Practical and efficient synthesis of alkyl, alkenyl and aryl-alkyl α,α-difluoro esters as precursors of potential inhibitors of the pheromone catabolism in insects

Article abstract of DOI:10.1055/s-2000-8226

An efficient method for the synthesis of long chain alkyl, alkenyl and aryl-alkyl α,α-difluoro esters through reductive cleavage of the corresponding S-methyl dithiocarbonates with diphenylphosphine oxide and di-tert-butyl peroxide as initiator is reported. The α,α-difluoro esters 4a-j have been obtained for the first time and in good overall yields. A limitation of the method is the presence of radical-sensitive functions, such as disubstituted double or triple bonds, in the substrate since the concomitant addition of the phosphonyl radical to the unsaturated carbons may induce isomerization of the double bond or polymerization. If stereomerically pure alkenyl α,α-difluoro esters are required, it is suggested to run the reductive cleavage on the S-methyl dithiocarbonate of the acetylenic precursor followed by stereoselective hydrogenation to the alkene.

Full text of DOI:10.1055/s-2000-8226

SPECIAL TOPIC
1917
Practical and Efficient Synthesis of Alkyl, Alkenyl and Aryl-alkyl a,a-Difluoro
Esters as Precursors of Potential Inhibitors of the Pheromone Catabolism in
Insects
Oscar Jiménez, Maria Pilar Bosch,* Angel Guerrero*
Department of Biological Organic Chemistry, Institute of Chemical and Environmental Research (CSIC), Jordi Girona 18-26, E-08034
Barcelona, Spain
Fax +34(93)2045904; E-mail: agpqob@iiqab.csic.es
Received 24 July 2000
efficient synthesis of new a,a-difluoro esters by reductive
Abstract: An efficient method for the synthesis of long chain alkyl,
dehydroxylation of a,a-difluoro-b-hydroxyesters, ob-
alkenyl and aryl-alkyl a,a-difluoro esters through reductive cleav-
tained under classical Reformatsky conditions. The use of
age of the corresponding S-methyl dithiocarbonates with diphe-
nylphosphine oxide and di-tert-butyl peroxide as initiator is
the Reformatsky reaction to prepare 1,1-difluoro-3-hy-
reported. The a,a-difluoro esters 4a-j have been obtained for the droxy esters was first described by McBee.21 Since then,
first time and in good overall yields. A limitation of the method is
several authors have introduced modifications of the reac-
tion by using several additives,22-24 under different
the presence of radical-sensitive functions, such as disubstituted
double or triple bonds, in the substrate since the concomitant addi-
thermal25 or sonication conditions.22,26 A new variant of
tion of the phosphonyl radical to the unsaturated carbons may in-
the Reformatsky reaction was disclosed by Kobayashi,27
duce isomerization of the double bond or polymerization. If
who used 2,2-difluoroketene silyl acetal as substrate for
an aldol reaction with aldehydes or ketones.
stereomerically pure alkenyl a,a-difluoro esters are required, it is
suggested to run the reductive cleavage on the S-methyl dithiocar-
bonate of the acetylenic precursor followed by stereoselective hy-
drogenation to the alkene.
We initially tried the preparation of ethyl 2,2-difluoro-
tridecanoate (4a) by direct fluorination of the correspond-
ing parent non-fluorinated ester with (PhSO2)2NF28 as
source of electrophilic fluoride.20 However, metallation of
the ester with potassium bis(trimethylsilyl)amide or LDA
as base in THF, in the presence or absence of MnBr2, fol-
lowed by reaction with the fluorinating agent was un-
successful. Then, we turned our attention to the deoxy-
genation of a,a-difluoro-b-hydroxy esters. Addition of
ethyl bromodifluoroacetate to a refluxing suspension of
Zn dust and the aldehyde 1a-j in THF, so that the initially
formed metal-halide complex reacts immediately with
the aldehyde, provided the expected fluorinated alcohols
2a-j in good yields (Table 1). This procedure was superi-
or to the addition of a mixture of the aldehyde and the
halide to a refluxing suspension of the metal in THF,29 or
to the addition of the aldehyde to a previously heated
mixture of zinc and the halide in THF30 due to the self-
coupling reaction of the halide ester. Our process worked
better for aromatic aldehydes than for aliphatic long-chain
ones, regardless of the type of substitution present in the
substrate (either electron-donating or electron-withdraw-
ing groups). An exception occurs with 4-nitrobenzalde-
hyde, in which the extremely potent electron-withdrawing
nitro group31 completely inhibits the reaction.
Key words: a,a-difluoro esters, synthesis, reductive cleavage,
pheromone catabolism
Introduction of one or more fluorine atoms into specific
positions of bioorganic molecules leads to significant
changes in stability, lipophilicity and subsequently in bio-
logical activities.1 The change of properties of these com-
pounds can be visualized as a consequence of the high
electronegativity of the fluorine atom, the strong carbon-
fluorine bond and the comparable size of this halogen and
hydrogen. In the last decades, fluorinated compounds
have been largely used in medicinal chemistry2,3 and agro-
chemistry.4 The CF2/O replacement5 has been vaunted as
isoelectronic and isosteric, and consequently this substitu-
tion has given rise to the synthesis of analogues of several
natural products with significant biological activity, such
as antitumor agents6 and enzyme inhibitors.7-9 Likewise,
utilization of organofluorine compounds may be a useful
tool in the search for new strategies in insect control10-13
and as potential inhibitors of the b-oxidation process in
pheromone biosynthesis.14
a,a-Difluoro esters have been prepared by a number of
methods, such as photoreaction of Barton esters with 1,1-
dichloro-2,2-difluoroethylene followed by hydrolysis
with AgNO3/H2O-THF,15 fluorination of a-keto esters
i
X
C10H21CHCF2CO2Et
C10H21CH2CF2CO2Et
16
with SF4 or DAST,17 copper-initiated reaction of iodo-
OC(S)OPh
ii
difluoroacetates to alkenes followed by reduction with
Zn/NiCl2,18,19 or electrophilic fluorination of the parent
keto ester enolate.20
5
4a
Reagents and conditions: I) Bu3SnH/AIBN; ii) Ph2P(O)H/(t-BuO)2,
40-50%
In our current interest to develop new inhibitors of the
pheromone catabolism of insects,10-13 we now report an
Scheme 1
Synthesis 2000, No. 13, 1917–1924 ISSN 0039-7881 © Thieme Stuttgart · New York

1918
O. Jiménez et al.
SPECIAL TOPIC
Table 1 Synthesis of a,a-Difluoro-b-hydroxy Esters 2a−j
difluoro-b-hydroxyesters, which have been fully charac-
terized for the first time. The required xanthate esters
3a-j were obtained in the conventional way in excellent
yields (Table 2). Then, treatment of the xanthates with
diphenylphosphine oxide and di-tert-butyl peroxide as
initiator in anhydrous dioxane affords the desired prod-
ucts 4a-j in good to excellent yields, provided that no rad-
ical-sensitive function is present in the molecule (Tables
3 and 4). The entire process is outlined in Scheme 1.
R
Time (h)
Product
2a
Yield (%)a
1a
1b
1c
1d
1e
1f
C10H21
1.16
1
64
67
71
72
54b
60
77
81
88
86
C14H29
2b
2c
C15H31
1.75
1
(Z)-10-C15H29
(E)-10-C13H25
Yn-10-C15H27
4-Me-Ph
4-MeO-Ph
4-F-Ph
2d
2e
1.5
1.16
1.75
1.5
1
When the substrate contains radical-sensitive groups, for
example, in unsaturated xanthate esters 3d, 3e and 3f, the
reaction progress has to be controlled by GC up to approx.
40-50% conversion (3-4 hours), since the radicals gener-
ated in the process can add to the double or triple bond
promoting partial isomerization (4d and 4e were obtained
as mixtures Z/E in 84/16 and 87/13 ratio, respectively) and
polymerization. This fact was also previously noted by
Barton et al.,36 who reported addition of dimethylphos-
phite radicals to the C=C double bond of cholesteryl ace-
tate to give the 6a-phosphonate derivative of cholestanyl
acetate. The use of a "sacrificial olefin" as reported by
Barton36 to prevent attack of the diphenylphosphine oxide
radical to the triple bond of 3f was also tried. The process
was indeed slowed down, as a consequence of the higher
rate of addition of the phosphinyl radical to the olefin than
to the xanthate group or to the triple bond, and an excess
2f
1g
1h
1i
2g
2h
2i
1j
4-NC-Ph
4-O2N-Ph
1
2j
c
c
1k
4
−
-
a Isolated yields after column chromatography purification.
b Non-optimized yield.
c No reaction occurred.
Deoxygenation of alcohols through the intermediate for- of the reducing agent (5 equivalents) and 1-octene (4.5
mation of dithiocarbonate esters and subsequent treatment equivalents) (the sacrificial olefin) was required. Under
with tri-n-butyltin hydride has been known since Barton’s these conditions, however, and after 8 hours of reaction,
pioneering work.32 Later, the methodology was extended only a 40% conversion was obtained by GC analysis and
to primary alcohols using other thiocarbonyl deriva- 18% isolated yield of 4f. Protection of the triple bond with
39
tives.33 We initially tried the reductive cleavage of the Co2(CO)8 was also ineffective since deprotection, and
phenyl thionocarbonate of ethyl 3-hydroxy-2,2-difluoro- consequently addition of the phosphinyl radical to the tri-
tridecanoate 5 with tri-n-butyltin hydride/AIBN, as de- ple bond and polymerization occurred. On the other hand,
scribed by Posner and co-workers,30 but a mixture of com- electrochemical reduction of a solution of xanthate 3d in
pounds was obtained (Scheme 1). Similarly, treatment of acetonitrile in the presence of tetrabutylammonium per-
5 with diphenylphosphine oxide as a radical hydrogen chlorate, in a similar manner to the electrochemical reduc-
source34 in the presence of di-tert-butyl peroxide afforded tion of vinyl halides,40 also failed. Other reductive
the expected deoxygenated product in only 40-50% con- methods of xanthate 3d involving the use of non-radical
version (Scheme 1).
reactions, such as treatment with NaI/Zn,41 Zn/HOAc42 or
Na/NH3 were unsuccessful, providing recovered 3d in
43
Diphenylphosphine oxide was developed by Jang and co-
workers34 to replace the toxic organotin hydrides by a
more environmentally safe reagent35-38 and was used for
deoxygenation of primary, secondary and tertiary alco-
hols through the corresponding S-methyl dithiocarbon-
ates. However, the alcohols contained no other
functionalization. We have extended this methodology
the deoxygenation of new long chain alkyl and aryl a,a-
the first case or mixtures of 3d and the unprotected prod-
uct 2d in the two latter cases. Use of NaBH3CN44 in
HMPA led to a mixture of compounds from which the de-
sired product 4d was obtained in stereomerically pure
form but only in 25% isolated yield. Compound 4d was
alternatively prepared in 97/3 Z/E ratio and 89% yield by
stereoselective hydrogenation of 4f with 5% Pd-Lindlar
for 47 hours in hexane/methanol, 1:1. It is noteworthy that
1) DBU, CS2
Zn / THF
Ph2P(O)H
DMF
RCHCF2CO2Et
RCHCF2CO2Et
RCHO
RCH2CF2CO2Et
tBuOOtBu
dioxane
BrCF2CO2Et
2) MeI
OC(S)SMe
OH
1
2
4
3
Scheme 2
Synthesis 2000, No. 13, 1917–1924 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Practical and Efficient Synthesis of Alkyl, Alkenyl and Aryl-alkyl a,a-Difluoro Esters
1919
Table 2 Synthesis of S-Methyl Dithiocarbonates 3a-j
In summary, an efficient and practical method for the syn-
thesis of long chain a,a-difluoro esters through reductive
cleavage of the intermediate S-methyl dithiocarbonates
with diphenylphosphine oxide and di-tert-butyl peroxide
has been developed. The procedure has been applied to
new alkyl, alkenyl and aryl-alkyl a,a-difluoro esters in
good overall yields. A limitation of the method is the pres-
ence of radical-sensitive functions (disubstituted double
or triple bonds) in the molecule, in which case, addition of
the phosphonyl radical to the unsaturated carbons may
lead to isomerization or polymerization. If stereomerical-
ly pure alkenyl a,a-difluoro esters are needed, it is advis-
able to run the reductive cleavage on the S-methyl
dithiocarbonate of the acetylenic a,a-difluoro ester pre-
cursor followed by stereoselective hydrogenation of the
triple bond to the alkene.
R
Time (h)
Product
3a
Yield (%)a
2a
2b
2c
2d
2e
2f
C10H21
1
90
90
97
96
88
93
90
91
94
87
C14H29
1
3b
3c
C15H31
1
(Z)-10-C15H29
(E)-10-C13H25
Yn-10-C15H27
4-Me-Ph
4-MeO-Ph
4-F-Ph
1.16
1
3d
3e
1
3f
2g
2h
2i
0.75
1.5
1
3g
3h
3i
2j
4-NC-Ph
1
3j
All experiments were carried out under Ar. All solvents were puri-
fied by distillation and dried if necessary, prior to use. Analytical
grade reagents were obtained from commercial sources and used
without further purification. Diphenylphosphine oxide was pre-
pared from diphenylphosphinous chloride in CCl4 and H2O in 74%
yield, as previously described.45 (Z)-Hexadec-11-enal, hexadec-11-
ynal and (E)-tetradec-11-enol were kindly provided by SEDQ, S.A.
and the non-commercially available aldehydes were prepared by
Swern oxidation of the corresponding alcohols. Products were puri-
fied by flash column chromatography on silica gel (40-60 mm) or
aluminum oxide (activity III). Elemental analyses (C, H) were de-
termined on Carlo-Erba models 1106 and 1108. For elemental anal-
yses of F, a titroprocessor Metrohm 635 was used. The IR spectra
a Isolated yields after column chromatography purification.
the more hindered trisubstituted endocyclic double bonds,
such as those of methyl hederagenin and erythrodiol33 and
indenyl derivatives,30 are not affected by tin radicals, so it
is expected that substrates containing this type of unsatur-
ation should also be amenable to our reductive conditions
without isomerization or polymerization.
The aromatic substrates 3g-j required longer reaction
times than the aliphatic ones for full transformation into
the expected difluoro esters 4g-j, but the yields of the re-
action were satisfactory regardless of the type of substitu-
ent (electron-donating or electron-withdrawing) present
in the substrate.
were taken on a BOMEM MB-120 spectrophotometer. 1H and 13
C
NMR spectra were determined in CDCl3 solutions on a Varian Uni-
ty 300 spectrometer, operating at 299.949 MHz for 1H and 75.429
MHz for 13C. Chemical shifts (d, ppm) are relative to TMS. 19F
NMR spectra were recorded on a Varian Unity 300 instrument op-
erating at 282 MHz and the values are reported relative to trichlo-
rofluoromethane. Low-resolution mass spectra were run on a Fisons
MD800 coupled to a GC equipped with a HP-1 (30 m ¥ 0.20 mm)
or BP-20 (30 m ¥ 0.22 mm) column. Exact mass measurements
were done on a Autospec-Q instrument at 70 eV at a source temper-
ature of 225 ºC.
Table 3 Synthesis of Difluoro Esters 4a-j
R
Time (h)
Product
4a
Yield (%)a
97
Reformatsky Reaction. Ethyl 2,2-Difluoro-3-hydroxytridec-
anoate (2a): Typical Procedure
3a
3b
3c
3d
3e
3f
C10H21
6.5
8
A flask fitted with a stirring bar and an inert atmosphere inlet was
charged with 53 mg (0.8 mmol) of Zn dust and anhyd THF (5 mL).
Then, a solution of undecanal (106 mg, 0.62 mmol) in anhyd THF
(5 mL) was added, and the mixture brought to reflux. Then, ethyl
bromodifluoroacetate (96 mL, 0.74 mmol) was slowly added via sy-
ringe. After refluxing for 1 h, the mixture was cooled, quenched by
the addition of NaHSO4 (3 mL), and the solvent removed under re-
duced pressure. The residue was extracted with Et2O (4 ¥ 10 mL),
the organic layer was washed with brine (2 ¥ 10 mL), and dried
(MgSO4). After filtration, the solvent was removed and the residue
purified by flash chromatography yielding 117 mg (64%) of ethyl
2,2-difluoro-3-hydroxytridecanoate (2a).
C14H29
4b
87
C15H31
6
4c
91
(Z)-10-C15H29
(E)-10-C13H25
Yn-10-C15H27
4-Me-Ph
4-MeO-Ph
4-F-Ph
3
4db
4ed
4f
49 (78c)
42 (67c)
38 (61c)
83
3
4
3g
3h
3i
22
21
25
32
4g
4h
75
4i
72
IR (film): n = 3250, 1760 cm-1.
1H NMR (CDCl3): d = 4.33 (q, 2H, J = 7.2 Hz, OCH2), 4.00 (m, 1H,
CHOH), 1.97 (d, 1H, J = 7.5 Hz, OH), 1.55 (m, 2H, CH2CHOH),
1.34 (t, 3H, J = 7.2 Hz, OCH2CH3), 1.24 (br, 16H, 8CH2), 0.86 (t,
3H, J = 6.5 Hz, CH3).
13C NMR (CDCl3): d = 163.7 (dd, J = 30, 31 Hz, CO), 114.7 (dd,
J = 253, 255 Hz, CFAFB), 71.6 (dd, J = 30, 24.8 Hz, CHCFAFB),
3j
4-NC-Ph
4j
62
a Isolated yields after column chromatography purification.
b Obtained as 84/16 Z/E isomer.
c Based on recovered starting material.
d Obtained as 87/13 E/Z isomer.
Synthesis 2000, No. 13, 1917–1924 ISSN 0039-7881 © Thieme Stuttgart · New York

1920
O. Jiménez et al.
SPECIAL TOPIC
Table 4 1H and 19F NMR Spectral Data of Difluoro Esters 4a-j
Product
1H NMR (300 MHz, CDCl3), d, J (Hz)
19F NMR (282 MHz, CDCl3), d, J (Hz)
4a
4.30 (q, J = 7.2, 2 H, OCH2), 2.10-1.95 (c, 2 H, CH2CF2), 1.45 (c, 2 H,
CH2CH2CF2), 1.33 (t, J = 7.2, 3 H, OCH2CH3), 1.23 (br, 16 H, 8CH2), 0.85
(t, J = 6.6, 3 H, CH3)
-106.44 (t, J = 16.6, CF2)
-106.43 (t, J = 17.0, CF2)
-106.44 (t, J = 16.6, CF2)
-106.44 (t, J = 16.8, CF2)
-106.43 (t, J = 16.6, CF2)
-106.43 (t, J = 16.6, CF2)
4b
4c
4d
4e
4f
4.30 (q, J = 7.2, 2 H, OCH2), 2.10-1.95 (c, 2 H, CH2CF2), 1.45 (m, 2 H,
CH2CH2CF2), 1.35 (t, J = 7.2, 3 H, OCH2CH3), 1.25 (br, 24 H, 12CH2), 0.87
(t, J = 6.9, 3 H, CH3)
4.30 (q, J = 7.2, 2 H, OCH2), 2.10-1.95 (c, 2 H, CH2CF2), 1.45 (c, 2 H,
CH2CH2CF2), 1.33 (t, J = 7.2, 3 H, OCH2CH3), 1.23 (br, 26 H, 13CH2), 0.85
(t, J = 6.9, 3 H, CH3)
5.32 (m, 2 H, CH=CH), 4.30 (q, J = 7.2, 2 H, OCH2), 2.10-1.90 (c, 6 H,
CH2CF2, CH2C=CCH2), 1.45 (m, 2 H, CH2CH2CF2), 1.33 (t, J = 7.2, 3 H,
OCH2CH3), 1.23 (br, 18 H, 9CH2), 0.86 (t, J = 6.6, 3 H, CH3)
5.40-5.30 (c, 2 H, CH=CH), 4.30 (q, J = 7.2, 2 H, OCH2), 2.10-1.90 (m, 6 H,
CH2C=CCH2, CH2CF2), 1.45 (m, 2 H, CH2CH2CF2), 1.32 (t, J = 7.2, 3 H,
OCH2CH3), 1.23 (br, 14 H, 7CH2), 0.93 (t, J = 7.2, 3 H, CH3)
4.29 (q, J = 7.2, 2H, OCH2), 2.10 (m, 4 H, CH2C∫CCH2), 2.00 (c, 2 H,
CH2CF2), 1.42 (m, 2 H, CH2CH2CF2), 1.32 (t, J = 7.2, 3 H, OCH2CH3), 1.24
(sa, 18 H, 9CH2), 0.87 (t, J = 7.2, 3 H, CH3)
4g
4h
7.12 (s, 4 H, 4CHarom), 4.23 (q, J = 7.2, 2 H, OCH2), 3.32 (t, J = 16.6, 2 H,
CH2CF2), 2.31 (s, 3 H, CH3), 1.24 (t, J = 7.2, 3 H, OCH2CH3)
-105.26 (t, J = 16.6, CF2)
-105.42 (t, J = 16.0, CF2)
7.50 (d, J = 8.1, 2 H, 2CHmeta), 6.83 (d, J = 8.1, 2 H, 2Cortho), 4.22 (q, J = 7.2,
2 H, OCH2), 3.77 (s, 3 H, OCH3), 3.29 (t, J = 16.0, 2 H, CH2CF2), 1.24 (t, J =
7.2, 3 H, OCH2CH3)
4i
4j
7.23-7.19 (m, 2 H, 2CHmeta), 7.03-6.95 (m, 2 H, 2Cortho), 4.23 (q, J = 7.2, 2 H,
OCH2), 3.33 (t, J = 16.5, 2 H, CH2CF2), 1.24 (t, J = 7.2, 3 H, OCH2CH3)
-105.42 (t, J = 16.0, CF2), -114.98
(tt, JF-Hortho = 8.2, JF-Hmeta = 6.0, Farom
)
7.65-7.61 (m, 2 H, 2CHortho), 7.41-7.38 (m, 2 H, 2CHmeta), 4.28 (q, J = 7.2,
2 H, OCH2), 3.43 (t, J = 16.5, 2 H, CH2CF2), 1.28 (t, J = 7.2, 3 H, OCH2CH3)
-104.96 (t, J = 16.5, CF2)
62.9 (OCH2), 31.8, 29.55, 29.52, 29.4, 29.2, 29.1, 25.17, 22.6, 14.2,
13.8 (CH3).
EI-MS: m/z (%) = 351 (M++1, 0.7), 332 (M-18, 1), 124 (82), 97
(68), 83 (73), 69 (81), 57 (95), 43 (100).
19F NMR (CDCl3): d = -115.49 (dd, J = 264, 7.5 Hz, CHCFAFB),
-122.95 (dd, J = 264, 15 Hz, CHCFAFB).
Anal. Calcd for C19H36F2O3: C, 65.11; H, 10.37; F, 10.84. Found: C,
65.02; H, 10.44; F, 11.06.
EI-MS: m/z (%) = 124 (78), 97 (87), 83 (88), 69 (92), 55 (100).
Ethyl 2,2-Difluoro-3-hydroxyoctadecanoate (2c)
Mp = 52-54 ºC
IR (film): n = 3597, 1764 cm-1.
Anal. Calcd for C15H28F2O3: C, 61.20; H, 9.58; F, 12.90. Found: C,
61.34; H, 9.52; F, 12.99.
Ethyl 2,2-Difluoro-3-hydroxyheptadecanoate (2b)
Mp = 50-52 ºC
IR (film): n = 3427, 1768 cm-1.
1H NMR (CDCl3): d = 4.33 (q, 2H, J = 7.2 Hz, OCH2), 3.97 (m, 1H,
CHOH), 2.50 (br s, 1H, OH), 1.55 (m, 2H, CH2CHOH), 1.34 (t, 3H,
J = 7.2 Hz, OCH2CH3), 1.24 (br, 24H, 12CH2), 0.86 (t, 3H, J = 7.2
Hz, CH3).
13C NMR (CDCl3): d = 163.7 (dd, J = 32, 31 Hz, CFAFBCO), 114.7
(dd, J = 253, 255 Hz, CFAFB), 71.6 (dd, J = 27, 25 Hz, CHCFAFB),
62.9 (OCH2), 31.9, 29.6, 29.5, 29.4, 29.3, 29.2, 29.0, 25.1, 22.6,
14.0, 13.8 (CH3).
1H NMR (CDCl3): d = 4.33 (q, 2H, J = 7.2 Hz, OCH2), 3.97 (m, 1H,
CHOH), 2.30 (br s, 1H, OH), 1.55 (m, 2H, CH2CHOH), 1.33 (t, 3H,
J = 7.2 Hz, OCH2CH3), 1.22 (br, 26H, 13CH2), 0.85 (t, 3H, J = 7.2
Hz, CH3).
13C NMR (CDCl3): d = 163.7 (dd, J = 32, 31 Hz, CFAFBCO), 114.6
(dd, J = 253, 255 Hz, CFAFB), 71.7 (dd, J = 27, 25 Hz, CHCFAFB),
62.9 (OCH2), 31.9, 29.67, 29.64, 29.61, 29.5, 29.4, 29.3, 29.2, 25.1,
22.6, 14.0, 13.8 (CH3).
19F NMR (CDCl3): d = -115.36 (dd, J = 263, 7.3 Hz, CHCFAFB), -
123.0 (dd, J = 263, 14.9 Hz, CHCFAFB).
EI-MS: m/z (%) = 124 (62), 97 (80), 83 (97), 69 (78), 57 (100), 43
(96).
19F NMR (CDCl3): d = -115.3 (dd, J = 263, 7.6 Hz, CHCFAFB),
-123.1 (dd, J = 263, 14.6 Hz, CHCFAFB).
Anal. Calcd for C20H38F2O3: C, 65.88; H, 10.53; F, 10.42. Found: C,
65.77; H, 10.53; F, 10.44.
Synthesis 2000, No. 13, 1917–1924 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Practical and Efficient Synthesis of Alkyl, Alkenyl and Aryl-alkyl a,a-Difluoro Esters
1921
Ethyl (Z)-2,2-Difluoro-3-hydroxyoctadec-13-enoate (2d)
IR (film): n = 3400, 3004, 1765, 721 cm-1.
1H NMR (CDCl3): d = 5.32 (m, 2H, CH=CH), 4.33 (q, 2H, J = 7.2
Hz, OCH2), 4.00 (m, 1H, CHOH), 1.99 (m, 4H, 2C=CHCH2), 1.50
(m, 2H, CH2CHOH), 1.34 (t, 3H, J = 7.2 Hz, OCH2CH3), 1.26 (br,
18H, 9CH2), 0.87 (t, 3H, J = 6.9 Hz, CH3).
13C NMR (CDCl3): d = 163.7 (dd, J = 32, 31 Hz, CFAFBCO),
129.81 (C=C), 114.6 (dd, J = 255, 252 Hz, CFAFB), 71.7 (dd, J = 27,
24.8 Hz, CHCFAFB), 62.9 (OCH2), 31.9, 29.7, 29.4, 29.3, 29.2, 29.1,
27.1, 26.8, 25.1, 22.3, 13.9, 13.8 (CH3).
19F NMR (CDCl3): d = -115.48 (dd, J = 264, 7.3 Hz, CHCFAFB),
-122.99 (dd, J = 264, 14.6 Hz, CHCFAFB).
EI-MS: m/z (%) = 362 (0.25, M+), 344 (2.3), 324 (1), 124 (25), 96
(70), 83 (75), 69 (90), 67 (78), 55 (100), 41 (72).
(dd, J = 258, 252 Hz, CFAFB), 73.4 (dd, J = 25.7, 24 Hz, CHCFAFB),
63.0 (OCH2), 21.0, 13.6 (CH3).
19F NMR (CDCl3): d = -114.46 (dd, J = 261, 7.8 Hz, CHCFAFB),
-121.06 (dd, J = 261, 15.5 Hz, CHCFAFB).
EI-MS: m/z (%) = 244 (1, M+), 121 (100), 93 (50), 91 (29), 77 (22),
65 (10).
Anal. Calcd for C12H14F2O3: C, 59.01; H, 5.77. Found: C, 58.85; H,
5.94.
Ethyl 2,2-Difluoro-3-hydroxy-3-(4-methoxyphenyl)propanoate
(2h)
IR (film): n = 3481, 3050, 1758, 1614, 1515, 1315 cm-1.
1H NMR (CDCl3): d = 7.31 (d, 2H, J = 8.7 Hz, 2C3aromH), 6.86 (d,
2H, J = 8.7 Hz, 2C2aromH), 5.65 (dd, 1H, J = 15.3, 8.4 Hz, CHOH),
4.25 (c, 2H, J = 7.2 Hz, OCH2), 3.76 (s, 3H, OCH3), 3.17 (br s, 1H,
OH), 1.25 (t, 3H, J = 7.2 Hz, OCH2CH3).
Anal. Calcd for C20H36F2O3: C, 66.26; H, 10.00; F, 10.48. Found: C,
66.15; H, 9.96; F, 10.87.
13C NMR (CDCl3): d = 163.7 (dd, J = 32.2, 30.5 Hz, CFAFBCO),
160.1 (C4arom), 128.9 (2C3arom), 126.5 (C1arom), 113.78 (dd, J = 258,
250 Hz, CFAFB), 113.73 (2C2arom), 73.2 (dd, J = 27.7, 24 Hz, CHC-
FAFB), 63.2 (OCH2), 55.1 (CH3O), 13.7 (CH3).
19F NMR (CDCl3): d = -114.61 (dd, J = 259, 8.1 Hz, CHCFAFB),
-121.03 (dd, J = 259, 15.5 Hz, CHCFAFB).
Ethyl (E)-2,2-Difluoro-3-hydroxyhexadec-13-enoate (2e)
IR (film): n = 3500, 3005, 1760, 966 cm-1.
1H NMR (CDCl3): d = 5.40 (m, 2H, CH=CH), 4.32 (q, 2H, J = 7.2
Hz, OCH2), 3.98 (m, 1H, CHOH), 2.30 (br s, 1H, OH), 1.95 (m, 4H,
CH2CH=CHCH2), 1.55 (m, 2H, CH2CHOH), 1.33 (t, 3H, J = 7.2
Hz, OCH2CH3), 1.24 (br, 14H, 7CH2), 0.93 (t, 3H, J = 7.2 Hz, CH3).
13C NMR (CDCl3): d = 163.7 (dd, J = 32.2, 31.5 Hz, CFAFBCO),
131.8 (C=C), 129.3 (C=C), 114.6 (dd, J = 253, 255 Hz, CFAFB),
71.7 (dd, J = 28.5, 25 Hz, CHCFAFB), 62.8 (OCH2), 32.5, 29.6,
29.46, 29.43, 29.3, 29.2, 29.1, 25.5, 25.1, 13.9, 13.8 (CH3).
19F NMR (CDCl3): d = -115.35 (dd, J = 263, 8.1 Hz, CHCFAFB),
-123.0 (dd, J = 263, 14.9 Hz, CHCFAFB).
EI-MS: m/z (%) = 260 (2, M+), 137 (100), 109 (20), 94 (12), 77 (11).
Anal. Calcd for C12H14F2O4: C, 55.37; H, 5.43; F, 14.60. Found: C,
55.33; H, 5.62; F, 14.58.
Ethyl 2,2-Difluoro-3-hydroxy-3-(4-fluorophenyl)propanoate
(2i)
IR (film): n = 3490, 3082, 1758, 1606, 1514, 1377 cm-1.
EI-MS: m/z (%) = 334 (0.2, M+), 316 (3.4), 296 (2), 124 (22), 109
(30), 96 (82), 81 (82), 69 (100), 55 (92), 41 (83).
1H NMR (CDCl3): d = 7.38 (m, 2H, 2C3aromH), 7.04 (q, 2H,
2C2aromH), 5.11 (dd, 1H, J = 15.3, 7.8 Hz, CHOH), 4.26 (m, 2H,
J = 7.2 Hz, OCH2), 3.21 (br s, 1H, OH), 1.25 (t, 3H, J = 7.2 Hz,
OCH2CH3).
Anal. Calcd for C18H32F2O3: C, 64.64; H, 9.64; F, 11.36. Found: C,
64.79; H, 9.75; F, 11.69.
13C NMR (CDCl3): d = 163.5 (dd, J = 32.2, 30.5 Hz, CFAFBCO),
163.1 (d, J = 246 Hz, C4arom), 130.2 (C1arom), 129.5 (d, J = 8.1 Hz,
2C2arom), 115.32 (d, J = 21.6 Hz, 2C3arom), 113.5 (dd, J = 258, 253
Hz, CFAFB), 72.9 (dd, J = 27.8, 24.3 Hz, CHCFAFB), 63.2 (OCH2),
13.7 (CH3).
19F NMR (CDCl3): d = -112.88 (m, Farom), -114.11 (dd, J = 262,
8.3 Hz, CHCFAFB), -121.42 (dd, J = 262, 15.7 Hz, CHCFAFB).
Ethyl 2,2-Difluoro-3-hydroxyoctadec-13-ynoate (2f)
IR (film): n = 3500, 1760 cm-1.
1H NMR (CDCl3): d = 4.31 (q, 2H, J = 7.2 Hz, OCH2), 3.97 (m, 1H,
CHOH), 2.30 (br s, 1H, OH), 2.10 (m, 4H, CH2C∫CCH2), 1.55 (m,
2H, CH2CHOH), 1.32 (t, 3H, J = 7.2 Hz, OCH2CH3), 1.25 (br, 18H,
9CH2), 0.86 (t, 3H, J = 7.2 Hz, CH3).
13C NMR (CDCl3): d = 163.7 (dd, J = 33, 31 Hz, CFAFBCO), 114.6
(dd, J = 254, 255 Hz, CFAFB), 80.1 (C∫C), 71.7 (dd, J = 27.7, 24.5
Hz, CH2CFAFB), 62.9 (OCH2), 31.2, 29.38, 29.33, 29.2, 29.1, 29.0,
28.77, 25.1, 21.8, 18.6, 18.3, 13.8, 13.5 (CH3).
19F NMR (CDCl3): d = -115.39 (dd, J = 263, 7.3 Hz, CHCFAFB),
-123.0 (dd, J = 263, 14.9 Hz, CHCFAFB).
EI-MS: m/z (%) = 248 (2, M+), 230 (0.8), 228 (0.9), 125 (100), 97
(27), 77 (10).
Anal. Calcd for C11H11F3O3: C, 53.23; H, 4.46; F, 22.96. Found: C,
53.38; H, 4.54; F, 23.14.
Ethyl 3-(4-Cyanophenyl)-2,2-difluoro-3-hydroxypropanoate
(2j)
EI-MS: m/z (%) = 360 (0.25, M+), 124 (8), 96 (100), 81 (55), 67
(40), 55 (32).
IR (film): n = 3448, 3050, 2234, 1760, 1612, 1506, 1375 cm-1.
1H NMR (CDCl3): d = 7.67 (m, 2H, 2C2aromH), 7.57 (m, 2H,
2C3aromH), 5.29-5.20 (m, 1H, CHOH), 4.33 (q, 2H, J = 7.2 Hz,
OCH2), 3.30 (d, 1H, J = 5.1 Hz, OH), 1.32 (t, 3H, J = 7.2 Hz,
OCH2CH3).
13C NMR (CDCl3): d = 163.0 (dd, J = 32.2, 30.6 Hz, CFAFBCO),
140.3 (C1arom), 131.7 (2C2arom), 128.3 (2C3arom), 118.2 (CN), 113.3
(dd, J = 259, 252 Hz, CFAFB), 112.0 (C4arom), 72.3 (dd, J = 28, 24
Hz, CHCFAFB), 63.1 (OCH2), 13.5 (CH3).
Anal. Calcd for C20H34F2O3: C, 66.64; H, 9.51; F, 10.54. Found: C,
66.64; H, 9.67; F, 10.74.
Ethyl 2,2-Difluoro-3-hydroxy-3-(4-methylphenyl)propanoate
(2g)
IR (film): n = 3503, 3050, 1758, 1375 cm-1.
1H NMR (CDCl3): d = 7.30 (d, 2H, J = 8.1 Hz, 2C2aromH), 7.18 (d,
2H, J = 8.1 Hz, 2C3aromH), 5.11 (dd, 1H, J = 15.4, 7.8 Hz, CHOH),
4.29 (q, 2H, J = 7.2 Hz, OCH2), 2.60 (br s, 1H, OH), 2.34 (s, 3H,
19F NMR (CDCl3): d = -112.48 (dd, J = 267, 7 Hz, CHCFAFB),
-121.24 (dd, J = 267, 15.8 Hz, CHCFAFB).
C4aromCH3), 1.28 (t, 3H, J = 7.2 Hz, OCH2CH3).
13C NMR (CDCl3): d = 163.7 (dd, J = 33, 30.6 Hz, CFAFBCO),
138.9 (C4arom), 131.5 (C1arom), 128.9 (2C2arom), 127.5 (2C3arom), 113.7
EI-MS: m/z (%) = 255 (4, M+), 235 (3), 132 (100), 124 (22), 104
(27), 77 (8).
Synthesis 2000, No. 13, 1917–1924 ISSN 0039-7881 © Thieme Stuttgart · New York

1922
O. Jiménez et al.
SPECIAL TOPIC
Anal. Calcd for C12H11F2NO3: C, 56.47; H, 4.34; N, 5.49; F, 14.89.
Found: C, 56.53, H, 4.46; N, 5.30; F, 14.60.
13C NMR (CDCl3): d = 215.4 (C=S), 162.4 (dd, J = 32, 30.6 Hz,
CFAFBCO), 129.7 (C=C), 112.90 (dd, J = 252, 257 Hz, CFAFB),
78.8 (dd, J = 30, 24 Hz, CHCFAFB), 63.2 (OCH2), 31.9, 29.7, 29.3,
29.2, 29.1, 27.5 (d, J = 2 Hz, CH2CH), 27.1, 26.8, 24.5, 22.2, 19.1,
13.9, 13.8 (CH3).
19F NMR (CDCl3): d = -112.84 (dd, J = 263, 7.3 Hz, CHCFAFB),
-119.04 (dd, J = 263, 15.7 Hz, CHCFAFB).
S-Methyldithiocarbonate Esters: Ethyl 2,2-Difluoro-3-(S-meth-
yldithiocarbonyloxy)tridecanoate (3a); Typical Procedure
A solution of ethyl 2,2-difluoro-3-hydroxytridecanoate (151 mg,
0.51 mmol), anhyd DMF (1.5 mL), DBU (300 mL, 2.04 mmol), and
CS2 (300 mL, 5.1 mmol) was stirred at r.t. for 1 h under Ar. Then,
MeI (320 mL, 5.1 mmol) was added and stirred for 1 h more. The
volatile solvents were evaporated under reduced pressure and then
H2O (10 mL) was added and the mixture extracted with EtOAc
(4 ¥ 10 mL). The combined organic phases were washed with brine
(2 ¥ 10 mL) and dried (MgSO4). Evaporation of the solvent gave a
residue, which was chromatographed on silica gel to yield 117 mg
(90%) of compound 3a.
IR (film): n = 1776, 1066 cm-1.
1H NMR (CDCl3): d = 6.27 (m, 1H, CHOC), 4.28 (m, 2H, OCH2),
2.25 (s, 3H, SCH3), 1.84 (m, 2H, CH2CH), 1.30 (t, 3H, J = 7.2 Hz,
OCH2CH3), 1.22 (br, 16H, 8CH2), 0.86 (t, 3H, J = 6.6 Hz, CH3).
13C NMR (CDCl3): d = 215.4 (C=S), 162.4 (dd, J = 32.2, 30.6 Hz,
CFAFBCO), 112.92 (dd, J = 253, 257 Hz, CFAFB), 78.8 (dd, J = 30,
24.3 Hz, CHCFAFB), 63.3 (OCH2), 31.8, 29.5, 29.4, 29.3, 29.26,
29.22, 27.5 (d, J = 2 Hz, CH2CH), 24.6, 22.6, 19.23, 14.0, 13.8
(CH3).
19F NMR (CDCl3): d = -112.86 (dd, J = 263, 7.3 Hz, CHCFAFB),
-119.02 (dd, J = 263, 15 Hz, CHCFAFB).
Ethyl (E)-2,2-Difluoro-3-(S-methyldithiocarbonyloxy)hexa-
dec-13-enoate (3e)
IR (film): n = 3005, 1776, 1068, 966 cm-1.
1H NMR (CDCl3): d = 6.26 (m, 1H, CHOC), 5.56-5.30 (c, 2H,
CH=CH), 4.27 (m, 2H, OCH2), 2.54 (s, 3H, SCH3), 2.00-1.80 (m,
6H, CH2CH=CHCH2, CH2CH), 1.30 (t, 3H, J = 7.2 Hz, OCH2CH3),
1.23 (br, 14H, 7CH2), 0.93 (t, 3H, J = 7.5 Hz, CH3).
13C NMR (CDCl3): d = 215.4 (C=S), 162.4 (dd, J = 33, 30.3 Hz,
CFAFBCO), 131.8 (C=C), 129.3 (C=C), 112.9 (dd, J = 257, 252 Hz,
CFAFB), 78.8 (dd, J = 25.5, 24.3 Hz, CHCFAFB), 63.3 (OCH2),
32.25, 29.5, 29.3, 29.28, 29.20, 29.0, 27.5 (d, J = 2 Hz, CH2CH),
25.5, 24.5, 19.2, 13.9, 13.8 (CH3).
19F NMR (CDCl3): d = -112.84 (dd, J = 263, 7.3 Hz, CHCFAFB),
-119.02 (dd, J = 263, 15.5 Hz, CHCFAFB).
Ethyl 2,2-Difluoro-3-(S-methyldithiocarbonyloxy)octa-
dec-13-ynoate (3f)
IR (film): n = 1776, 1068 cm-1.
1H NMR (CDCl3): d = 6.27 (m, 1H, CHOC), 4.26 (m, 2H, OCH2),
2.53 (s, 3H, SCH3), 2.10 (m, 4H, CH2C∫CCH2), 1.83 (m, 2H,
CH2CH), 1.29 (t, 3H, J = 7.2 Hz, OCH2CH3), 1.23 (br, 18H, 9CH2),
0.86 (t, 3H, J = 7.2 Hz, CH3).
13C NMR (CDCl3): d = 215.4 (C=S), 162.4 (dd, J = 30.4, 30.6 Hz,
CFAFBCO), 112.92 (dd, J = 255, 252 Hz, CFAFB), 80.1 (C∫C), 78.8
(dd, J = 30, 24 Hz, CHCFAFB), 63.3 (OCH2), 31.2, 29.2, 29.16,
29.10, 29.0, 28.7, 27.5 (d, J = 2 Hz, CH2CH), 24.5, 21.8, 19.2, 18.7,
18.3, 13.8, 13.5 (CH3).
Ethyl 2,2-Difluoro-3-(S-methyldithiocarbonyloxy)heptadec-
anoate (3b)
IR (film): n = 1776, 1066 cm-1.
1H NMR (CDCl3): d = 6.28 (m, 1H, CHOC), 4.28 (m, 2H, OCH2),
2.56 (s, 3H, SCH3), 1.86 (m, 2H, CH2CH), 1.31 (t, 3H, J = 7.2 Hz,
OCH2CH3), 1.24 (br, 24H, 12CH2), 0.87 (t, 3H, J = 6.9 Hz, CH3).
13C NMR (CDCl3): d = 215.4 (C=S), 162.4 (dd, J = 32.1, 30.6 Hz,
CFAFBCO), 112.91 (dd, J = 252, 257 Hz, CFAFB), 78.8 (dd,
J = 30.6, 24.3 Hz, CHCFAFB), 63.2 (OCH2), 31.8, 29.6, 29.5, 29.4,
29.3, 29.29, 29.22, 27.5 (d, J = 2 Hz), 24.6, 22.6, 19.2, 14.0, 13.8
(CH3).
19F NMR (CDCl3): d = -112.83 (dd, J = 263, 7.3 Hz, CHCFAFB),
-119.05 (dd, J = 263, 14.9 Hz, CHCFAFB).
19F NMR (CDCl3): d = -112.86 (dd, J = 263, 7.3 Hz, CHCFAFB),
-119.05 (dd, J = 263, 15.2 Hz, CHCFAFB).
Ethyl 2,2-Difluoro-3-(S-methyldithiocarbonyloxy)-3-(4-meth-
ylphenyl)propanoate (3g)
IR (film): n = 1760, 1070 cm-1.
Ethyl 2,2-Difluoro-3-(S-methyldithiocarbonyloxy)octadecan-
oate (3c)
1H NMR (CDCl3): d = 7.24 (d, 2H, J = 8.0 Hz, 2C2aromH), 7.09 (d,
2H, J = 8.0 Hz, 2C3aromH), 6.87 (dd, 1H, J = 16.4, 8.4 Hz, CHOC),
4.21 (m, 2H, OCH2), 2.40 (s, 3H, C4aromCH3), 2.24 (s, 3H, SCH3),
1.19 (t, 3H, J = 7 Hz, OCH2CH3).
13C NMR (CDCl3): d = 213.4 (C = S), 162.2 (dd, J = 32.5, 30 Hz,
CFAFBCO), 139.7 (C4arom), 129.1 (2C3arom), 128.5 (2C2arom), 127
(C1arom), 112.4 (dd, J = 259, 251 Hz, CFAFB), 80.1 (dd, J = 31, 23.3
Hz, CHCFAFB), 63.2 (OCH2), 21.1, 19.2, 13.7 (CH3).
IR (film): n = 1766, 1068 cm-1.
1H NMR (CDCl3): d = 6.26 (m, 1H, CHOC), 4.27 (m, 2H, OCH2),
2.54 (s, 3H, SCH3), 1.84 (m, 2H, CH2CH), 1.30 (t, 3H, J = 7.2 Hz,
OCH2CH3), 1.22 (br, 26H, 13CH2), 0.85 (t, 3H, J = 6.6 Hz, CH3).
13C NMR (CDCl3): d = 215.4 (C=S), 162.4 (dd, J = 32.6, 30.3 Hz,
CFAFBCO), 112.93 (dd, J = 252, 257 Hz, CFAFB), 78.8 (dd,
J = 30.7, 24.6 Hz, CHCFAFB), 63.3 (OCH2), 31.8, 29.65, 29.60,
29.5, 29.4, 29.34, 29.30, 29.23, 27.5 (d, J = 2 Hz, CH2CH), 24.6,
22.6, 19.2, 14.0, 13.8 (CH3).
19F NMR (CDCl3): d = -112.62 (dd, J = 264, 8.1 Hz, CHCFAFB),
-117.61 (dd, J = 264, 16.3 Hz, CHCFAFB).
19F NMR (CDCl3): d = -112.83 (dd, J = 263, 7.6 Hz, CHCFAFB),
-119.05 (dd, J = 263, 15 Hz, CHCFAFB).
Ethyl 2,2-Difluoro-3-(S-methyldithiocarbonyloxy)-3-(4-meth-
oxyphenyl)propanoate (3h)
IR (film): n = 1760, 1068 cm-1.
Ethyl (Z)-2,2-Difluoro-3-(S-methyldithiocarbonyloxy)octa-
dec-13-enoate (3d)
1H NMR (CDCl3): d = 7.69 (d, 2H, J = 8.8 Hz, 2C2aromH), 7.24 (dd,
1H, J = 19.0, 8.6 Hz, CHOC), 7.21 (d, 2H, J = 8.8 Hz, 2C3aromH),
4.61 (m, 2H, OCH2), 4.08 (s, 3H, C4aromOCH3), 2.85 (s, 3H, SCH3),
1.59 (t, 3H, J = 7.2 Hz, OCH2CH3).
13C NMR (CDCl3): d = 213.5 (C=S), 162.2 (dd, J = 29.8, 30 Hz,
CFAFBCO), 160.5 (C4arom), 130.1 (2C2arom), 122.2 (C1arom), 113.8
(2C3arom), 112.4 (dd, J = 259, 251 Hz, CFAFB), 79.9 (dd, J = 30.6, 23
IR (film): n = 3002, 1776, 1068, 732 cm-1.
1H NMR (CDCl3): d = 6.26 (m, 1H, CHOC), 5.31 (m, 2H, CH=CH),
4.27 (m, 2H, OCH2), 2.54 (s, 3H, SCH3), 1.98 (m, 4H, 2CH2C=CH),
1.83 (m, 2H, CH2CH), 1.29 (t, 3H, J = 7.2 Hz, OCH2CH3), 1.23 (br,
18H, 9CH2), 0.86 (t, 3H, J = 6.8 Hz, CH3).
Synthesis 2000, No. 13, 1917–1924 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Practical and Efficient Synthesis of Alkyl, Alkenyl and Aryl-alkyl a,a-Difluoro Esters
1923
Hz, CHCFAFB), 63.2 (OCH2), 55.8 (CH3O), 19.2 (CH3S), 13.7
(CH3).
Anal. Calcd for C19H36F2O2: C, 68.22; H, 10.84; F, 11.36. Found: C,
68.39; H, 10.89; F, 11.08.
19F NMR (CDCl3): d = -112.83 (dd, J = 264, 8.4 Hz, CHCFAFB),
-117.51 (dd, J = 264, 19.1 Hz, CHCFAFB).
Ethyl 2,2-Difluorooctadecanoate (4c)
IR (film): n = 1760, 1095 cm-1.
Ethyl 2,2-Difluoro-3-(S-methyldithiocarbonyloxy)-3-(4-fluoro-
phenyl)propanoate (3i)
13C NMR (CDCl3): d = 164.4 (t, J = 32.6 Hz, CF2CO), 116.39 (t,
J = 248 Hz, CF2), 62.6 (OCH2), 34.4 (t, J = 23 Hz, CH2CF2), 31.9,
29.68, 29.65, 29.62, 29.5, 29.37, 29.35, 29.2, 29.0, 22.6, 21.41 (t,
J = 4.3 Hz, CH2CH2CF2), 14.1, 13.9 (CH3).
EI-MS: m/z (%) = 349 (M+, 3), 207 (6), 193 (21), 179 (27), 85 (26),
71 (47), 57 (100, C4H9), 43 (90).
IR (film): n = 3078, 1760, 1072 cm-1.
1H NMR (CDCl3): d = 7.43 (m, 2H, 2C2aromH), 7.06 (m, 2H,
2C3aromH), 6.96 (dd, 1H, J = 16.8, 7.8 Hz, CHOC), 4.30 (m, 2H,
OCH2), 2.53 (s, 3H, SCH3), 1.27 (t, 3H, J = 7.2 Hz, OCH2CH3).
13C NMR (CDCl3): d = 213.4 (C=S), 163.3 (d, J = 248 Hz, C4arom),
162.0 (dd, J = 32.4, 30 Hz, CFAFBCO), 130.6 (d, J = 8.4 Hz,
2C2arom), 126.3 (C1arom), 115.6 (d, J = 21.6 Hz, 2C3arom), 112.2 (dd,
J = 260, 251 Hz, CFAFB), 79.3 (dd, J = 31.4, 23 Hz, CHCFAFB),
63.3 (OCH2), 19.2 (CH3S), 13.7 (CH3).
19F NMR (CDCl3): d = -111.27 (tt, J = 5, 5.6 Hz, Farom), -112.23
(dd, J = 265, 8.1 Hz, CHCFAFB), -117.76 (dd, J = 265, 16.3 Hz,
CHCFAFB).
Anal. Calcd for C20H38F2O2: C, 68.92; H, 10.98; F, 10.90. Found: C,
68.80; H, 11.01; F, 10.92.
Ethyl (Z)-2´,2´-Difluorooctadec-13-enoate (4d)
IR (film): n = 3030, 1772, 1076, 727 cm-1.
13C NMR (CDCl3): d = 164.4 (t, J = 33 Hz, CF2CO), 129.83-
129.82 (C=C), 116.38 (t, J = 248 Hz, CF2), 62.6 (OCH2), 34.4 (t,
J = 23.1 Hz, CH2CF2), 32.5, 32.2, 31.8, 29.6, 29.5, 29.4, 29.3, 29.2,
29.1, 29.0, 22.1, 21.4 (t, J = 4.2 Hz, CH2CH2CF2), 14.0, 13.9 (CH3).
Ethyl 2,2-Difluoro-3-(S-methyldithiocarbonyloxy)-3-(4-cy-
anophenyl)propanoate (3j)
Mp = 71-73 ºC
IR (film): n = 3049, 2233, 1760, 1076 cm-1.
1H NMR (CDCl3): d = 7.68 (m, 2H, 2C2aromH), 7.53 (m, 2H,
2C3aromH), 6.95 (dd, 1H, J = 17.4, 6.6 Hz, CHOC), 4.30 (m, 2H,
OCH2), 2.53 (s, 3H, SCH3), 1.28 (t, 3H, J = 7.2 Hz, OCH2CH3).
EI-MS: m/z (%) = 346 (M+,1), 151 (10), 97 (50), 83 (65), 70 (55),
69 (79), 56 (60), 55 (100), 41 (68).
Anal. Calcd for C20H36F2O2: C, 69.32; H, 10.47; F, 10.96. Found: C,
69.18; H, 10.66; F, 10.48.
Ethyl (E)-2,2-Difluorohexadec-13-enoate (4e)
IR (film): n = 3005, 1772, 1076, 968 cm-1.
13C NMR (CDCl3): d = 213.1 (C=S), 161.4 (dd, J = 32.2, 29.5 Hz,
CFAFBCO), 135.4 (C1arom), 132.0 (2C2arom), 129.0 (2C3arom), 117.8
(CN), 113.39 (C4arom), 111.7 (dd, J = 261, 251 Hz, CFAFB), 78.9 (dd,
J = 32.2, 23 Hz, CHCFAFB), 63.5 (OCH2), 19.3 (CH3S), 13.6 (CH3).
13C NMR (CDCl3): d = 164.4 (t, J = 33 Hz, CF2CO), 131.8 (C=C),
129.3 (C=C), 116.3 (t, J = 248 Hz, CF2), 62.6 (OCH2), 34.4 (t,
J = 23 Hz, CH2CF2), 32.5, 29.6, 29.49, 29.45, 29.3, 29.2, 29.1, 29.0,
25.5, 21.4 (t, J = 4.3 Hz, CH2CH2CF2), 13.98, 13.95 (CH3).
19F NMR (CDCl3): d = -111.01 (dd, J = 269, 6.7 Hz, CHCFAFB),
-117.82 (dd, J = 269, 17.4 Hz, CHCFAFB).
EI-MS: m/z (%) = 318 (M+, 1.8), 97 (30), 83 (47), 70 (53), 69 (93),
56 (62), 55 (100), 41 (85).
Anal. Calcd for C18H32F2O2: C, 67.89; H, 10.12; F, 11.93: Found: C,
67.64; H, 10.37; F, 11.86
Reductive Cleavage of the S-Methyldithiocarbonate Esters:
Ethyl 2,2-Difluorotridecanoate (4a); Typical Procedure
A mixture of the S-methyldithiocarbonate 3a (51 mg, 0.132 mmol),
anhyd dioxane (5 mL), diphenylphosphine oxide (27 mg, 0.132
mmol) and di-tert-butyl peroxide (12 mL, 0.06 mmol) was stirred
and heated to reflux for 6.5 h under Ar. Removal of the solvent left
a residue, which was purified by column chromatography on silica
gel affording 35 mg (97%) of ethyl 2,2-difluorotridecanoate (4a).
Ethyl 2,2-Difluorooctadec-13-ynoate (4f)
IR (film): n = 1770 cm-1.
13C NMR (CDCl3): d = 164.4 (t, J = 33 Hz, CF2CO), 116.3 (t,
J = 248 Hz, CF2), 80.15-80.13 (C∫C), 62.6 (OCH2), 34.4 (t, J = 23
Hz, CH2CF2), 31.2, 29.4, 29.3, 29.18, 29.13, 29.08, 29.03, 28.7,
21.8, 21.4 (t, J = 4.3 Hz, CH2CH2CF2), 18.7, 18.4, 13.9, 13.6 (CH3).
EI-MS: m/z (%) = 344 (M+, 0.1), 110 (32), 96 (95), 95 (70), 82 (70),
81 (100), 68 (56), 67 (94), 54 (92), 41 (58).
IR (film): n = 1764, 1095 cm-1.
13C NMR (CDCl3): d = 164.4 (t, J = 32.7 Hz, CF2CO), 116.38 (t,
J = 248 Hz, CF2), 62.6 (OCH2), 34.4 (t, J = 23 Hz, CH2CF2), 31.8,
29.56, 29.55, 29.36, 29.30, 29.2, 29.0, 22.66, 21.41 (t, J = 4 Hz,
CH2CH2CF2), 14.0, 13.9 (CH3).
Anal. Calcd for C20H34F2O2: C, 69.73; H, 9.94; F, 11.03. Found: C,
69.62; H, 10.00; F, 10.79.
EI-MS: m/z (%) = 278 (0.8, M+), 207 (7, C6CF2CO2Et), 193 (20,
C5CF2CO2Et), 179 (25, C4CF2CO2Et), 57 (63), 55 (37), 43 (100).
Ethyl 2,2-Difluoro-3-(4-methylphenyl)propanoate (4g)
IR (film): n = 3028, 1778, 1515, 1375, 1070 cm-1.
Anal. Calcd for C15H28O2F2: C, 64.71; H, 10.13; F, 13.64. Found: C,
64.52; H, 10.19; F, 13.53.
13C NMR (CDCl3): d = 163.9 (t, J = 32.5 Hz, CO), 137.5 (C4arom),
130.2 (2C3arom), 129.2 (2C2arom), 127.5 (t, J = 4.3 Hz, C1arom), 115.3
(t, J = 250 Hz, CF2), 62.7 (OCH2), 40.5 (t, J = 23.7 Hz, CF2CH2),
21.0, 13.8 (CH3).
Ethyl 2,2-Difluoroheptadecanoate (4b)
IR (film): n = 1772, 1102 cm-1.
EI-MS: m/z (%) = 228 (4, M+), 208 (15), 105 (100), 77 (11).
13C NMR (CDCl3): d = 164.4 (t, J = 32.8 Hz, CF2CO), 116.40 (t,
J = 248 Hz, CF2), 62.7 (OCH2), 34.4 (t, J = 23 Hz, CH2CF2), 31.9,
29.68, 29.65, 29.61, 29.5, 29.36, 29.35, 29.2, 29.0, 22.6, 21.41 (t,
J = 4.1 Hz), 14.1, 13.9 (CH3).
Anal. Calcd for C12H14F2O2: C, 63.15; H, 6.18; F, 16.64. Found: C,
62.87; H, 6.31; F, 16.83.
Ethyl 2,2-Difluoro-3-(4-methoxyphenyl)propanoate (4h)
EI-MS: m/z (%) = 334 (M+, 5), 207 (15), 193 (45), 179 (49), 85 (38),
71 (62), 57 (99, C4H9), 43 (100).
IR (film): n = 3050, 1770, 1614, 1515, 1301, 1033 cm-1.
Synthesis 2000, No. 13, 1917–1924 ISSN 0039-7881 © Thieme Stuttgart · New York

1924
O. Jiménez et al.
SPECIAL TOPIC
13C NMR (CDCl3): d = 163.9 (t, J = 32.4 Hz, CO), 159.2 (C4arom),
131.4 (2C3arom), 122.5 (t, J = 4.3 Hz, C1arom), 115.3 (t, J = 250 Hz,
CF2), 113.9 (2C2arom), 62.7 (OCH2), 55.1 (OCH3), 40.0 (t, J = 24 Hz,
CF2CH2), 13.8 (CH3).
EI-MS: m/z (%) = 244 (4, M+), 224 (22, M+-HF), 121 (100), 77
(10).
(13) Durán, I.; Parrilla, A.; Feixas, J.; Guerrero, A. Bioorg. Med.
Chem. Lett. 1993, 3, 2593.
(14) Bosch, M. P.; Pérez, R.; Lahuerta, G.; Hernanz, D.; Camps, F.;
Guerrero, A. Bioorg. Med. Chem. 1996, 4, 467.
(15) Okano, T.; Takakura, N.; Nakano, Y.; Eguchi, S. Tetrahedron
Lett. 1992, 33, 3491.
(16) Bloschitsa, F. A.; Burmakov, A. I.; Kunshenko, B. V.;
Alekseeva, L. A.; Bel´ferman, A. L.; Pazderskii, Y. A.;
Yagupol´skii, L. M. J. Org. Chem. USSR Engl. Transl. 1981,
17, 1260.
Anal. Calcd for C12H14F2O3: C, 59.01; H, 5.77; F, 15.55. Found: C,
59.07; H, 5.87; F, 15.24.
Ethyl 2,2-Difluoro-3-(4-fluorophenyl)propanoate (4i)
(17) Middleton, W. J.; Bingham, E. M. J. Org. Chem. 1980, 45,
2883.
IR (film): n = 3051, 1770, 1514, 1375, 1074 cm-1.
(18) Yang, Z. Y.; Burton, D. J. J. Fluorine Chem. 1989, 45, 435.
(19) Yang, Z. -Y.; Burton, D. J. J. Org. Chem. 1991, 56, 5125.
(20) Nakano, T.; Makino, M.; Morizawa, Y.; Matsumura, Y.
Angew. Chem., Int. Ed. Engl. 1996, 35, 1019.
(21) McBee, E. T.; Pierce, O. R.; Christman, D. L. J. Am. Chem.
Soc. 1955, 77, 1581.
13C NMR (CDCl3): d = 163.7 (t, J = 32.2 Hz, CO), 162 (d, J = 245
Hz, C4arom), 131.5 (d, J = 8 Hz, 2C2arom), 126 (m, C1arom), 115.4 (d,
J = 21.3 Hz, 2C3arom), 115.1 (t, J = 250 Hz, CF2), 62.8 (OCH2), 40.0
(t, J = 24 Hz, CF2CH2), 13.8 (CH3).
EI-MS: m/z (%) = 232 (4, M+), 212 (22, M+-HF), 184 (10), 159
(14), 109 (100).
(22) Lang, R. W.; Schaub, B. Tetrahedron Lett. 1988, 29, 2943.
(23) Fürstner, A. Synthesis 1989, 571.
HRMS: Calcd for C11H11F3O2: 232.0711. Found: 232.0712.
(24) Curran, T. J. Org. Chem. 1993, 58, 6360.
(25) Schirlin, D.; Baltzer, S.; Altenburger, J. M. Tetrahedron Lett.
1991, 32, 7255.
(26) Schirlin, D.; Altenburger, J. M. Tetrahedron Lett. 1991, 32,
7255.
Ethyl 2,2-Difluoro-3-(4-cyanophenyl)propanoate (4j)
IR (film): n = 3035, 2231, 1768, 1612, 1508, 1375, 1074 cm-1.
13C NMR (CDCl3): d = 163.2 (t, J = 32 Hz, CO), 136.0 (C1arom),
132.2 (2C2arom), 131.2 (2C3arom), 118.4 (CN), 114.5 (t, J = 252 Hz,
CF2), 112.0 (C4arom), 63.1 (OCH2), 40.7 (t, J = 24 Hz, CF2CH2), 13.8
(CH3).
EI-MS: m/z (%) = 239 (5.5, M+), 219 (75, M+-HF), 191 (67, M+-HF
–CH2 = CH2), 166 (48), 116 (100).
(27) Kitagawa, O.; Taguchi, T.; Kobayashi, Y. Tetrahedron Lett.
1988, 29, 1803.
(28) Differding, E.; Ofner, H. Synlett 1991, 187.
(29) Hallinan, E. A.; Fried, J. Tetrahedron Lett. 1984, 25, 2301.
(30) Posner, G. H.; Lee, J. K.; Wang, Q.; Peleg, S.; Burke, M.;
Brem, H.; Dolan, P.; Kensler, T. W. J. Med. Chem. 1998, 41,
3008.
HRMS:. Calcd for C12H11F2NO2: 239.0758. Found: 239.0760.
(31) March, J. Advanced Organic Chemistry, 3rd Ed.; Wiley:
New York, 1985.
(32) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin
Trans. 1 1975, 1574.
(33) Barton, D. H. R.; Motherwell, W. B.; Stange, A. Synthesis
1981, 743.
(34) Jang, D. O.; Cho, D. H.; Kim, J. Synth. Commun. 1998, 28,
3559.
Acknowledgement
The authors gratefully acknowledge CICYT (Project AGF 97-1217-
C0201), EC (FAIR CT96-1302) and Comissionat per a Universitats
i Recerca (1997SGR 00021) for financial support and MEC for a
predoctoral fellowship to O. J. We are indebted to SEDQ, S.A. for
providing us with some starting materials.
(35) Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. C. Tetrahedron
1993, 49, 7193.
(36) Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. C. Tetrahedron
Lett. 1992, 33, 5709.
(37) Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 188.
(38) Motherwell, W. B. Free Radical Chain Reactions in Organic
Synthesis; Academic: London, 1992.
(39) Nicholas, K. M.; Pettit, R. Tetrahedron Lett. 1971, 12, 3475.
(40) Hudlicky, T.; Claeboe, C. D.; Brammer, L. E.; Koroniak, L.;
Butora, G.; Ghiviriga, I. J. Org. Chem. 1999, 64, 4909.
(41) Fujimoto, Y.; Tatsuno, T. Tetrahedron Lett. 1976, 37, 3325.
(42) Shue, Y. -K.; Carrera, G. M.; Nadzan, A. M. Tetrahedron Lett.
1987, 28, 3225.
(43) Boar, R. B.; Joukhadar, L.; McGhie, J. F.; Misra, S. C.; Barret,
A. G. M.; Barton, D. H. R.; Prokopiou, P. A. J. Chem. Soc.,
Chem. Commun. 1978, 68.
(44) Hutchins, R. O.; Kandasamy, D.; Maryanoff, C. A.;
Masilamani, D.; Maryanoff, B. E. J. Org. Chem. 1977, 42, 82.
(45) Camp, D.; Healy, P. C.; Jenkins, I. D.; Skelton, B. W.; White,
A. H. J. Chem. Soc., Perkin Trans. 1 1991, 1323.
References
(1) Seebach, D. Angew. Chem., Int. Ed. Engl. 1990, 29, 1320.
(2) Welch, J. T.; Eswarakrishnan, S. Fluorine in Bioorganic
Chemistry; Wiley: New York, 1991.
(3) Filler, R.; Kobayashi, Y.; Yagupolskii, L. M. Organofluorine
Compounds in Medicinal Chemistry and Biomedical
Applications; Elsevier: Amsterdam, 1993.
(4) Walker, S. B. Fluorine Compounds as Agrochemicals;
Fluorochem Limited: Old Glossop: U.K., 1989.
(5) Blackburn, G. M.; Kent, D. E.; Kolkmann, F. J. Chem. Soc.,
Perkin Trans. 1 1984, 1119.
(6) Welch, J. T. Tetrahedron 1987, 43, 3123.
(7) Dreyer, G. B.; Metcalf, B. W. Tetrahedron Lett. 1988, 29,
6885.
(8) Rozen, S.; Filler, R. Tetrahedron 1985, 41, 1111.
(9) Gelb, M. H.; Svaren, J. P.; Abeles, R. H. Biochemistry 1985,
24, 1813.
(10) Rosell, G.; Herrero, S.; Guerrero, A. Biochem. Biophys. Res.
Commun. 1996, 226, 2887.
(11) Renou, M.; Lucas, P.; Malo, E.; Quero, C.; Guerrero, A.
Chem. Senses 1997, 22, 407.
(12) Parrilla, A.; Guerrero, A. Chem. Senses 1994, 19, 1.
Article Identifier:
1437-210X,E;2000,0,13,1917,1924,ftx,en;E10800SS.pdf
Synthesis 2000, No. 13, 1917–1924 ISSN 0039-7881 © Thieme Stuttgart · New York