies in our laboratory revealed that not
only carbanions reacted through a thiophilic addition
onto the dithioester function activated by an electron-
withdrawing group but also thiolates.16 Moreover, as
shown in Scheme 1, the formation of small amount of
monofluorodithioester 3 occurred due to the liberation
of methanethiol in the medium.9 These results incited
us to investigate the synthesis of 3 from its difluorinated
analogue 1 through successive sulfanylation-defluori-
nation and desulfanylation reactions. At first, the reac-
tion of dithioester 1 with 1 equiv of lithium terbutylthi-
olate at -78 °C was carried out and found to afford the
monofluorinated ketenedithioacetal disulfide 4d in 65%
yield (Scheme 3). The desulfanylation was then ac-
complished by treating 4d with 1 equiv of lithium
ethanethiolate at -78 °C, which, by a thiaphilic attack,
induced the selective cleavage of the sulfur-sulfur bond.
The resulting enethiolate was finally protonated to
provide the expected methyl fluoro(diethoxyphosphono)-
dithioacetate 3 in 60% yield.
A more straightforward synthesis of 3 was attempted
by treating directly the dithioester 1 with 2 equiv of
lithium ethanethiolate. This one-pot procedure was found
to give efficiently monofluorinated dithioacetate 3 in a
very satisfactory yield (Scheme 4).
The synthesis of R-fluoro-R,â-unsaturated dithioesters
was then investigated from 3 and aldehydes. Benzalde-
hyde or nonanal was added to a solution of the anion
generated from 3 by deprotonation with LDA, n-BuLi,
(11) (a) Uneyama, K.; Mizutani, G. Chem. Commun. 1999, 613-
614. (b) Amii, H.; Kobayashi, T.; Matamoto, Y.; Uneyama, K. Chem.
Commun. 1999, 1323-1324. (c) Mae, M.; Amii, H.; Uneyama, K.
Tetrahedron Lett. 2000, 41, 7893-7896. (d) Amii, H.; Koayashi, T.;
Uneyama, K. Synthesis 2000, 2001-2003. (e) Uneyama, K.; Amii, H.
J . Fluorine Chem. 2002, 114, 127-131. (f) Hata, H.; Kobayashi, T.;
Amii, H.; Uneyama, K.; Welch, J . T. Tetrahedron Lett. 2002, 43, 6099-
6102.
(12) Le´ger, L.; Saquet, M. Bull. Soc. Chim. Fr. 1975, 657-666.
(13) Meyers, A. I.; Tait, T. A.; Comins, D. L. Tetrahedron Lett. 1978,
4657-4660.
(14) Portella, C.; Shermolovitch, Y. Tetrahedron Lett. 1997, 38,
4063-4064.
(15) Hartke, K.; Hoederath, W. Sulfur Lett. 1983, 1, 191-198 (The
NMR spectra of ketenedithioacetals agree with the characteristic
patterns of the Z isomers, and for 4a , HOESY experiments showed a
spatial proximity between the fluorine atom and the methylsulfanyl
group).
(16) Bulpin, A.; Masson, S. J . Org. Chem. 1992, 57, 4507-4512.
J . Org. Chem, Vol. 69, No. 14, 2004 4671

Pfund et al.
SCHEME 5
TABLE 1. P r ep a r a tion of F lu or op h osp h on om eth ylth ia zolin es a n d -th ioa ceta m id es
a
A mixture of two isomers was obtained in a 1/1 ratio.
SCHEME 6
SCHEME 7
or t-BuOK at -78 or 0 °C. No reaction occurred, the
starting materials being recovered unchanged after
workup. On the other hand, when the lithiated anion was
trapped at -78 °C with iodomethane, ketene dithioacetal
5 was produced (Scheme 5). The absence of reactivity of
this anion as HWE reagent is probably due to the high
stability of its enethiolate form.10 It is interesting to note
that alkyl phosphonodithioacetates themselves are not
very efficient HWE reagents.15
By contrast, phosphonomethylthiazolines and -thio-
acetamides, prepared by thioacylation of amines, have
been reported as good HWE reagents to give access to
vinylthiazolines and R,â-unsaturated thioamides.17 Con-
sequently, we turned our attention to the synthesis of
monofluorophosphonomethylthiazolines and -thioaceta-
mides from 3. This dithioester reacted smoothly at room
temperature with primary amines, including protected
amino acids and amino alcohols (Scheme 6). The R-fluo-
rophosphonothioamides 6a -e were isolated in 70-91%
yields (Table 1).
reagent during the thioacylation. From bromoethylamine,
the intermediate â-bromothioamide was not isolated, and
its spontaneous cyclization afforded the fluorophospho-
nomethylthiazoline 7 in 87% yield.
The use of R-fluoromethylenephosphonates 6a or 7 as
HWE reagents for the synthesis of the corresponding
R-fluoro-R,â-unsaturated thioamides or R-fluorovinyl-
thiazolines was then studied (Scheme 7, Table 2). At first,
deprotonation of substrates 6a and 7 were performed by
addition of a solution of butyllithium at -78 °C, and the
resulting carbanions were reacted with aldehydes (method
A). In a second procedure, the reaction was carried out
by addition of a THF solution of t-BuOK to a mixture of
fluorophosphonates 6a or 7 and aldehydes in THF at -78
or 0 °C (method B). The reactions were monitored by TLC
analysis.
By using the method A, and for the four aldehydes
tested, the conversion of 6a or 7 was completed after 4 h
at -78 °C. From benzaldehyde and the thioamide deriva-
tive 6a , a mixture of fluoroolefin isomers 8a was obtained
in a 65/35 E/Z ratio and in 92% isolated yield. From
aliphatic aldehydes and 6a , the R-fluoro-R,â-unsaturated
thioamides 8b-d were isolated in 67-72% yields. The
E alkene was also the major isomer but the selectivity
was still moderate (E/Z up to 4/1). From the thiazoline
derivative 7 and the four aldehydes examinated here,
fluorovinylthiazolines 9a -d were isolated in good yields
(90-93%). Compared to unsaturated thioamides 8b-d ,
thiazolines 9b-d were formed in a higher selectivity in
favor of the E alkenes (E/Z up to 95/5). By using method
B, no formation of fluoroalkenes occurred when the
From (S)-phenylglycinol, (S)-phenylalanine, and (1R,2R)-
norephedrine resulted a 1/1 mixture of two diastereo-
meric thioamides 6c-e. It has been previously observed
that the reaction of the difluorophosphonodithioacetate
1 with enantiopure aminoesters and alcohols occurred
without any racemization.9 The formation of only two
diastereomers for 6d confirms also the absence of epimeri-
zation at the stereogenic centers of the norephedrine
(17) (a) Sundberg, R. J .; Biswas, S.; Murthi, K. K.; Rowe, D. J . Med.
Chem. 1998, 41, 4317-4328. (b) Leflemme, N.; Marchand, P. Gulea,
M.; Masson, S. Synthesis 2000, 1143-1147. (c) LeRoy-Gourvennec, S.;
Masson, S. Synthesis 1995, 1393-1396. (d) Shaumann, E.; Fittkau,
S. Tetrahedron Lett. 1984, 25, 2325-2328.
4672 J . Org. Chem., Vol. 69, No. 14, 2004

Syntheses of R-Fluoro-R,â-unsaturated Thioamides and Thiazolines
TABLE 2. Syn th esis of r-F lu or o-r,â-u n sa tu r a ted Th ioa m id es a n d Th ia zolin es fr om 6a a n d 7
a
b
3
Method (A): 1.1 equiv of BuLi/THF/-78 °C/4 h. Method (B): 1.1 equiv of t-BuOK/THF/0 °C/4 h. c Based on the J HF value.
reaction was carried out at -78 °C, and the starting
phosphonates 6a and 7 were recovered. Their complete
consumption with aldehydes was observed when the
reaction was performed at 0 °C over 4 h. The overall
yields of R,â-unsaturated thioamides 8a -d and vinyl-
thiazolines 9a -d were as high as those obtained by
method A. Nevertheless, with the thiazoline derivative
7, the E/Z selectivity decreased to a ratio of 75/25. As
shown for the triethyl fluorophosphonoacetate,4b from
6a and 7 a better E selectivity was observed when
reactions were performed at -78 °C. It is noteworthy that
the replacement of one hydrogen by one fluorine atom
favors the relative cis relationship between the alkyl
and thiazoline groups compared with the good trans
selectivity of the alkenes obtained from aldehydes and
nonfluorinated 2-phosphonomethylthiazolines.17
Numerous reports have described methods for the
preparation of modified peptides as alternative peptide
backbones, enzyme inhibitors (vinylogous peptides),18 or
stable glycopeptides isosteres (C-glycopeptides).8 The
incorporation of a fluorine atom appeared attractive to
prepare fluorinated enzyme inhibitors or NMR probes for
the study of metabolisms in biological systems. The rapid
and simple methods described above for the syntheses
of R-fluoro-R,â-unsaturated thioamides and fluorovi-
nylthiazolines can be extended to the preparation of
modified peptides and glycosides. A convergent one-step
approach to design such structures was here explored
from the reaction of PCHF-based phenylalanylthioamide
6e and thiazoline 7 with functionalized aldehydes.
moderate but opposite selectivity. In an analogous way,
with Garner’s aldehyde the reaction takes place readily
when subjected under basic conditions to fluorophospho-
nates 6e and 7; the yields of olefinic products 10b and
11b ranged from 78% to 83%, and the ratio of isomers
was considerably shifted in favor of the E alkene.
According to known procedures, a preliminary attempt
for the deprotection of 10b in the presence of Dowex-50
led to the formation of the vinylogous N-Boc-protected
Ser-Phe thiopeptide in nonoptimized yield of 40%. Sur-
prisingly, the E-fluorovinylic thiazolines 11a and 11b
were found to slowly isomerize affording the Z olefin as
the major product after 6 months at 4 °C. Fluoroalkenes
10b and 11b, prepared from Garner’s aldehyde, showed
two conformations as detected by 19F NMR at 295 K. The
average conformers were observed by heating a sample
at 343 K, demonstrating a restricted rotation of the amide
or thioamide functions. On the other hand, 19F{1H} NMR
experiments revealed that 11a exhibited an unexpected
long-range coupling constant between the fluorine atom
and the thiazolyl N-methylene protons (5J HF ) 3 Hz) only
for the E-isomer.
The synthesis of C-glycopeptide precursors, glycosyl-
ated at the N-terminus of the peptide chain through a
vinylic linkage, has been previously described from
phosphonates.19 We carried out the reaction of the
fluorophosphonothioacetamide 6e with a protected ga-
lactosaldehyde. Despite a complete consumption of the
starting materials, the fluoroolefin 10c was isolated in
modest yield (20%) without any selectivity. By contrast,
the fluorophosphonomethylthiazoline 7 was more reac-
tive, and the fluorovinylic pyranosylthiazoline 11c was
produced in good yield (79%) with high selectivity
(E/Z ) 98/2).
By using the method A or B, no reaction took place
from 6e or 7 and ethyl glyoxalate after 4 h at -78 °C.
However, as shown in Table 3, the desired fluoroalkenes
10a and 11a were accessible provided the reaction of
lithiated anion derived from 6e and 7 is conducted
between -78 and -10 °C. Thus, isomeric R-fluoro-R,â-
unsaturated thioamides 10a and fluorovinylthiazolines
11a were isolated in satisfactory yields (60-79%) with a
Con clu sion
In conclusion, we have described the first preparation
of a fluorophosphonomethyldithioacetate 3 through a one-
(18) Grison, C.; Gene`ve, S.; Hablin, E.; Coutrot, P. Tetrahedron 2001,
57, 4903-4923.
(19) Coutrot, P.; Grison, C.; Lecouvey, M. Bull. Soc. Chim. Fr. 1997,
134, 27-45.
J . Org. Chem, Vol. 69, No. 14, 2004 4673

Pfund et al.
TABLE 3. Syn th esis of P ep tid e Isoster es fr om P h osp h on a tes 6e a n d 7
a
3
b
Based on the J HF value. Obtained as a mixture of confomers.
phoryl)difluoroethanedithioate 1 (11.5 g, 78%): 1H NMR (250
pot defluorination-desulfanylation procedure starting
from its difluorinated precursor 1. The thioacylation of
amines, aminoesters, or amino alcohols with dithioester
3 allowed the preparation of a variety of fluorophospho-
nothioacetamides and -methylthiazolines as HWE re-
agents. These reagents were used to prepare new R-fluoro-
R,â-unsaturated-thioamides and fluorovinylthiazolines
from alkyl, aryl, and diversely functionalized aldehydes.
The potential of this convergent method for the synthesis
of modified peptides and glycosides was also illustrated
through the preparation of the vinylogous dipeptide Ser-
Phe precursor from Garner’s aldehyde and modified
glycosides from galactosaldehyde. We noticed a con-
trasted reactivity between fluorophosphonates 6a , 6e,
and 7 substituted by a thioamide or a thiazoline function.
Compound 7 gave almost selectively the E-fluorovinyl-
thiazolines in good yields. Encouraged by these results,
we are currently investigating the syntheses of confor-
mationally constrained peptidomimetics and glycopep-
tides containing a fluorovinylthiazolyl linkage.
3
MHz, CDCl3) δ 1.38 (t, J HH ) 7.0 Hz, 6H), 2.70 (s, 3H), 4.30
2
(m, 4H); 19F NMR (235 MHz, CDCl3) δ -98.7 (d, J FP ) 104.0
2
Hz); 31P NMR (101.2 MHz, CDCl3) δ 3.6 (t, J PF ) 104.0 Hz);
3
13C NMR (62.9 MHz, CDCl3) δ 16.3 (d, J CP ) 5.7 Hz), 19.4 (t,
4J CP ) 2.5 Hz), 65.6 (d, 2J CP ) 6.8 Hz), 117.21 (dt, 1J CP ) 209.7
1
2
2
Hz, J CF ) 271.0 Hz), 219.8 (dt, J CP ) 17.2 Hz, J CF ) 21.7
Hz); MS (EI, 70 eV) m/z (relative intensity) 278 (M+• 17), 258
(20), 233 (16), 207 (15), 122 (12), 109 (14), 91 (100), 81 (12), 51
(30), 47 (66), 45 (86); HRMS (EI, 70 eV) m/z [M+] calcd for
C7H13F2O3PS2 278.0012, found 278.0036.
Meth yl (Dieth oxyp h osp h or yl)flu or oeth a n ed ith ioa te
(3). In a 250 mL flask containing 150 mL of anhydrous THF
and ethanethiol (2.7 mL, 35.9 mmol) stirred under N2 was
slowly added BuLi 2.5 M (15 mL, 37.7 mmol) at -78 °C. After
30 min, methyl (diethoxyphosphoryl)difluoroethanedithioate
1 (5 g, 17.9 mmol) was introduced, and the mixture was stirred
for 15 h from -78 °C to rt. The solution was then hydrolyzed
with 1 M HCl and extracted with CH2Cl2. The organic layer
was dried with anhydrous MgSO4, filtered, and concentrated.
The methyl (diethoxyphosphoryl)fluoroethanedithioate 3 was
isolated by flash chromatography (Et2O/pentane 7/3) in 92%
3
yield (4.3 g): 1H NMR (250 MHz, CDCl3) δ 1.38 (t, J HH ) 7.0
2
Hz, 6H), 2.69 (s, 3H), 4.35 (m, 4H), 5.74 (dd, J HP ) 12.6 Hz,
Exp er im en ta l Section
2J HF ) 47.2 Hz, 1H); 19F NMR (235 MHz, CDCl3) δ -183.2
2
2
(dd, J FP ) 77.0 Hz, J FH ) 47.2 Hz); 31P NMR (101.2 MHz,
CDCl3) δ 10.2 (d, 2J PF ) 77.0 Hz); 13C NMR (62.9 MHz, CDCl3)
δ 16.7 (d, 3J CP ) 6.1 Hz), 18.7 (d, 4J CP ) 4.8 Hz), 64.7 and 65.0
(d, 2J CP ) 6.7 Hz), 98.0 (dd, 1J CP ) 160.3 Hz, 1J CF ) 200.9 Hz),
Meth yl (Dieth oxyp h osp h or yl)d iflu or oeth a n ed ith ioa te
(1). To a solution of LDA prepared from diisopropylamine (9
mL, 66.5 mmol) and BuLi 2.5 M (25.6 mL, 69.0 mmol) in 300
mL of anhydrous THF under N2 was slowly added diethyl
difluoromethylphosphonate (10 g, 53.0 mmol) at -78 °C. The
mixture was stirred for 1 h at -78 °C, and carbon disulfide
(16 mL, 265.0 mmol) was introduced dropwise. The solution
was maintained at -78 °C for 30 min, and methyl iodide (16.5
mL, 265.0 mmol) was then added. The reaction mixture was
stirred for 5 min, hydrolyzed with 1 M HCl, and extracted
three times with Et2O. The organic layers were dried with
anhydrous MgSO4, filtered, and concentrated. The resulting
oil was purified by flash column chromatography (petroleum
ether/ethyl acetate 6/4) affording the methyl (diethoxyphos-
2
224.8 (d, J CP ) 16.3 Hz); MS (EI, 70 eV) m/z (relative
intensity) 260 (M+• 97), 240 (28), 215 (23), 196 (62), 195 (43),
189 (21), 185 (24), 169 (46), 167 (24), 157 (27), 155 (20), 137
(25), 124 (33), 109 (100), 104 (32), 91 (68), 81 (49), 80 (23), 77
(26); HRMS (EI, 70 eV) m/z [M+] calcd for C7H14FO3PS2
260.0106, found 260.0112.
Gen er a l P r oced u r e for th e Syn th esis of Keten e F lu o-
r op h osp h on od ith ioa ceta ls (4a -c). To a solution of difluo-
rophosphonodithioacetate 1 (300 mg, 1.07 mmol) in 50 mL of
anhydrous THF under N2 was added dropwise ethyl-, phenyl-,
4674 J . Org. Chem., Vol. 69, No. 14, 2004

Syntheses of R-Fluoro-R,â-unsaturated Thioamides and Thiazolines
or vinylmagnesium bromide 1 M (5.4 mL, 10.7 mmol) at -78
°C. The reaction was monitored by TLC, and after complete
conversion, the reaction mixture was hydrolyzed with 1 M HCl
and extracted with CH2Cl2. The organic layer was dried with
anhydrous MgSO4 and filtered, and solvents were evaporated.
The resulting oil was purified by flash chromatography af-
fording the corresponding ketene phosphonodithioacetal de-
rivative.
acetate 45/55) starting from 3 (1 g, 3.84 mmol) and propyl-
amine (355 µL, 4.25 mmol): 1H NMR (250 MHz, CDCl3) δ 1.00
(t, J HH ) 7.2 Hz, 3H), 1.39 (t, J HH ) 7.0 Hz, 6H), 1.74 (m,
2H), 3.68 (m, 2H), 4.25 (m, 4H), 5.52 (dd, 2J HP ) 11.9 Hz, 2J HF
) 47.7 Hz, 1H), 8.23 (sbr, 1H); 19F NMR (235 MHz, CDCl3) δ
3
3
4
2
2
-189.7 (ddd, J FH ) 5.0 Hz, J FH ) 47.0 Hz, J FP ) 77.0 Hz);
31P NMR (101.2 MHz, CDCl3) δ 12.2 (d, J PF ) 73.6 Hz); 13C
2
3
NMR (62.9 MHz, CDCl3) δ 11.7, 16.7 (d, J CP ) 5.9 Hz), 21.5,
2
1
47.1, 64.6 and 65.2 (d, J CP ) 6.8 Hz), 92.4 (dd, J CP ) 160.1
Diet h yl (Z)-1-flu or o-2-(et h ylsu lfa n yl)-2-(m et h ylsu l-
fa n yl)vin ylp h osp h on a te (4a ) (265 mg, 85%, eluent: Et2O/
pentane 55/45): 1H NMR (250 MHz, CDCl3) δ 1.24 (m, 9H),
2.35 (s, 3H), 2.74 (q, 3J HH ) 7.0 Hz, 2H), 4.12 (m, 4H); 19F NMR
(235 MHz, CDCl3) δ -95.3 (d, 2J FP ) 105.0 Hz); 31P NMR (101.2
1
2
Hz, J CF ) 203.4 Hz), 190.7 (d, J CF ) 13.2 Hz); MS (EI, 70
eV) m/z (relative intensity) 271 (M+•, 71), 251 (56), 236 (46),
218 (47), 195 (100), 140 (47), 134 (56), 115 (66), 114 (60), 87
(24), 81 (31), 77 (22); HRMS (EI, 70 eV) m/z [M+] calcd for
C9H19FNO3PS 271.0807, found 271.0816.
2
MHz, CDCl3) δ 4.3 (d, J PF ) 105.3 Hz); 13C NMR (62.9 MHz,
4
3
CDCl3) δ 14.4, 16.2 (d, J CF ) 5.5 Hz), 16.5 (d, J CP ) 6.5 Hz),
Dieth yl 1-Flu or o-2-[(2-h ydr oxy-1-m eth yl-2-ph en yleth yl)-
a m in o]-2-th ioxoeth ylp h osp h on a te (6d ). In a 25 mL flask
containing 5 mL of CH2Cl2, NEt3 (60 µL, 0.423 mmol), and
(1R, 2R)-norephedrine (80 mg, 0.423 mmol) under N2 was
introduced the fluorophosphonodithioacetate 3 (100 mg, 0.384
mmol). The solution was stirred for 15 h at room temperature
and then concentrated under vacuum. The thioamidophos-
phonate 6d was isolated by flash chromatography (pentane/
ethyl acetate 6/4) as two separate diastereomers in 70% overall
yield (98 mg). Dia 1: 1H NMR (250 MHz, CDCl3) δ 1.07 (d,
2
2
2
29.1, 63.5 (d, J CP ) 6.0 Hz), 132.8 (dd, J CP ) 16.7 Hz, J CF
)
1
1
30.2 Hz), 151.4 (dd, J CP ) 241.7 Hz, J CF ) 286.1 Hz); MS
(EI, 70 eV) m/z (relative intensity) 288 (M+• 71), 228 (29), 213
(62), 185 (60), 157 (100), 138 (24), 119 (65), 109 (26), 103 (26),
101 (25), 93 (22), 91 (52), 81 (48), 76 (23), 73 (26); HRMS (EI,
70 eV) m/z [M+] calcd for C9H18FO3PS2 288.0419, found
288.0420.
Dieth yl 1-F lu or o-2-(ter t-bu tyld isu lfa n yl)-2-(m eth ylsu l-
fa n yl)vin ylp h osp h on a te (4d ). In a 50 mL flask containing
20 mL of anhydrous THF and tert-butyl thiol (135 µL, 1.18
mmol) at -78 °C stirred under N2 was added dropwise BuLi
2.5 M (475 µL, 1.18 mmol). After 30 min, the difluorophospho-
nodithioacetate 1 (300 mg, 1.07 mmol) was introduced, and
the solution was stirred for an additional 1 h at -78 °C. The
mixture was hydrolyzed with HCl 1 M and extracted with
CH2Cl2. The organic layer was dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure. The result-
ing oil was purified by flash chromatography column (Et2O/
pentane 1/1) affording the diethyl 1-fluoro-2-tert-butyldisulfanyl-
2-methylsulfanylvinylphosphonate 4d in 60% yield (225 mg):
3J HH ) 6.8 Hz, 3H), 1.36 (t, 3J HH ) 7.0 Hz, 3H), 1.37 (t, 3J HH
)
3
7.0 Hz, 3H), 4.25 (m, 4H), 4.35 (d, J HH ) 4.5 Hz, 1H), 4.85
(m, 1H), 5.31 (dd, 3J HH ) 3.6 Hz, 3J HH ) 3.0 Hz, 1H), 5.53 (dd,
2
2J HP ) 10.0 Hz, J HF ) 47.8 Hz, 1H), 7.29 (m, 5H), 8.35 (sbr,
4
1H); 19F NMR (235 MHz, CDCl3) δ -190.1 (ddd, J FH ) 4.7
2
2
Hz, J FH ) 47.0 Hz, J FP ) 78.0 Hz); 31P NMR (101.2 MHz,
CDCl3) δ 12.2 (d, 2J PF ) 77.8 Hz); 13C NMR (62.9 MHz, CDCl3)
3
2
δ 11.6, 16.7 (d, J CP ) 5.9 Hz), 56.4, 72.0, 64.8 (d, J CP ) 6.8
2
1
1
Hz), 66.1 (d, J CP ) 6.9 Hz), 92.6 (dd, J CP ) 159.3 Hz, J CF
)
204.1 Hz), 126.0, 127.5, 128.6, 141.0, 189.8 (d, 2J CF ) 13.7 Hz).
Dia 2: 1H NMR (250 MHz, CDCl3) δ 1.05 (d, J HH ) 6.8 Hz,
3
3
3
3
1H NMR (250 MHz, CDCl3) δ 1.30 (t, J HH ) 7.1 Hz, 6H), 1.33
3H), 1.25 (t, J HH ) 7.0 Hz, 3H), 1.26 (t, J HH ) 7.1 Hz, 3H),
3
(s, 9H), 3.34 (s, 3H), 4.14 (m, 4H); 19F NMR (235 MHz, CDCl3)
3.84 (d, J HH ) 3.3 Hz, 1H), 4.15 (m, 4H), 4.87 (m, 1H), 5.02
2
2
2
δ -96.0 (d, J FP ) 105.0 Hz); 31P NMR (101.2 MHz, CDCl3) δ
(m, 1H), 5.48 (dd, J HP ) 10.5 Hz, J HF ) 47.1 Hz, 1H), 7.24
(m, 5H), 8.74 (sbr, 1H); 19F NMR (235 MHz, CDCl3) δ -190.2
(ddd, 4J FH ) 5.0 Hz, 2J FH ) 47.0 Hz, 2J FP ) 75.0 Hz); 31P NMR
2
1.7 (d, J PF ) 105.1 Hz); 13C NMR (62.9 MHz, CDCl3) δ 16.6
4
3
(d, J CF ) 6.3 Hz), 16.6 (d, J CP ) 5.2 Hz), 30.2, 50.5, 63.7 (d,
2J CP ) 5.9 Hz), 138.8 (dd, J CP ) 13.0 Hz, J CF ) 30.7 Hz),
(101.2 MHz, CDCl3) δ 12.0 (d, J PF ) 74.7 Hz); 13C NMR (62.9
2
2
2
1
1
3
148.3 (dd, J CP ) 238.7 Hz, J CF ) 283.8 Hz); MS (EI, 70 eV)
m/z (relative intensity) 348 (M+, 12), 294 (40), 292 (100), 272
(47), 244 (32), 226 (63), 201 (86), 198 (33), 157 (58), 119 (42),
109 (53), 93 (25), 91 (60), 88 (23), 81 (67); HRMS (EI, 70 eV)
m/z [M+] calcd for C11H22FO3PS3 348.0452, found 348.0469.
MHz, CDCl3) δ 11.6, 16.7 (d, J CP ) 5.9 Hz), 56.3, 73.9, 64.7
2
2
1
(d, J CP ) 6.8 Hz), 65.4 (d, J CP ) 6.9 Hz), 92.3 (dd, J CP
)
1
159.3 Hz, J CF ) 204.1 Hz), 126.1, 127.9, 128.7, 141.1, 189.7
2
(d, J CP ) 13.7 Hz).
Dieth yl (4,5-Dih ydr o-1,3-th iazol-2-yl)flu or om eth ylph os-
p h on a te (7). In a 100 mL flask were introduced bromoethy-
lamine hydrobromide (1.75 g, 8.46 mmol), NEt3 (1.2 mL, 8.46
mmol), and 40 mL of CH2Cl2 under N2. The fluorophosphono-
dithioacetate 3 (2 g, 7.69 mmol) was then added, and the
resulting salts were dissolved by further addition of NEt3 (1.2
mL, 8.46 mmol). The solution was stirred for 15 h at room
temperature and concentrated. The residue was purified by
flash chromatography (ethyl acetate) to give the thiazolino-
phosphonate 7 in 87% yield (1.7 g): 1H NMR (250 MHz, CDCl3)
Diet h yl 1-F lu or o-2,2-b is(m et h ylsu lfa n yl)vin ylp h os-
p h on a te (5). In a 25 mL flask containing 5 mL of anhydrous
THF and difluorophosphonodithioacetate 1 (200 mg, 0.719
mmol) at -78 °C under N2 was slowly added BuLi 2.5 M (335
µL, 0.790 mmol). The reaction mixture was stirred for 1 h, and
methyl iodide (225 µL, 3.6 mmol) was then added. Stirring was
maintained for 15 h from -78 to +20 °C, and the solution was
hydrolyzed with saturated NH4Cl and extracted with CH2Cl2.
The organic layer was dried with anhydrous MgSO4 and
filtered, and the solvent was removed under reduced pressure.
The diethyl 1-fluoro-2,2-bis(methylsulfanyl)vinylphosphonate
5 was obtained by flash chromatography (Et2O/pentane 55/
45) in 65% yield (130 mg): 1H NMR (250 MHz, CDCl3) δ 1.27
(t, 3J HH ) 7.0 Hz, 6H), 2.18 and 2.25 (two s, 6H), 4.13 (m, 4H);
3
δ 1.30 (t, J HH ) 6.9 Hz, 6H), 3.27 (m, 2H), 4.27 (m, 6H), 5.48
2
2
(dd, J HP ) 10.0 Hz, J HF ) 45.9 Hz, 1H); 19F NMR (235 MHz,
CDCl3) δ -203.3 (dd, 2J FH ) 47.0 Hz, 2J FP ) 75.3 Hz); 31P NMR
(101.2 MHz, CDCl3) δ 11.3 (d, J PF ) 73.8 Hz); 13C NMR (62.9
2
3
MHz, CDCl3) δ 16.7, 16.7 (d, J CP ) 5.5 Hz), 33.6, 64.3 and
2
19F NMR (235 MHz, CDCl3) δ -95.1 (d, J FP ) 109.0 Hz); 31P
2
4
1
64.6 (d, J CP ) 6.7 Hz), 65.1 (d, J CF ) 1.0 Hz), 87.9 (dd, J CP
2
1
2
NMR (101.2 MHz, CDCl3) δ 4.2 (d, J PF ) 109.0 Hz).
) 166.2 Hz, J CF ) 186.9 Hz), 165.7 (d, J CF ) 24.6 Hz); MS
(EI, 70 eV) m/z (relative intensity) 255 (M+•, 34), 168 (22), 140
(86), 119 (100), 113 (37), 109 (30), 81 (26); HRMS (EI, 70 eV)
m/z [M+] calcd for C8H15FNO3PS 255.0494, found 255.0453.
Gen er a l P r oced u r e for th e Syn th esis of F lu or in a ted
P h osp h on oth ioa m id es 6a -c,e. In a 50 mL flask containing
20 mL of anhydrous CH2Cl2 and the appropriate amine (4.25
mmol) under N2 was introduced the fluorophosphonodithio-
acetate 3 (1 g, 3.84 mmol). The mixture was stirred for 15 h
at room temperature, and the solvent was evaporated. The
fluorinated phosphonothioamides 6a -c,e were purified by
flash column chromatography.
Gen er a l P r oced u r e for th e Syn th esis of F lu or oa lk en es
8a -d a n d 9a -d . Meth od A. Phosphonate 6a (200 mg, 0.738
mmol) or 7 (200 mg, 0.784 mmol) was dissolved in anhydrous
THF (20 mL) under N2. The solution was cooled to -78 °C,
and BuLi 2.5 M (320 µL, 0.811 mmol or 350 µL, 0.862 mmol)
was added dropwise. After 1 h at -78 °C, the corresponding
aldehyde (0.811 or 0.862 mmol) was added. The mixture was
Dieth yl 1-F lu or o-2-(p r op yla m in o)-2-th ioxoeth ylp h os-
p h on a te (6a ). Isolated in 91% yield (950 mg; pentane/ethyl
J . Org. Chem, Vol. 69, No. 14, 2004 4675

Pfund et al.
stirred for 4 h at -78 °C, hydrolyzed with 1 M HCl, and
extracted with CH2Cl2. The organic layer was dried over
anhydrous MgSO4, filtered, and concentrated under vacuum.
The residue was purified by flash chromatography or distilled
to afford fluoroalkenes 8a -d and 9a -d . Meth od B. Phos-
phonate 6a (200 mg, 0.738 mmol) or phosphonate 7 (200 mg,
0.784 mmol) and the corresponding aldehyde (0.811 or 0.862
mmol) were dissolved in THF (20 mL) under N2 at 0 °C. A
solution of t-BuOK (0.811 or 0.862 mmol) in anhydrous THF
(1 mL) was slowly added. Stirring was maintained for 4 h, and
then the solution was hydrolyzed with HCl 1 M and extracted
with CH2Cl2. The organic layer was dried over anhydrous
MgSO4, filtered, and concentrated under vacuum. The residue
was purified by flash column chromatography or distilled to
afford fluoroalkenes 8a -d and 9a -d .
purified with flash column chromatography to give fluoroalk-
enes 10a -c and 11a -c.
Meth yl N-[4-Eth oxy-2-flu or o-4-oxobu t-2-en eth ioyl]ph e-
n yla la n in a te (10a ). Isolated in 60% yield (104 mg; Et2O/
pentane 45/55), starting from 6e (200 mg, 0.511 mmol) and
ethyl glyoxalate (111 µL, 0.562 mmol, 50% in toluene): 1H NMR
(250 MHz, CDCl3) δ 1.29 (t, 3J HH ) 7.1 Hz, 3H, E) and 1.30 (t,
3
2
3J HH ) 7.1 Hz, 3H, Z), 3.24 (dd, J HH ) 4.1 Hz, J HH ) 13.9
3
2
Hz, 1H, Z) and 3.26 (dd, J HH ) 6.0 Hz, J HH ) 13.9 Hz, 1H,
2
2
E), 3.39 (dd, J HH ) 6.1 Hz, J HH ) 13.9 Hz, 1H, E) and 3.40
(dd, 3J HH ) 5.7 Hz, 2J HH ) 13.9 Hz, 1H, Z), 3.72 (s, 3H, E) and
3
3.75 (s, 3H, Z), 4.21 (q, J HH ) 7.1 Hz, 2H, E) and 4.23 (q,
3J HH ) 7.0 Hz, 2H, Z), 5.36 (ddd, J HH ) J HH ) J HH ) 6.3
3
3
3
3
3
Hz, 2H,), 5.96 (d, J HF ) 19.2 Hz, 1H, E) and 6.78 (d, J HF
32.0 Hz, 1H, Z), 7.18 (m, 10H), 8.45 (sbr, 1H, Z) and 10.75
(sbr, 1H, E); 19F NMR (235 MHz, CDCl3) δ -111.1 (dd, 3J FH
)
(N-P r opyl-2-flu or o-3-p h en yl)pr op -2-en eth ioa m ide (8a ).
Isolated in 92% yield (152 mg; Et2O/pentane 6/4), starting from
6a (200 mg, 0.738 mmol) and benzaldehyde (80 µL, 0.811
)
4
3
32.0 Hz, J FH ) 6.0 Hz, Z) and -78.6 (d, J FH ) 19.2 Hz, E);
13C NMR (62.9 MHz, CDCl3) δ 13.9 (E) and 14.1 (Z), 36.0 (Z)
and 36.3 (E), 52.5 (E) and 52.7 (Z), 58.6 (E) and 59.4 (Z), 61.1
1
3
mmol): H NMR (250 MHz, CDCl3) δ 0.70 (t, J HH ) 7.4 Hz,
3
3
2
3H, E) and 0.94 (t, J HH ) 7.3 Hz, 3H, Z), 1.39 (sext, J HH
)
(Z) and 62.1 (E), 103.5 (d, J CF ) 36.0 Hz, E) and 107.1 (d,
3
2J CF ) 7.5 Hz, Z), 127.2, 128.5, 129.2 (E) and 127.5, 128.8,
7.4 Hz, 2H, E) and 1.68 (sext, J HH ) 7.3 Hz, 2H, Z), 3.44 (dt,
3J HH ) 7.3 Hz, J HH ) 5.9 Hz, 2H, E) and 3.66 (dt, J HH ) 7.3
3
3
1
129.1 (Z), 134.8 (Z) and 135.5 (E), 156.8 (d, J CF ) 293.0 Hz,
Hz, 3J HH ) 5.9 Hz, 2H, Z), 6.18 (d, J HF ) 39.0 Hz, 1H, Z) and
3
1
3
E) and 159.6 (d, J CF ) 261.0 Hz, Z), 162.4 (d, J CF ) 3.0 Hz,
6.38 (d, 3J HF ) 18.7 Hz, 1H, E), 7.18-7.57 (m, 5H, Z) and 7.24
3
Z) and 165.7 (d, J CF ) 22.0 Hz, E), 170.2 (s, E) and 170.4 (s,
(m, 6H, E), 7.95 (sbr, 1H, Z); 19F NMR (235 MHz, CDCl3) δ
2
2
Z), 183.8 (d, J CP ) 20.0 Hz, Z) and 184.1 (d, J CF ) 38.0 Hz,
E); MS (EI, 70 eV) m/z (relative intensity) 339 (M+•, 48), 310
(42), 293 (18), 162 (100), 161 (39), 133 (26), 131 (91), 116 (15),
91 (42); HRMS (EI, 70 eV) m/z [M+] calcd for C16H18FNO4S
339.0940, found 339.0931.
3
4
-126.5 (dd, J FH ) 39.0 Hz, J FH ) 7.0 Hz, Z) and -98.9 (d,
3J FH ) 18.7 Hz, E); 13C NMR (69.2 MHz, CDCl3) δ 11.7 (E)
and 11.9 (Z), 20.9 (E) and 21.7 (Z), 47.4 (E) and 48.0 (Z), 110.6
2
2
(d, J CF ) 28.5 Hz, E) and 117.9 (d, J CF ) 9.2 Hz, Z), 129.1,
4
4
129.2 (E,Z), 129.8 (d, J CF ) 2.3 Hz, Z) and 130.7 (d, J CF
)
8.1 Hz, E), 131.8 (d, 3J CF ) 9.9 Hz, E) and 132.3 (d, J CF ) 3.9
3
Ack n ow led gm en t. This work has been performed
within the PUNCHOrga network (Poˆle Universitaire de
Chimie Organique). Le Ministe`re de la Recherche et des
Nouvelles Technologies, the CNRS (Centre National de
la Recherche Scientifique), the Re´gion Basse-Nor-
mandie, and the European Union (FEDER funding) are
gratefully acknowledged for their financial support.
Hz, Z), 153.9 (d, 1J CF ) 249.9 Hz, E) and 154.4 (d, 1J CF ) 272.1
2
2
Hz, Z), 186.3 (d, J CF ) 17.6 Hz, Z) and 188.2 (d, J CF ) 33.8
Hz, E); MS (EI, 70 eV) m/z (relative intensity) 223 (M+•, 100),
180 (35), 165 (41), 148 (26), 133 (54), 78 (11); HRMS (EI, 70
eV) m/z [M+] calcd for C12H14FNS 223.0831, found 223.0847.
Gen er a l P r oced u r e for th e Syn th esis of F lu or oa lk en es
10a -c a n d 11a -c. Phosphonate 6e (200 mg, 0.511 mmol) or
phosphonate 7 (200 mg, 0.784 mmol) and 20 mL of anhydrous
THF were placed in a 50 mL flask under N2. The solution was
cooled at -78 °C, and BuLi 2.5 M (320 µL, 0.811 mmol or 350
µL, 0.862 mmol) was slowly added. After 1 h, the corresponding
aldehyde (0.811 or 0.862 mmol) was added. The mixture was
stirred for 2 h from -78 to -10 °C, hydrolyzed with 1 M HCl,
and extracted with CH2Cl2. The organic layer was dried over
anhydrous MgSO4, filtered, and evaporated. The residue was
Su p p or tin g In for m a tion Ava ila ble: Preparation of com-
pounds 4b,c, 6b,c, 6e, 8b-d , 9a -d , 10b,c, and 11a -c and
selected 1H, 19F, 31P, and 13C NMR spectra of compounds 3,
6a ,d ,e, 7, 8a -d , 9a -d , 10a -c, and 11a -c. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O049560X
4676 J . Org. Chem., Vol. 69, No. 14, 2004