Synthesis of 5-[(Pentafluorosulfanyl)methyl]-γ-butyrolactones via a Silver-Promoted Intramolecular Cyclization Reaction

Article abstract of DOI:10.1002/ejoc.201901163

The synthesis of 5-[(pentafluorosulfanyl)methyl]-γ-butyrolactones bearing different substituents at position 3 or 4 is reported. A silver-promoted intramolecular cyclization of substituted 4-chloro-5-(pentafluorosulfanyl)pentanoic acids allows the preparation of the substituted SF₅-containing γ-butyrolactones in up to 96 % yield.

Full text of DOI:10.1002/ejoc.201901163

DOI: 10.1002/ejoc.201901163
Full Paper
Organofluorine Chemistry
Synthesis of 5-[(Pentafluorosulfanyl)methyl]-γ-butyrolactones
via a Silver-Promoted Intramolecular Cyclization Reaction
Majdouline Roudias,[a] Audrey Gilbert,[a] and Jean-François Paquin*[a]
Abstract: The synthesis of 5-[(pentafluorosulfanyl)methyl]-γ- stituted 4-chloro-5-(pentafluorosulfanyl)pentanoic acids allows
butyrolactones bearing different substituents at position 3 or 4 the preparation of the substituted SF5-containing γ-butyro-
is reported. A silver-promoted intramolecular cyclization of sub- lactones in up to 96 % yield.
Introduction
The incorporation of fluorinated groups, with the CF3 being the
prevalent one, in relevant molecules has a significant impact on
their physical, chemical and biological properties[1] due to the
electronic characteristics and the relatively small size of the
fluorine atom.[2] Out of the emerging fluorinated groups,[3] the
pentafluorosulfanyl (SF5) group[4,5] has become a promising
substituent in pharmaceutical,[6] agrochemical[7] and material
sciences.[8] This is mostly because of its unique chemical and
metabolic stability, lipophilicity and electron-withdrawing na-
ture combined with a large dipole moment.[5,9] Often compared
to the trifluoromethyl (CF3) group, the SF5 group possesses
however enhanced properties (electron-withdrawing ability, li-
pophilicity, chemical and metabolic stability, etc.) and is there-
fore often referred to as a “super CF3” (Scheme 1a).[10]
Apart from being the constituent in many natural products
used in the flavors and fragrances industries,[11] lactones exhibit
antioxidant, antimicrobial and anticancer activity.[12] They have
not only attracted the attention of medicinal chemists, but also
the one of synthetic chemists as they afford valuable building
blocks (Scheme 1a).[13]
In that context, we envisioned that SF5-containing γ-butyro-
lactones could represent attractive fluorinated heterocycles for
drug development and related fields.[14] While a number of
methods have been reported for the synthesis of 5-trifluoro-
methyl-γ-butyrolactones,[15] the preparation of the correspond-
ing 5-(pentafluorosulfanyl)methyl-substituted lactones remains
unknown. We have recently reported the synthesis of 5-[(penta-
fluorosulfanyl)methyl]-2-oxazolines using a silver-promoted cy-
clization reaction of N-(2-chloro-3-(pentafluorosulfanyl)propyl)-
amides (Scheme 1b).[16] Inspired by this work, we report herein
its extension for the preparation of 5-[(pentafluorosulfanyl)-
methyl]-γ-butyrolactones (Scheme 1c).
Scheme 1. Previous and current work.
Results and Discussion
First, the required 4-chloro-5-(pentafluorosulfanyl)pentanoic
acids possessing diverse functional groups on carbons 2 or 3
were prepared by the radical addition of pentafluorosulfanyl
chloride (SF5Cl) on the appropriate pent-4-enoic acids using
Dolbier's protocol.[17] To the best of our knowledge, this repre-
sents the first addition of SF5Cl on an alkene bearing a free
carboxylic acid elsewhere on the molecule.[18] As shown in
Scheme 2, the acyclic precursors were obtained in moderate to
excellent yields (42–98 %) and as a pair of diastereoisomers
(except for 2a, 2b and 2c). To examine the limits of the intra-
molecular cyclization, we have also prepared carboxylic acids
with either a shorter (4) or a longer carbon chain (6) by one
carbon length in order to form the corresponding 4- and
6-membered lactones.
Having a series of 4-chloro-5-(pentafluorosulfanyl)pentanoic
acids in hands, we selected 2a as the model substrate for the
optimization of the intramolecular cyclization (Scheme 3). We
then employed the conditions developed in our prior work on
the synthesis of 5-[(pentafluorosulfanyl)methyl]-2-oxazolines[16]
to set a starting point. When using AgOTf (1.1 equiv.) in toluene
[a] CCVC, PROTEO, Département de chimie, Université Laval,
1045 Avenue de la Médecine, Pavillon Alexandre-Vachon
Québec, Québec, G1V 0A6, Canada
E-mail: jean-francois.paquin@chm.ulaval.ca
http://www.chm.ulaval.ca/jfpaquin
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201901163.
(0.05
M
) at 110 °C, but during 19 h instead of the 3 h initially
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Scheme 3. Selected results for the optimization. [a] Yield estimated by NMR
analysis of the crude mixture.
lactone 7b was isolated as a mixture with the inseparable sub-
stituted δ-valerolactone 8. Interestingly, the latter results from
the displacement of the pentafluorosulfanyl group by the carb-
oxylic acid, documenting another example of the substituent
acting as a leaving group.[19] For the substrate bearing a pro-
tected alcohol in the form of a benzyl 3i, good yield was
obtained. When switching to a fluorine substituent, the
corresponding lactone 7j was isolated in moderate yields
(52 %). Finally, when applying the optimal conditions to sub-
strates bearing a shorter (4) or a longer (6) carbon chain, the
corresponding 4-[(pentafluorosulfanyl)methyl]-ꢀ-propiolactone
(9) and 6-[(pentafluorosulfanyl)methyl]-δ-valerolactone (10)
Scheme 2. Preparation of substituted 4-chloro-5-(pentafluorosulfanyl)pentan-
oic acids and related substrates.
reported, 25 % of the desired 5-[(pentafluorosulfanyl)methyl]-γ-
butyrolactone (7a) was observed by NMR, with the remaining
mass balance being the starting material. Adding 1.1 equiv. of
Et3N resulted in a full conversion after 3 h of reaction with the
desired lactone 7a isolated in 85 % yield. We believe that the
role of the base is solely to deprotonate the carboxylic acid,
resulting in a more nucleophilic group for the intramolecular
cyclization. It is interesting to note that this cyclization reaction
proceeds without elimination of the chlorine atom, a typical
reaction pathway for ꢀ-chloro-SF5-alkyl compounds in the
presence of a base.[5c]
We next evaluated the reactivity of the different 4-chloro-5-
(pentafluorosulfanyl)pentanoic acids and the results are sum-
marized in Scheme 4. Under our optimized conditions, the 5-
[(pentafluorosulfanyl)methyl]-γ-butyrolactones bearing an alkyl
group 7d–f were obtained in moderate to excellent yields (47–
96 %). The cyclization of gem-disubstituted carboxylic acids also
performed well, providing the corresponding lactones 7b and
7c with 54 % and 88 % yield respectively. Aromatic substituent
was also tolerated and the cyclized products 7g and 7h were
isolated in 47 % and 96 % yield respectively. In general, we no-
ticed that the yields were higher for the lactones having a
substituent at position 3 (7c, 7e and 7h) than for the lactones
substituted at position 4 (7b, 7d and 7g). The 3,3-dimethyl-
Scheme 4. Scope of the silver promoting intramolecular cyclization of 4-
chloro-5-SF5-pentanoic acids. [a] Compounds 7b and 8 were inseparable by
column chromatography. Yields are estimated by NMR analysis of the purified
mixture. [b] Yield estimated by 19F NMR analysis of the crude mixture.
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were observed in very low yield (< 3 %) by NMR analysis of the lactone 7a with LiAlH4 provided the desired diol 14 in 61 %
crude mixture.
yield, giving therefore access to a new SF5-containing derivative
and also, a potential versatile building block (Scheme 7).
As it is well known that γ-butyrolactone can also be obtained
from the intramolecular cyclization of 4-halobutanamides and
their derivatives,[20] we wondered if primary amides could also
act as a suitable precursor in our case. To test this hypothesis,
we subjected amide 11 to the cyclization conditions
(Scheme 5). Gratifyingly, the desired lactone 7a was isolated in
61 % yield, offering the possibility to use alternative starting
materials to access the same product.
Scheme 7. Reduction of γ-butyrolactone 7a.
Conclusions
In conclusion, we have reported the silver-promoted synthesis of
5-[(pentafluorosulfanyl)methyl]-γ-butyrolactones in moderate to
excellent yields. Notably, this transformation represents a rare
example of the substitution reaction, without elimination, of
the chlorine atom on ꢀ-chloro-SF5-alkyl compounds. These new
SF5-containing heterocycles, accessible in two steps from sub-
stituted pent-4-enoic acids, represent potentially useful fluorin-
ated building blocks for the synthesis of biologically active com-
pounds.
Scheme 5. 4-Chloro-5-(pentafluorosulfanyl)pentanamide (11) as a suitable
precursor for the preparation of γ-butyrolactone 7a.
Interestingly, the reaction pathway can also be strongly influ-
enced by the nature of the substituent (Scheme 6). Indeed,
when submitting the cyano-containing substrate (2k) to the
cyclization conditions, the desired lactone was not observed.
Instead, unexpected decarboxylation of 2k occurred to afford
4-chloro-5-(pentafluorosulfanyl)pentanenitrile (12) in 57 % iso-
lated yield.[21] For the ester substrate 2l, under the optimized
conditions, a complex mixture of products was obtained, out of
which, 22 % of ethyl 5-(pentafluorosulfanyl)pentanoate (13), the
result of the decarboxylation of 2l, could be isolated. An NMR
analysis of the mixture also indicated the presence of trace
amount of the desired lactone 7l along with traces of 7a. Run-
ning the reaction in the absence of Et3N for 18 h provided a
55:45 mixture of 13 and 7a as determined by NMR analysis of
the crude mixture. Compound 7a, the product of the de-
carboalkoxylation of lactone 7l, could be isolated in 43 % yield.
In those cases, while the desired lactones could not be ob-
tained, products 12 and 13 represent potentially interesting
and versatile SF5-containing building blocks.
Experimental Section
General Remarks: All commercial compounds were used as re-
ceived. Gaseous SF5Cl was condensed in hexanes at –40 °C and was
used as a normal reagent in solution (typically, 1 to 2 M solutions
in hexanes were obtained). Caution: as SF5Cl is highly toxic, it
should be used in a well-ventilated fume hood. Solvents were used
as purchased unless stated as dry. Et2O, THF and CH2Cl2 were puri-
fied using a Vacuum Atmospheres Inc. Solvent Purification System.
All air and water sensitive reactions were carried out under an ar-
gon atmosphere. Reactions were monitored by TLC on precoated
plates (Silicycle silica gel 60 Å F254) and products were visualized
under 254 nm UV light followed by staining with KMnO4 or bromo-
cresol when appropriate. Purification was carried out on silica gel
(Silicycle silica gel 60 Å F254) or was carried out on a Biotage Isolera
One Flash Chromatography System (AFP) using Silicycle SiliaSep sil-
ica gel cartridges. NMR spectra were recorded on an Agilent DD2
500 spectrometer in the indicated solvent at 298 K. Chemical shifts
1
for H and 13C spectra are reported on the delta scale in ppm and
were referenced to residual solvent references or internal TMS refer-
ence. CFCl3 was used as an external standard for 19F NMR. Resonan-
ces are reported as follows: chemical shift (δ ppm), multiplicity
(s = singlet, d = doublet, t = triplet, q = quartet, p = quintet, sxt =
sextet, m = multiplet or a combination of the above), coupling con-
stant (Hz), integration and attribution. H and C signals were as-
signed using 2D correlations (HSQC and COSY) and DEPT experi-
ment. High-resolution mass (HRMS) spectra were recorded on a LC/
MS-TOF Agilent 6210 using electrospray ionization in both positive
(ESI+) and negative (ESI–) modes. Infrared spectra (IR) were recorded
on an ABB MB 3000 FT-IR spectrometer. Absorptions are described
as s (strong), m (medium), w (weak) and br. (broad) and reported in
cm–1. Melting points were measured on a Stanford Research System
OptiMelt MPA100 automated melting point apparatus.
Scheme 6. Unexpected decarboxylation/decarboalkoxylation reaction with
precursors 2k and 2l. [a] Estimated by NMR analysis of the crude mixture.
Synthesis of the Carboxylic Acids
Finally, to further extend the utility of the new SF5-contain-
ing lactones generated, we investigated the reduction of 7a.
3,3-Dimethylpent-4-enoic Acid (1b): Prepared according to the
method of Cottrell et al.[22] A mixture of prenyl alcohol (2.00 mL,
Hence, reaction of 5-[(pentafluorosulfanyl)methyl]-γ-butyro- 19.7 mmol), triethyl orthoacetate (7.20 mL, 39.4 mmol) and
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propionic acid (89 μL, 1.18 mmol) was heated under a Dean–Stark
Et2O/hexanes) afforded the product (1.40 g, 6.86 mmol, 44 %) as
colorless oil. Spectroscopic data were in accordance with the one
apparatus at 145 °C for 4 days with daily addition of a drop of acid.
The reaction mixture was then cooled down to r.t., washed with described in the literature.[26] Then, to a solution of ethyl 3-phenyl-
water and with a sat. solution of NaHCO3. The organic phase was
then refluxed with a solution of NaOH (1.88 g, 46.9 mmol) in EtOH
(14 mL) and water (7 mL) for 1 h. The reaction mixture was then
cooled down to r.t. and the ethanol was removed in vacuo leaving
the aqueous phase which was acidified 0 °C by the addition of 10 %
HCl solution then extracted with Et2O (3 ×). The organic phases
were combined, dried with Na2SO4 and concentrated in vacuo. Puri-
fication by flash column chromatography (2 % MeOH/CH2Cl2) af-
forded the product (170 mg, 1.33 mmol, 7 %) as a colorless oil.
Spectroscopic data were in accordance with the one described in
the literature.[22]
pent-4-enoate (1.30 g, 6.35 mmol) in MeOH (6.4 mL) was added
KOH (713 mg, 12.7 mmol). After 16 h at reflux, the reaction mixture
was concentrated in vacuo and the residue was dissolved Et2O and
extracted with a sat. solution of NaHCO3 (3 ×). The aqueous phases
were combined, acidified by the addition of a 10 % solution of HCl
and extracted with CH2Cl2 (3 ×). The organic phases were com-
bined, dried with Na2SO4 and concentrated in vacuo to afford the
product (1.09 g, 6.17 mmol, 97 %) as a colorless oil. Spectroscopic
data were in accordance with the one described in the literature.[26]
2-Phenylpent-4-enoic Acid (1h): Prepared according to the
method of Duguet et al.[27] To a solution of phenylacetic acid
(1.00 g, 7.34 mmol) in dry THF (23 mL) at –78 °C was added nBuLi
3-Methylpent-4-enoic Acid (1d): Prepared according to the
method of Cottrell et al.[22] A mixture of crotyl alcohol (2.00 mL,
23.4 mmol), triethyl orthoacetate (8.60 mL, 46.9 mmol) and pro-
pionic acid (0.11 mL, 1.41 mmol) was heated under a Dean–Stark
apparatus at 145 °C for 24 h. The reaction mixture was then cooled
down to r.t., washed with water and with a sat. solution of NaHCO3.
The organic phase was then refluxed with a solution of NaOH
(1.88 g, 46.9 mmol) in water (63 mL) for 1.5 h. The reaction mixture
was then cooled down to 0 °C, acidified by the addition of 10 %
HCl solution and extracted with Et2O (3 ×). The organic phases were
combined, dried with Na2SO4 and concentrated in vacuo. Purifica-
tion by flash column chromatography (30 % EtOAc/hexanes) af-
forded the product (1.13 g, 9.90 mmol, 42 %) as colorless oil. Spec-
troscopic data were in accordance with the one described in the
literature.[22]
(2.5
M in hexanes, 6.50 mL, 16.2 mmol). After 10 min, allyl bromide
(2.03 mL, 23.5 mmol) was added. After 19 h at r.t, the reaction
mixture was quenched by the addition of H2O, acidified by the
addition of a 10 % solution of HCl and extracted with CH2Cl2 (3 ×).
The organic phases were combined, dried with MgSO4, filtered and
concentrated in vacuo. Purification by AFP (10–40 % EtOAc/hex-
anes, 3–15–3 CV) afforded the product (1.22 g, 6.93 mmol, 94 %) as
a colorless oil. Spectroscopic data were in accordance with the one
described in the literature.[27]
2-(Benzyloxy)pent-4-enoic Acid (1i): To a solution of iPr2NH
(0.85 mL, 6.02 mmol) in dry THF (20 mL) at –78 °C was added nBuLi
(2.5
M in hexanes, 2.40 mL, 6.02 mmol). The reaction mixture was
warmed to 0 °C and a solution of benzyloxyacetic acid (500 mg,
3.01 mmol) in THF (10 mL) was added. After 30 min at 0 °C, allyl
bromide (0.31 mL, 3.61 mmol) was added. After 17 h at r.t., the
reaction mixture was quenched by the addition of H2O, acidified by
the addition of a 10 % solution of HCl and extracted with EtOAc
(3 ×). The organic phases were combined, dried with MgSO4, fil-
tered and concentrated in vacuo. Purification by AFP (1–10 %
MeOH/CH2Cl2, 3–15–3 CV) afforded the product (96.0 mg,
0.47 mmol, 15 %) as a colorless oil. FT-IR: ν = 3074 (w), 3032 (w),
2924 (w), 2872 (w), 1718 (s), 1562 (m), 1454 (m), 1416 (m), 1271 (s),
2-Methylpent-4-enoic Acid (1e): To a solution of ethyl 2-methyl-
pent-4-enoate (1.00 g, 7.03 mmol) in a 1:1 mixture of THF/H2O
(35 mL) was added LiOH·H2O (948 mg, 21.1 mmol). After 19 h at
r.t., CH2Cl2 was added and the aqueous phase was separated and
acidified by the addition of a 10 % solution of HCl then extracted
with CH2Cl2 (1 ×). The organic phases were combined, dried with
MgSO4, filtered and concentrated in vacuo to afford the product
(793 mg, 6.95 mmol, 99 %) as a colourless oil. Spectroscopic data
were in accordance with the one described in the literature.[23]
1209 (s), 1103 (s), 1028 (m) cm–1 1H NMR (500 MHz, CDCl3): δH
. =
7.42–7.30 (m, 5H, 5 × ArH), 5.85 (ddt, J = 17.2, 10.2, 7.0 Hz, 1H,
CH=CH2), 5.19 (app. dq, J = 17.2, 1.5 Hz, 1H, CHH=CH), 5.16 (ddt,
J = 10.2, 1.9, 1.1 Hz, 1H, CHH=CH), 4.73 (d, J = 11.7 Hz, 1H, CHHOAr),
4.58 (d, J = 11.6 Hz, 1H, CHHOAr), 4.10 (dd, J = 6.6, 5.0 Hz, 1H,
CHOBn), 2.69–2.54 (m, 2H, CH2CHOBn) ppm. 13C NMR (125 MHz,
CDCl3): δC = 175.2 (C, CO2H), 136.7 (C, CAr), 132.3 (CH, CH=CH2),
128.6 (CH, CHAr), 128.3 (CH, CHAr), 128.1 (CH, CHAr), 118.7 (CH2, CH2=
CH), 77.3 (CH, CHOBn), 72.6 (CH2, CH2OAr), 36.7 (CH2, CH2CHOBn)
ppm. HRMS (ESI-TOF, m/z): Calcd for C12H13O3 [M – H]– 205.0870,
found 205.0870.
2-Ethylpent-4-enoic Acid (1f): Prepared according to the method
of Kuehne et al.[24] To a solution of diisopropylamine (4.15 mL,
29.5 mmol) in dry THF (57 mL) at –78 °C was added nBuLi (2.5
M in
hexanes, 11.8 mL, 29.5 mmol). After 30 min at r.t., the reaction mix-
ture was cooled down to 0 °C and butyric acid (1.00 g, 11.3 mmol)
and HMPA (2.56 mL, 14.7 mmol) were added. After 1 h at r.t., the
reaction mixture was cooled down to 0 °C and allyl bromide
(1.27 mL, 14.7 mmol) was added. After 20 h at r.t., the reaction
mixture was quenched by the addition of H2O, acidified by the
addition of a 10 % solution of HCl and extracted with EtOAc (3 ×).
The organic phases were combined, dried with MgSO4, filtered and
concentrated in vacuo. Purification by AFP (30–100 % EtOAc/hex-
anes, 3–15–3 CV) afforded the product (425 mg, 3.32 mmol, 30 %)
as a colorless oil. Spectroscopic data were in accordance with the
one described in the literature.[24,25]
2-Fluoropent-4-enoic Acid (1j): First, diethyl 2-allyl-2-fluoromalon-
ate was prepared according to the method of Leeper et al.[28] To a
solution of NaH (60 % in oil, 247 mg, 6.17 mmol) in dry DMF (28 mL)
was added diethyl 2-fluoro malonate (1.00 g, 5.61 mmol). After 3 h
at r.t., allyl bromide (0.53 mL, 6.17 mmol) was added. After a further
17 h at r.t., the reaction mixture was cooled down to 0 °C, quenched
3-Phenylpent-4-enoic Acid (1g): First, ethyl 3-phenylpent-4-eno-
ate was prepared according to the method of Adrio et al.[26] A mix- by the addition of H2O and extracted with EtOAc (3 ×). The organic
ture of cinnamyl alcohol (2.00 mL, 15.6 mmol), triethyl orthoacetate phases were combined, dried with MgSO4, filtered and concen-
(14.30 mL, 77.8 mmol) and propionic acid (70 μL, 0.93 mmol) was
heated under a Dean–Stark apparatus at 145 °C for 16 h. The reac-
tion mixture was then cooled down to r.t. and the ethanol was
removed in vacuo. The residue was dissolved in Et2O and washed
trated in vacuo. Purification by AFP (0–30 % EtOAC/hexanes, 3–15–
3 CV) afforded the product (895 mg, 4.10 mmol, 73 %) as a colorless
oil. Spectroscopic data were in accordance with the one described
in the literature.[28] Then, a solution of diethyl 2-allyl-2-fluoro-
with a sat. solution of NaHCO3 (3 ×), dried with MgSO4 and concen- malonate (882 mg, 4.04 mmol), NaCl (472 mg, 8.08 mmol) and H2O
trated in vacuo. Purification by flash column chromatography (5 % (0.15 mL, 8.08 mmol) in DMSO (17 mL) was heated at reflux during
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6 h. The reaction mixture was then cooled down to r.t. and H2O
CH=CH2), 118.1 (CH2, CH2=CH), 61.9 (CH2, CH3CH2O), 51.2 (CH,
(10 mL) and Et2O (10 mL) were added. The aqueous phase was CHCO2Et), 32.9 (CH2, CH2CHCO2Et), 14.0 (CH3, CH3CH2O). HRMS (ESI-
separated and extracted with Et2O (2 ×). The organic phases were
combined, dried with MgSO4, filtered and a solution of KOH
(453 mg, 8.08 mmol) in EtOH (22 mL) was added. After 1 h at r.t.,
the reaction mixture was concentrated in vacuo. The residue was
dissolved in EtOAc and 2 M NaOH and the aqueous phase was
separated, acidified by the addition of 10 % HCl then extracted with
EtOAc (3 ×). The organic phases were combined, dried with MgSO4,
filtered and concentrated in vacuo. Purification by AFP (1–10 %
MeOH/CH2Cl2, 3–15–3 CV) afforded the product (224 mg,
1.90 mmol, 47 % over two steps) as a brownish oil. FT-IR: ν = 3084
TOF, m/z): Calcd for C8H11O4 [M – H]– 171.0663, found 171.0664.
Synthesis of an Amide
Pent-4-enamide: Prepared according to the method of Lo et al.[32]
To a solution of 4-pentenoic acid (3.15 mL, 30.8 mmol) in CH2Cl2
(40 mL) were added oxalyl chloride (3.10 mL, 37.0 mmol) and DMF
(2 drops). After 18 h at r.t., the reaction mixture was concentrated in
vacuo and the residue was dissolved in CH2Cl2 (20 mL) and aqueous
NH4OH (28 %, 50 mL) was added dropwise at 0 °C. After 18 h at r.t.,
the aqueous phase was separated and extracted with CH2Cl2 (2 ×).
The organic phases were combined, dried with MgSO4, filtered and
concentrated in vacuo to afford the product (957 mg, 9.65 mmol,
31 %) as a yellow solid. Spectroscopic data were in accordance with
the one described in the literature.[33]
1
(w), 2989 (w), 1738 (s), 1433 (m), 1223 (m), 1076 (s) cm–1. H NMR
(500 MHz, CDCl3): δH = 9.66 (br. s, 1H, CO2H), 5.85 (app. ddt, J =
17.1, 10.2, 6.9 Hz, 1H, CH=CH2), 5.29–5.20 (m, 2H, CH2=CH), 5.04
(dddd, J = 48.6, 6.8, 4.4, 0.8 Hz, 1H, CHF), 2.83–2.61 (m, 2H, CH2CHF)
ppm. 13C NMR (125 MHz, CDCl3) δC = 174.8 (C, CO2H), 130.4 (d, J =
3.3 Hz, CH, CH=CH2), 119.9 (CH2, CH2=CH), 87.7 (d, J = 186.9 Hz, CH,
CHF), 36.4 (d, J = 20.9 Hz, CH2, CH2CHF) ppm. 19F NMR (470 MHz,
CDCl3): δF = –192.1 (dt, J = 51.8, 25.5 Hz, 1F, CHF) ppm. HRMS (ESI-
TOF, m/z): Calcd for C5H6FO2 [M – H]– 117.0357, found 117.0359.
Preparation of Substituted 4-Chloro-5-(pentafluorosulfanyl)-
pentanoic Acid and Derivatives
General Procedure: To a solution of carboxylic acid (1 equiv.) in
CH2Cl2 (0.25
M) at –40 °C were added SF5Cl (solution in hexanes,
1.5 equiv.) and Et3B (1 M in THF, 0.1 equiv.). After 3 h at –40 °C, the
reaction mixture was warmed up to r.t. and a sat. solution of
NaHCO3 was added. The aqueous phase was separated, acidified by
the addition of a 10 % solution of HCl and extracted with CH2Cl2
(3 ×). The organic phases were combined, dried with MgSO4, fil-
tered and concentrated in vacuo.
4-Chloro-5-(pentafluoro-λ6-sulfanyl)pentanoic Acid (2a): Follow-
ing the general procedure on 4.99 mmol scale of pent-4-enoic acid
1a, the desired product was isolated as a colorless oil (1.28 g,
2-Cyanopent-4-enoic Acid (1k): First, ethyl 2-cyanopent-4-enoate
was prepared according to the method of Malmedy et al.[29] To a
solution of ethyl cyanoacetate (2.00 g, 17.7 mmol) in dry THF
(18 mL) were added, at 0 °C, NaH (60 % in oil, 778 mg, 19.5 mmol)
and allyl bromide (1.44 mL, 17.7 mmol). After 18 h at r.t., the reac-
tion mixture was quenched with H2O and extracted with CH2Cl2
(3 ×). The organic phases were combined, dried with MgSO4, fil-
tered and concentrated in vacuo. Purification by AFP (10–30 %
EtOAc/hexanes, 3–15–3 CV) afforded the product (484 mg,
3.16 mmol, 36 %) as a colorless oil. Spectroscopic data were in ac-
cordance with the one described in the literature.[30] To a solution
of ethyl 2-cyanopent-4-enoate (176 mg, 1.15 mmol) in a 1:1 mixture
of THF/H2O (11.5 mL) was added LiOH·H2O (72.4 mg, 1.73 mmol).
After 4 h at r.t., CH2Cl2 was added and the aqueous phase was
separated and acidified by the addition of a 10 % solution of HCl
then extracted with CH2Cl2 (3 ×). The organic phases were com-
bined, dried with MgSO4, filtered and concentrated in vacuo to af-
ford the product (120 mg, 0.96 mmol, 84 %) as a yellow oil. FT-IR:
4.89 mmol, 98 %). FT-IR: ν = 2982 (w), 2932 (w), 1713 (m), 1429 (w),
1
1416 (w), 1248 (w), 1223 (w) cm–1. H NMR (500 MHz, CDCl3): δH
=
11.29 (br s, 1H, CO2H), 4.48 (app. dtd, J = 9.6, 6.3, 3.0 Hz, 1H, CHCl),
4.13–3.99 (m, 1H, CHHSF5), 3.98–3.87 (m, 1H, CHHSF5), 2.75–2.61 (m,
2H, CH2CO2H), 2.39 (app. dtd, J = 15.2, 7.8, 3.0 Hz, 1H, CHHCHCl),
2.03–1.94 (m, 1H, CHHCHCl) ppm. 13C NMR (125 MHz, CDCl3): δC
=
178.0 (C, CO2H), 76.4 (p, J = 13.9 Hz, CH2, CH2SF5), 54.7 (p, J = 4.2 Hz,
CH, CHCl), 32.1 (CH2, CH2CHCl), 30.4 (CH2, CH2CO2H) ppm. 19F NMR
(470 MHz, CDCl3): δF = 83.4–81.8 (m, 1F, SFF4), 66.6 (dt, J = 146.4,
8.2 Hz, 4F, SFF4) ppm. HRMS (ESI-TOF, m/z): Calcd for C5H7ClF5O2S
[M – H]– 260.9781, found 260.9776.
ν = 3173 (m), 3086 (m), 2932 (m), 2608 (w), 2260 (w), 1728 (m),
1
1420 (m), 1242 (m), 1188 (s) cm–1. H NMR (500 MHz, CDCl3): δH
=
4-Chloro-3,3-dimethyl-5-(pentafluoro-λ6-sulfanyl)pentanoic
Acid (2b): Following the general procedure on 1.17 mmol scale of
1b, the desired product was isolated as a white solid (144 mg,
0.50 mmol, 42 %) after purification by flash column chromatogra-
phy (2 % MeOH/CH2Cl2). Mp: 90.0–92.1 °C. FT-IR: ν = 3034 (w), 2974
9.16 (br. s, 1H, CO2H), 5.85 (ddt, J = 17.1, 10.2, 7.0 Hz, 1H, CH=CH2),
5.37–5.26 (m, 2H, CH2=CH), 3.68 (dd, J = 7.5, 5.9 Hz, 1H, CHCN),
2.80–2.66 (m, 2H, CH2CHCN) ppm. 13C NMR (125 MHz, CDCl3): δC
=
170.9 (C, CO2H), 130.8 (CH, CH=CH2), 120.7 (CH2, CH2=CH), 115.3 (C,
CN), 37.5 (CH, CHCN), 33.7 (CH2, CH2CHCN) ppm. HRMS (ESI-TOF,
m/z): Calcd for C6H7NO2 [M – H]– 124.0404, found 124.0433.
(w), 2934 (w), 1705 (s), 1470 (m), 1429 (w), 1236 (w), 932 (w) cm–1
.
1H NMR (500 MHz, CDCl3): δH = 11.14 (br s, 1H, CO2H), 4.65 (app. d,
J = 9.4 Hz, 1H, CHCl), 4.14–4.03 (m, 1H, CHHSF5), 3.96–3.81 (m, 1H,
CHHSF5), 2.72 (d, J = 15.6 Hz, 1H, CHHCO2H), 2.36 (d, J = 15.6 Hz,
1H, CHHCO2H), 1.25 (s, 3H, CH3), 1.13 (s, 3H, CH3) ppm. 13C NMR
(125 MHz, CDCl3): δC = 176.9 (C, CO2H), 75.1 (p, J = 14.3 Hz, CH2,
CH2SF5), 62.9 (p, J = 3.3 Hz, CH, CHCl), 43.3 (CH2, CH2CO2H), 39.1 (C,
C(CH3)2), 24.4 (CH3, CH3), 23.1 (CH3, CH3) ppm. 19F NMR (470 MHz,
CDCl3): δF = 84.3–82.0 (m, 1F, SFF4), 66.1 (dt, J = 146.9, 7.5 Hz, 4F,
SFF4) ppm. HRMS (ESI-TOF, m/z): Calcd for C7H16ClF5NO2S [M +
NH4]+ 308.0505, found 308.0497.
2-(Ethoxycarbonyl)pent-4-enoic Acid (1l): Prepared according to
the method of Tellitu et al.[31] To a solution of diethyl allylmalonate
(1.00 g, 4.99 mmol) in EtOH (8 mL) was added KOH (280 mg,
4.99 mmol). After 18 h at r.t., the reaction mixture was concentrated
in vacuo and the residue was dissolved in CH2Cl2 and a sat. solution
of K2CO3. The aqueous phase was separated and acidified by the
addition of a 10 % solution of HCl then extracted with EtOAc (3 ×).
The organic phases were combined, dried with MgSO4, filtered and
concentrated in vacuo to afford the product (743 mg, 4.31 mmol,
86 %) as a colorless oil. FT-IR: ν = 3084 (w), 2984 (w), 2937 (w), 1713
(s), 1597 (m), 1335 (m), 1178 (s) cm–1
δH = 5.79 (ddt, J = 17.0, 10.2, 6.9 Hz, 1H, CH=CH2), 5.20–5.12 (m, Acid (2c): Following the general procedure on 2.34 mmol scale of
1H, CHH=CH), 5.13–5.09 (m, 1H, CHH=CH), 4.24 (q, J = 7.1 Hz, 2H, 1c, the desired product was isolated as a white solid (604 mg,
.
1H NMR (500 MHz, CDCl3): 4-Chloro-2,2-dimethyl-5-(pentafluoro-λ6-sulfanyl)pentanoic
CH3CH2O), 3.49 (t, J = 7.4 Hz, 1H, CHCO2Et), 2.73–2.64 (m, 2H, 2.08 mmol, 89 %). Mp: 77.1–82.0 °C. FT-IR: ν = 2984 (w), 2934 (w),
CH2CHCO2Et), 1.30 (t, J = 7.1 Hz, 3H, CH3CH2O) ppm. 13C NMR 1703 (s), 1479 (w), 1416 (w), 1292 (w), 1279 (w), 1223 (m), 1159 (m)
(125 MHz, CDCl3): δC = 173.7 (C, CO2H), 169.0 (C, CO2Et), 133.5 (CH,
cm–1
.
1H NMR (500 MHz, CDCl3): δH = 11.29 (br s, 1H, CO2H), 4.46
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(app. dtd, J = 9.4, 6.2, 3.1 Hz, 1H, CHCl), 4.09–3.98 (m, 1H, CHHSF5),
0.75H, CHaEt), 2.75–2.66 (m, 0.25H, CHbEt), 2.37 (ddd, J = 13.8, 11.0,
4.00–3.86 (m, 1H, CHHSF5), 2.31 (dd, J = 15.0, 9.8 Hz, 1H, CHHCHCl), 2.5 Hz, 0.81H, CHaHCHCl), 2.16 (app. t, J = 6.9 Hz, 0.39H, CHbHCHCl),
2.13 (dd, J = 15.0, 3.0 Hz, 1H, CHHCHCl), 1.34 (s, 3H, CH3), 1.31 (s,
3H, CH3) ppm. 13C NMR (125 MHz, CDCl3): δC = 182.9 (C, CO2H), 77.5
(p, J = 13.4 Hz, CH2, CH2SF5), 52.3 (p, J = 4.4 Hz, CH, CHCl), 46.8
(CH2, CH2CHCl), 41.3 (C, C(CH3)2), 26.7 (CH3, CH3), 23.5 (CH3, CH3)
ppm. 19F NMR (470 MHz, CDCl3): δF = 83.8–82.2 (m, 1F, SFF4), 66.5
(dt, J = 146.5, 8.2 Hz, 4F, SFF4) ppm. HRMS (ESI-TOF, m/z): Calcd for
C7H11ClF5O2S [M – H]– 289.0094, found 289.0088.
1.84–1.61 (m, 2.98H, CHHaCHCl, CHHbCHCl, CH2aCH3CH2bCH3), 1.03–
0.96 (m, 3H, CH3a, CH3b) ppm. 13C NMR (125 MHz, CDCl3): δC = 180.8
(C, CO2bH), 180.6 (C, CO2aH), 76.9 (app. s, CH2, CH2bSF5), 76.8 (p, J =
6.8 Hz, CH2, CH2aSF5), 54.2 (p, J = 4.4 Hz, CH, CHaCl), 53.5 (p, J =
4.6 Hz, CH, CHbCl), 43.51 (CH, CHaEt), 43.46 (CH, CHbEt), 38.9 (CH2,
CH2aCHCl), 38.1 (CH2, CH2bCHCl), 25.8 (CH2, CH2aCH3), 23.6 (CH2,
CH2bCH3), 11.3 (CH3, CH3a), 10.9 (CH3, CH3b) ppm. 19F NMR
(470 MHz, CDCl3): δF = 83.5–82.0 (m, 1F, SFF4), 67.0–66.2 (m, 4F,
SFF4) ppm. HRMS (ESI-TOF, m/z): Calcd for C7H11ClF5O2S [M – H]–
289.0094, found 289.0085.
4-Chloro-3-methyl-5-(pentafluoro-λ6-sulfanyl)pentanoic Acid
(2d): Following the general procedure on 1.75 mmol scale of 1d,
the desired product was isolated as a colorless oil (436 mg,
1.58 mmol, 90 %) in a 83:17 mixture of diastereoisomers after purifi-
cation by flash column chromatography (2 % MeOH/CH2Cl2). FT-IR:
4-Chloro-5-(pentafluoro-λ6-sulfanyl)-3-phenylpentanoic Acid
(2g): Following the general procedure on 1.14 mmol scale of 1g,
ν = 3034 (w), 2978 (w), 2922 (w), 1709 (s), 1418 (m), 1298 (w), 1194 the desired product was isolated as a colorless oil (374 mg,
(w), 928 (w) cm–1. 1H NMR (500 MHz, CDCl3): δH = 11.20 (br. s, 0.44H,
CO2Ha, CO2Hb), 4.64 (app. ddd, J = 6.9, 5.4, 2.5 Hz, 0.83H, CHaCl),
1.10 mmol, 97 %) in a 80:20 mixture of diastereoisomers after purifi-
cation by flash column chromatography (2 % MeOH/CH2Cl2). FT-IR:
4.42 (app. dt, J = 7.8, 4.1 Hz, 0.17H, CHbCl), 4.06–3.89 (m, 2.06H, ν = 3065 (w), 3036 (w), 2916 (w), 1701 (s), 1418 (m), 1271 (w), 1244
CH2aSF5, CH2bSF5), 2.65 (dd, J = 16.4, 6.8 Hz, 0.85H, CHaHCO2H),
2.60–2.50 (m, 1.18H, CHaCH3, CHbCH3, CHbHCO2H), 2.42 (dd, J = 16.4,
6.7 Hz, 0.87H, CHHaCO2H), 2.37 (app. d, J = 7.4 Hz, 0.17H,
CHHbCO2H), 1.20 (d, J = 6.9 Hz, 0.53H, CH3b), 1.06 (d, J = 6.6 Hz,
2.52H, CH3a) ppm. 13C NMR (125 MHz, CDCl3): δC = 177.7 (C, CO2bH),
(w), 1184 (w) cm–1 1H NMR (500 MHz, CDCl3): δH = 7.40–7.28 (m,
.
4.63H, 5 × ArHa, 3 × ArHb), 7.24–7.19 (m, 0.41H, 2 × ArHb), 4.85 (app.
dt, J = 7.6, 3.9 Hz, 0.82H, CHaCl), 4.55 (app. td, J = 8.3, 3.8 Hz, 0.20H,
CHbCl), 3.93–3.76 (m, 1.28H, CHaHSF5, CHbHSF5, CHHbSF5), 3.69–3.53
(m, 1.71H, CHHaSF5, CHaPh), 3.40 (app. td, J = 9.4, 4.2 Hz, 0.20H,
177.5 (C, CO2aH), 75.7–75.2 (m, 2 × CH2, CH2aSF5+CH2bSF5), 60.1– CHbPh), 3.22 (dd, J = 16.5, 4.2 Hz, 0.21H, CHbHCO2H), 3.11 (dd, J =
59.8 (m, CH, CHbCl), 59.4 (p, J = 4.3 Hz, CHaCl), 38.7 (CH2, CH2aCO2H), 17.2, 7.5 Hz, 0.81H, CHaHCO2H), 2.89 (dd, J = 17.1, 7.0 Hz, 0.81H,
36.0 (CH2, CH2bCO2H), 35.9 (CH, CHbCH3), 35.0 (CH, CHaCH3), 18.0
(CH3, CH3b), 13.3 (CH3, CH3a) ppm. 19F NMR (470 MHz, CDCl3): δF =
83.5–81.9 (m, 1F, SFF4), 66.7–66.1 (m, 4F, SFF4) ppm. HRMS (ESI-TOF,
CHHaCO2H), 2.82 (dd, J = 16.5, 9.7 Hz, 0.22H, CHHbCO2H) ppm. 13C
NMR (125 MHz, CDCl3): δC = 177.3 (C, CO2bH), 177.2 (C, CO2aH),
138.6 (C, CbAr), 136.1 (C, CaAr), 129.5 (CH, CHAr), 129.3 (CH, CHAr),
m/z): Calcd for C6H14ClF5NO3S [M + NH4]+ 294.0348, found 128.9 (CH, CHAr), 128.60 (CH, CHAr), 128.58 (CH, CHAr), 128.0 (CH,
294.0347.
CHAr), 75.9 (p, J = 14.0 Hz, 2 × CH2, CH2aSF5, CH2bSF5), 59.1 (p, J =
3.7 Hz, CH, CHbCl), 58.2 (p, J = 3.9 Hz, CH, CHaCl), 47.9 (CH, CHbPh),
45.9 (CH, CHaPh), 37.9 (CH2, CH2bCO2H), 37.4 (CH2, CH2aCO2H) ppm.
19F NMR (470 MHz, CDCl3): δF = 84.1–81.5 (m, 1F, SFaF4, SFbF4), 66.8
(dt, J = 146.5, 7.9 Hz, 3.22F, SFF4a), 66.3 (dt, J = 147.2, 8.3 Hz, 0.80F,
SFF4b) ppm. HRMS (ESI-TOF, m/z): Calcd for C11H16ClF5NO2S [M +
NH4]+ 358.0477, found 358.0475.
4-Chloro-2-methyl-5-(pentafluoro-λ6-sulfanyl)pentanoic Acid
(2e): Following the general procedure on 1.75 mmol scale of 1e,
the desired product was isolated as a yellow oil (471 mg, 1.70 mmol,
97 %) in a 56:44 mixture of diastereoisomers. FT-IR: ν = 2980 (w),
2941 (w), 1709 (m), 1468 (m), 1416 (m), 1292 (w), 1211 (w), 1190
(w) cm–1. H NMR (500 MHz, CDCl3): δH = 10.0 (br s, 1.14H, CO2Ha,
CO2Hb), 4.53 (app. dtd, J = 11.1, 6.2, 2.7 Hz, 0.55H, CHaCl), 4.41 (app.
1
4-Chloro-2-phenyl-5-(pentafluoro-λ6-sulfanyl)pentanoic Acid
dtd, J = 10.4, 6.1, 3.1 Hz, 0.41H, CHbCl), 4.13–4.00 (m, 1.02H, (2h): Following the general procedure on 1.70 mmol scale of 1h,
CH2bSF5), 4.00–3.82 (m, 1.07H, CH2aSF5), 2.95 (qdd, J = 7.2, 3.3,
3.0 Hz, 0.56H, CHaCH3), 2.86 (dqd, J = 9.4, 7.1, 4.6 Hz, 0.40H,
CHbCH3), 2.38 (ddd, J = 13.6, 10.6, 2.7 Hz, 0.56H, CHaHCHCl), 2.22
the desired product was isolated as a white solid (513 mg,
1.51 mmol, 89 %) in a 70:30 mixture of diastereoisomers after purifi-
cation by AFP (10–100 % EtOAc/hexanes, 3–15–3 CV). Mp: 81.2–
(ddd, J = 15.2, 10.8, 4.6 Hz, 0.42H, CHbHCHCl), 2.06 (ddd, J = 14.4, 84.9 °C. FT-IR: ν = 3069 (w), 3034 (w), 2978 (w), 2959 (w), 1707 (s),
9.4, 3.3 Hz, 0.44H, CHHbCHCl), 1.71 (ddd, J = 14.4, 11.1, 3.2 Hz, 0.57H,
CHHaCHCl), 1.28 (d, J = 7.1 Hz, 1.54H, CH3b), 1.32 (d, J = 7.2 Hz,
1.02H, CH3a) ppm. 13C NMR (125 MHz, CDCl3): δC = 181.2 (C, CO2bH),
1497 (m), 1456 (m), 1427 (m), 1416 (m), 1283 (m) cm–1 1H NMR
.
(500 MHz, CDCl3): δH = 10.69 (br. s, 0.97H, CO2Ha, CO2Hb), 7.45–7.28
(m, 4.58H, 5 × ArHa, 5 × ArHb), 4.53 (app. dtd, J = 10.4, 6.2, 3.0 Hz,
181.0 (C, CO2aH), 76.9 (app. s, CH2, CH2aSF5), 76.7 (app. s, CH2, 0.30H, CHaCl), 4.10–3.95 (m, 1.83H, CHbCl, CHaHSF5, CHbHSF5), 3.95–
CH2bSF5), 54.1 (p, J = 4.4 Hz, CH, CHbCl), 53.2 (p, J = 4.8 Hz, CH, 3.83 (m, 1.56H, CHHaSF5, CHHbSF5), 2.81 (ddd, J = 14.1, 10.8, 3.0 Hz,
CHaCl), 41.0 (CH2, CH2aCHCl), 40.0 (CH2, CH2bCHCl), 36.5 (CH, 0.30H, CHaHCHCl), 2.65 (ddd, J = 14.3, 11.6, 2.0 Hz, 0.70H,
CHaCH3), 36.4 (CH, CHbCH3), 18.0 (CH3, CH3a), 15.3 (CH3, CH3b) ppm.
19F NMR (470 MHz, CDCl3): δF = 83.5–82.0 (m, 1F, SFF4), 67.0–66.3
(m, 4F, SFF4) ppm. HRMS (ESI-TOF, m/z): Calcd for C6H9ClF5O2S [M –
H]– 274.9937, found 274.9930.
CHbHCHCl), 2.32 (ddd, J = 14.8, 11.0, 4.0 Hz, 0.70H, CHHbCHCl), 1.95
(ddd, J = 14.4, 10.7, 3.8 Hz, 0.31H, CHHaCHCl) ppm. 13C NMR
(125 MHz, CDCl3): δC = 178.8 (C, CO2aH), 178.4 (C, CO2bH), 137.3 (C,
CbAr), 135.3 (C, CaAr), 129.23 (CH, CHAr), 129.17 (CH, CHAr), 128.5 (CH,
CHAr), 128.3 (CH, CHAr), 128.2 (CH, CHAr), 127.8 (CH, CHAr), 76.6 (p,
J = 13.7 Hz, CH2, CH2SF5), 76.4 (p, J = 13.4 Hz, CH2, CH2SF5), 54.0 (p,
J = 4.6 Hz, CH, CHaCl), 53.1 (p, J = 4.6 Hz, CH, CHbCl), 48.4 (CH,
CHbPh), 48.2 (CH, CHaPh), 40.9 (CH2, CH2aCHCl ), 39.5 (CH2,
CH2bCHCl) ppm. 19F NMR (470 MHz, CDCl3): δF = 83.4–81.9 (m, 1F,
SFF4), 67.0–66.6 (m, 4F, SFF4) ppm. HRMS (ESI-TOF, m/z): Calcd for
C11H11ClF5O2S [M – H]– 337.0094, found 337.0078.
4-Chloro-2-ethyl-5-(pentafluoro-λ6-sulfanyl)pentanoic Acid (2f):
Following the general procedure on 1.75 mmol scale of 1f, the de-
sired product was isolated as a yellow oil (220 mg, 0.76 mmol, 49 %)
in a 75:25 mixture of diastereoisomers after purification AFP (20–
100 % EtOAc/hexanes, 3–15–3 CV). FT-IR: ν = 2972 (w), 2939 (w),
2883 (w), 1705 (s), 1464 (w), 1429 (w), 1279 (w), 1234 (w), 1184 (w),
1034 (w) cm–1 1H NMR (500 MHz, CDCl3): δH = 11.39 (br s, 1.05H,
.
CO2Ha, CO2Hb), 4.46 (app. dtd, J = 11.2, 6.3, 2.5 Hz, 0.75H, CHaCl),
4.41 (app. p, J = 6.5 Hz, 0.23H, CHbCl), 4.12–3.97 (m, 1.04H, CHHaSF5,
CHHbSF5), 3.99–3.82 (m, 1.05H, CHHaSF5, CHHbSF5), 2.85–2.76 (m,
2-(Benzyloxy)-4-chloro-5-(pentafluoro-λ6-sulfanyl)pentanoic
Acid (2i): Following the general procedure on 1.19 mmol scale of
1i, the desired product was isolated as a yellow solid (412 mg,
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1.12 mmol, 94 %) in a 75:25 mixture of diastereoisomers after purifi-
cation by AFP (10–100 % EtOAc/hexanes, 3–15–3 CV). Mp: 65.2–
68.8 °C. FT-IR: ν = 3069 (w), 2970 (w), 2932 (w), 2880 (w), 1722 (m),
4-Chloro-2-(ethoxycarbonyl)-5-(pentafluoro-λ6-sulfanyl)pentan-
oic Acid (2l): Following the general procedure on 2.32 mmol scale
of 1l, the desired product was isolated as a yellow oil (759 mg,
2.27 mmol, 98 %) and a mixture of diastereoisomers for which the
1456 (m), 1427 (w), 1209 (w), 1122 (m), 1013 (w) cm–1 1H NMR
.
(500 MHz, CDCl3): δH = 7.43–7.33 (m, 4.78H, 5 × ArHa, 5 × ArHb), 4.85 diastereoisomeric ratio could not be unambiguously determined by
(d, J = 11.2 Hz, 0.75H, OCHaHAr), 4.81 (d, J = 11.3 Hz, 0.25H,
OCHbHAr), 4.71–4.63 (m, 0.29H, CHbCl), 4.59 (app. dtd, J = 11.0, 6.3,
2.8 Hz, 0.81H, CHaCl), 4.54 (d, J = 11.1 Hz, 0.97H, OCHHaAr,
OCHHbAr), 4.36 (dd, J = 11.0, 2.6 Hz, 0.78H, CHaOAr), 4.31 (dd, J =
6.5, 5.7 Hz, 0.26H, CHbOAr), 4.10–3.98 (m, 1.21H, CHaHSF5, CHbHSF5),
NMR. FT-IR: ν = 2993 (w), 2939 (w), 1736 (m), 1718 (m), 1375 (w),
1
1304 (s), 1273 (m), 1167 (m) cm–1. H NMR (500 MHz, CDCl3): δH
=
4.56–4.42 (m, 1H, CHa, bCl), 4.34–4.21 (m, 2H, OCH2a+bCH3), 4.13–
4.01 (m, 1H, CHHa+bSF5), 4.00–3.88 (m, 1H, CHHa+bSF5), 3.84 (dd, J =
10.5, 3.7 Hz, 1H, CHa+bCO2Et), 2.92–2.60 (m, 1H, CHa+bHCHCl), 2.26–
3.98–3.85 (m, 1.06H, CHHaSF5, CHHbSF5), 2.47 (app. dt, J = 14.9, 2.19 (m, 1H, CHHa+bCHCl), 1.32 (app. td, J = 7.2, 3.6 Hz, 1H,
5.4 Hz, 0.33H, CHbCHCl), 2.41–2.31 (m, 0.96H, CHaHCHCl, CHHbCHCl),
OCH2CH3a+b). 13C NMR (125 MHz, CDCl3): δC = 173.2 (C, C=O), 172.9
2.16 (ddd, J = 17.1, 10.9, 2.5 Hz, 0.67H, CHHaCHCl). 13C NMR (C, C=O), 168.2 (C, C=O), 168.0 (C, C=O), 76.5 (p, J = 14.2 Hz, 2 × CH2,
(125 MHz, CDCl3): δC = 176.7 (C, CO2aH), 176.1 (C, CO2bH), 136.4 (C,
CAr), 136.1 (C, CAr), 128.8 (CH, CHAr), 128.7 (CH, CHAr), 128.55 (CH,
CHAr), 128.46 (CH, CHAr), 128.4 (CH, CHAr), 128.3 (CH, CHAr), 76.4 (p,
J = 13.7 Hz, 2 × CH2, CH2aSF5, CH2bSF5), 74.2 (CH, CHaOBn), 74.0 (CH,
CH2aSF5, CH2bSF5), 62.60 (CH2, OCH2CH3), 62.64 (CH2, OCH2CH3),
53.7–53.3 (m, 2 × CH, CHaCl, CHbCl), 48.89 (CH, CHCO2Et), 48.87 (CH,
CHCO2Et), 36.3 (2 × CH2, CH2aCHCl, CH2bCHCl), 14.10 (CH3,
OCH2CH3), 14.08 (CH3, OCH2CH3) ppm. 19F NMR (470 MHz, CDCl3):
CHbOBn), 73.6 (CH2, OCH2aAr), 73.1 (CH, OCH2bAr), 52.1 (p, J = δF = 83.3–80.8 (m, 1F, SFF4), 67.3–65.9 (m, 4F, SFF4) ppm. HRMS (ESI-
4.9 Hz, 2 × CH, CHaCl, CHbCl), 40.3 (CH2, CH2aCHCl), 39.9 (CH2,
CH2bCHCl) ppm. 19F NMR (470 MHz, CDCl3): δF = 83.5–81.9 (m, 1F,
SFF4), 67.1–66.1 (m, 4F, SFF4) ppm. HRMS (ESI-TOF, m/z): Calcd for
TOF, m/z): Calcd for C8H11ClF5O4S [M – H]– 332.9992, found
332.9997.
3-Chloro-4-(pentafluoro-λ6-sulfanyl)butanoic Acid (4): Following
the general procedure on 2.32 mmol scale of but-3-enoic acid 3,
the desired product was isolated as an orange oil (503 mg,
2.03 mmol, 87 %) after purification by AFP (20–100 % EtOAc/hex-
anes, 3–15–3 CV). FT-IR: ν = 3040 (w), 2978 (w), 2932 (w), 1720 (s),
C
12H13ClF5O3S [M – H]– 367.0200, found 367.0186.
4-Chloro-2-fluoro-5-(pentafluoro-λ6-sulfanyl)pentanoic Acid
(2j): Following the general procedure on 1.97 mmol scale of 1j, the
desired product was isolated as a white solid (384 mg, 1.37 mmol,
70 %) in a 70:30 mixture of diastereoisomers after purification by
AFP (30–100 % EtOAc/hexanes, 3–15–3 CV). Mp: 47.8–50.1 °C. FT-IR:
ν = 3042 (w), 2932 (w), 1736 (s), 1427 (m), 1259 (m), 1240 (m), 1092
(m), 1014 (m) cm–1. 1H NMR (500 MHz, CDCl3): δH = 8.58 (br s, 1.24H,
CO2Ha, CO2Hb), 5.41–5.20 (m, 1H, CHaF, CHbF), 4.72 (app. qd, J = 6.5,
4.4 Hz, 0.30H, CHbCl), 4.61 (dddd, J = 11.3, 7.3, 5.6, 2.4 Hz, 0.70H,
CHaCl), 4.19–3.87 (m, 2.04H, CH2aSF5, CH2bSF5), 2.74–2.44 (m, 1.44H,
CHaHCHCl, CHbHCHCl, CHHbCHCl), 2.30 (dddd, J = 37.3, 15.0, 11.3,
1420 (m), 1281 (w), 1242 (w), 1173 (w) cm–1 1H NMR (500 MHz,
.
CDCl3): δH = 10.52 (br s, 1H, CO2H), 4.76 (dddd, J = 8.0, 6.8, 6.1,
4.5 Hz, 1H, CHCl), 4.15–4.05 (m, 2H, CH2SF5), 3.11 (dd, J = 17.1,
4.5 Hz, 1H, CHHCHCl), 2.94 (dd, J = 17.1, 8.0 Hz, 1H, CHHCHCl) ppm.
13C NMR (125 MHz, CDCl3): δC = 174.4 (C, CO2H), 75.1 (p, J = 14.4 Hz,
CH2, CH2SF5), 49.9 (p, J = 5.2 Hz, CH, CHCl), 41.8 (CH2, CH2CHCl)
ppm. 19F NMR (470 MHz, CDCl3): δF = 83.1–81.6 (m, 1F, SFF4), 66.6
(dt, J = 146.5, 8.2 Hz, 4F, SFF4) ppm. HRMS (ESI-TOF, m/z): Calcd for
C4H5ClF5O2S [M – H]– 246.9624, found 246.9617.
2.1 Hz, 0.82H, CHHaCHCl) ppm. 13C NMR (125 MHz, CDCl3): δC
=
173.8 (C, CO2H), 173.6 (C, CO2H), 85.1 (d, J = 187.4 Hz, 2 × CH, CHaF,
CHbF), 75.9 (p, J = 20.4 Hz, 2 × CH2, CH2aSF5, CH2bSF5), 51.1–50.8 (m,
2 × CH, CHaCl, CHbCl), 39.9 (CH2, CH2aCHCl), 39.8 (CH2, CH2bCHCl)
ppm. 19F NMR (470 MHz, CDCl3): δF = 84.1–80.3 (m, 1.09F, SFaF4,
SFbF4), 66.9 (app. dt, J = 146.2, 8.1 Hz, 2.97F, SFF4a), 66.4 (app. dt,
J = 146.5, 8.0 Hz, 1.35F, SFF4b), –191.3 (app. dt, J = 45.0, 21.5 Hz,
0.30F, CHFb), –195.8 (ddd, J = 49.1, 37.1, 12.0 Hz, 0.70F, CHFa) ppm.
HRMS (ESI-TOF, m/z): Calcd for C5H6ClF6O2S [M – H]– 278.9687,
found 274.9686.
5-Chloro-6-(pentafluoro-λ6-sulfanyl)hexanoic Acid (6): Following
the general procedure on 0.88 mmol scale of hex-5-enoic acid 4,
the desired product was isolated as a white solid (235 mg,
0.85 mmol, 97 %). Mp: 37.1–39.8 °C. FT-IR: ν = 2964 (w), 2924 (w),
1711 (s), 1545 (w), 1416 (m), 1267 (m), 1236 (m), 1200 (m) cm–1
.
1H NMR (500 MHz, CDCl3): δH = 11.15 (br s, 1H, CO2H), 4.38 (app.
dtd, J = 9.7, 6.3, 3.4 Hz, 1H, CHCl), 4.03 (app. dtd, J = 14.5, 8.3,
6.1 Hz, 1H, CHHSF5), 3.92 (app. dtd, J = 14.2, 7.9, 6.3 Hz, 1H, CHHSF5),
2.49–2.40 (m, 2H, CH2CO2H), 2.09–1.91 (m, 2H, CHHCHCl,
4-Chloro-2-cyano-5-(pentafluoro-λ6-sulfanyl)pentanoic Acid
(2k): Following the general procedure on 2.51 mmol scale of 1k,
the desired product was isolated as an off-white solid (425 mg,
1.58 mmol, 59 %) in a 63:37 mixture of diastereoisomers after purifi-
cation by AFP (10–100 % EtOAc/hexanes, 3–15–3 CV). Mp: 88.2–
89.9 °C. FT-IR: ν = 3159 (w), 3076 (w), 2359 (w), 1738 (m), 1416 (w),
CHHCH2CO2H), 1.87–1.75 (m, 2H, CHHCHCl, CHHCH2CO2H) ppm. 13
C
NMR (125 MHz, CDCl3): δC = 178.6 (C, CO2H), 76.5 (p, J = 13.7 Hz,
CH2, CH2SF5), 55.2 (p, J = 4.4 Hz, CH, CHCl), 36.5 (CH2, CH2CH2CO2H),
32.8 (CH2, CH2CO2H), 21.1 (CH2, CH2CHCl) ppm. 19F NMR (470 MHz,
CDCl3): δF = 84.7–79.8 (m, 1F, SFF4), 66.3 (dt, J = 146.5, 8.1 Hz, 4F,
SFF4) ppm. HRMS (ESI-TOF, m/z): Calcd for C6H9ClF5O2S [M – H]–
274.9937, found 274.9933.
1198 (w) cm–1
.
1H NMR (500 MHz, CDCl3): δH = 6.17 (br s, 1.22H,
CO2Ha, CO2Hb), 4.65 (dddd, J = 10.5, 7.9, 5.4, 2.8 Hz, 0.32H, CHbCl),
4.59 (dddd, J = 11.7, 7.5, 5.2, 2.3 Hz, 0.57H, CHaCl), 4.18–4.07 (m, 4-Chloro-5-(pentafluoro-λ6-sulfanyl)pentanamide (11): Follow-
0.88H, CHHaSF5, CHHbSF5), 4.05 (dd, J = 11.7, 4.1 Hz, 0.58H, CHaCN),
4.00 (dd, J = 9.7, 3.7 Hz, 0.40H, CHbCN), 4.00–3.89 (m, 0.86H,
CHHaSF5, CHHbSF5), 2.81 (ddd, J = 14.7, 9.7, 2.8 Hz, 0.37H,
CHbHCHCl), 2.64 (ddd, J = 14.3, 11.8, 2.4 Hz, 0.63H, CHaHCHCl), 2.40–
2.27 (m, 1H, CHaHCHCl, CHbHCHCl) ppm. 13C NMR (125 MHz, CDCl3):
ing the general procedure on 3.03 mmol scale of pent-4-enamide,
the desired product was isolated as an off-white solid (480 mg,
1.84 mmol, 61 %) after purification by AFP (100 % EtOAc). Mp: 47.8–
49.2 °C. FT-IR: ν = 3329 (w), 3225 (w), 2359 (w), 2345 (w), 1664 (m),
1620 (m), 1421 (w) cm–1. 1H NMR (500 MHz, CDCl3): δH = 5.50 (br s,
δC = 168.79 (C, CO2bH), 168.75 (C, CO2aH), 114.8 (C, CNb), 114.1 (C, 2H, NH2), 4.46 (dddd, J = 9.9, 6.6, 5.6, 3.0 Hz, 1H, CHCl), 4.07–3.86
CNa), 75.8–75.2 (m, 2 × CH2, CH2aSF5, CH2bSF5), 52.9–51.4 (m, 2 × CH, (m, 2H, CH2SF5), 2.58–2.44 (m, 2H, CH2C(O)NH2), 2.39 (app. dtd, J =
CHaCl, CHbCl), 36.9 (CH2, CH2bCHCl), 36.7 (CH2, CH2aCHCl), 35.3 (CH, 14.5, 7.7, 3.0 Hz, 1H, CHHCHCl), 1.96 (dddd, J = 14.4, 10.2, 7.4 Hz,
CHaCN), 33.9 (CH, CHbCN) ppm. 19F NMR (470 MHz, CDCl3): δF
=
1H, CHHCHCl) ppm. 13C NMR (125 MHz, CDCl3): δC = 173.2 (C, C=
O), 76.8 (p, J = 13.9 Hz, CH2, CH2SF5), 55.4 (p, J = 4.5 Hz, CH, CHCl),
32.8 (p, J = 1.3 Hz, CH2, CH2CHCl), 31.8 (CH2, CH2CO2H) ppm.
82.7–81.1 (m, 1F, SFF4), 67.5–66.8 (m, 4F, SFF4) ppm. HRMS (ESI-TOF,
m/z): Calcd for C6H6ClF5NO2S [M – H]– 285.9733, found 285.9734.
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19F NMR (470 MHz, CDCl3): δF = 83.7–81.8 (m, 1F, SFF4), 66.5 (dt,
J = 146.8, 8.0 Hz, 4F, SFF4) ppm. HRMS (ESI-TOF, m/z): Calcd for
C5H10ClF5NOS [M + H]+ 262.0086, found 262.0086.
(dd, J = 12.9, 6.0 Hz, 1H, CHHCH), 1.85 (dd, J = 12.9, 10.1 Hz, 1H,
CHHCH), 1.321 (s, 3H, CH3) 1.318 (s, 3H, CH3) ppm. 13C NMR
(125 MHz, CDCl3): δC = 180.2 (C, C=O), 73.7 (p, J = 14.2 Hz, CH2,
CH2SF5), 71.3 (p, J = 4.4 Hz, CH, CHCH2SF5), 42.7 (CH2, CH2CH), 40.0
(C, C(CH3)2), 24.8 (CH3, CH3), 24.2 (CH3, CH3) ppm. 19F NMR
(470 MHz, CDCl3): δF = 83.2–81.5 (m, 1F, SFF4), 67.3 (dt, J = 146.8,
8.3 Hz, 4F, SFF4) ppm. HRMS (ESI-TOF, m/z): Calcd for C7H12F5O2S [M
+ H]+ 255.0473, found 255.0487.
Silver-promoted Cyclization Reaction
General Procedure: To a solution of the 4-chloro-5-(pentafluoro-
sulfanyl)pentanoic acid derivative (1 equiv.) in toluene (0.05 M) were
added Et3N (1.1 equiv.) and AgOTf (1.1 equiv.) After 3 h at reflux,
the reaction mixture was cooled down to r.t., concentrated in vacuo
and purified on silica gel.
4-Methyl-5-((pentafluoro-λ6-sulfanyl)methyl)dihydrofuran-
2(3H)-one (7d): Following the general procedure on 50 mg scale
of 2d, the desired product was isolated as a colorless oil (32.8 mg,
0.14 mmol, 75 %) in a 85:15 mixture of diastereoisomers after purifi-
cation by flash column chromatography (20 % EtOAc/hexanes). FT-
IR: ν = 2970 (w), 2924 (w), 1782 (m), 1464 (w), 1209 (m), 1155 (m),
5-((Pentafluoro-λ6-sulfanyl)methyl)dihydrofuran-2(3H)-one
(7a): Following the general procedure on 50 mg scale of 2a, the
desired product was isolated as a white solid (36.6 mg, 0.162 mmol,
85 %) after purification by flash column chromatography (30 %
EtOAc/hexanes). Using the general procedure on a 50 mg scale of
amide 11 also provided 2a (26.4 mg, 0.117 mmol, 61 %). Mp: 57.7–
59.8 °C. FT-IR: ν = 2968 (w), 2922 (w), 1778 (m), 1421 (w), 1178 (m),
1149 (m), 1047 (m) cm–1. 1H NMR (500 MHz, CDCl3): δH = 5.05–4.96
(m, 1H, CHCH2SF5), 4.06–3.91 (m, 1H, CHHSF5), 3.87–3.72 (m, 1H,
CHHSF5), 2.65–2.59 (m, 2H, CH2C(O)), 2.59–2.50 (m, 1H, CHHCH),
1026 (m), 802 (s) cm–1 1H NMR (500 MHz, CDCl3): δH = 4.98 (app.
.
dt, J = 7.8, 4.7 Hz, 0.15H, CHbCH2SF5), 4.54 (app. td, J = 7.7, 3.7 Hz,
0.85H, CHaCH2SF5), 3.94–3.74 (m, 2.09H, CH2aSF5, CH2bSF5), 2.90–
2.63 (m, 1.24H, CHbCH3, CHaHC(O), CHbHC(O)), 2.39–2.12 (m, 1.94H,
CHaCH3, CHHaC(O), CHHbC(O)), 1.23 (d, J = 6.3 Hz, 2.58H, CH3a), 1.06
(d, J = 7.0 Hz, 0.49H, CH3b) ppm. 13C NMR (125 MHz, CDCl3): δC
=
2.15–1.90 (m, 1H, CHHCH) ppm. 13C NMR (125 MHz, CDCl3): δC
=
174.9 (C, Cb=O), 174.7 (C, Ca=O), 81.2 (p, J = 3.6 Hz, CH, CHaCH2SF5),
77.1 (p, J = 4.4 Hz, CH, CHbCH2SF5), 72.6 (p, J = 14.8 Hz, CH2,
CH2aSF5), 70.3 (p, J = 15.8 Hz, CH2, CH2bSF5), 37.5 (CH2, CH2bC(O)),
36.0 (CH2, CH2aC(O)), 35.5 (CH, CHaCH3), 33.5 (CH, CHbCH3), 17.0
(CH3, CH3a), 14.0 (CH3, CH3b) ppm. 19F NMR (470 MHz, CDCl3): δF =
83.3–80.8 (m, 1F, SFaF4, SFbF4), 67.4 (dt, J = 147.3, 8.1 Hz, 0.59F,
SFF4b), 66.6 (dt, J = 146.7, 8.1 Hz, 3.44F, SFF4a) ppm. HRMS (ESI-TOF,
m/z): Calcd for C6H10F5O2S [M + H]+ 241.0316, found 241.0319.
175.2 (C, C=O), 74.6 (p, J = 4.4 Hz, CH, CHCH2SF5), 73.3 (p, J =
14.3 Hz, CH2, CH2SF5), 28.0 (CH2, CH2C(O)), 37.5 (CH2, CH2CH) ppm.
19F NMR (470 MHz, CDCl3): δF = 83.2–81.6 (m, 1F, SFF4), 67.5 (dt, J =
146.6, 8.2 Hz, 4F, SFF4) ppm. HRMS (ESI-TOF, m/z): Calcd for
C5H8F5O2S [M + H]+ 227.0160, found 227.0175.
4,4-Dimethyl-5-((pentafluoro-λ6-sulfanyl)methyl)dihydrofuran-
2(3H)-one (7b) and 5-Chloro-4,4-dimethyltetrahydro-2H-pyran-
2-one (8): Following the general procedure on 50 mg scale of 2b,
23.4 mg of a colorless oil was isolated after purification by flash
column chromatography (20 % EtOAc/hexanes). Upon NMR analy-
sis, it was determined that the inseparable mixture was composed
of the desired 5-(pentafluorosulfanyl)methyl lactone 7b and 5-
chloro-4,4-dimethyltetrahydro-2H-pyran-2-one (8) in a 85:15 ratio.
With this information, it was possible to estimate the yield of 7b to
54 % (0.092 mmol) and of 8 to 10 % (0.017 mmol). FT-IR: ν = 2972
(w), 2924 (w), 1786 (s), 1468 (w), 1229 (m), 1149 (m), 1040 (m), 831
3-Methyl-5-((pentafluoro-λ6-sulfanyl)methyl)dihydrofuran-
2(3H)-one (7e): Following the general procedure on 100 mg scale
of 2e, the desired product was isolated as a white solid (75.7 mg,
0.315 mmol, 87 %) in a 58:42 mixture of diastereoisomers after puri-
fication by AFP (30–100 % EtOAc/hexanes, 1–15–2 CV). Mp: 66.7–
69.6 °C. FT-IR: ν = 2978 (w), 2943 (w), 2883 (w), 1774 (s), 1414 (w),
1352 (w), 1292 (w), 1163 (m), 1190 (m), 1059 (m), 1032 (m) cm–1
.
1H NMR (500 MHz, CDCl3): δH = 5.08–4.99 (m, 0.42H, CHbCH2SF5),
4.91–4.84 (m, 0.58H, CHaCH2SF5), 4.05–3.88 (m, 1.10H, CHaHSF5,
CHbHSF5), 3.84–3.72 (m, 1.05, CHHaSF5, CHHbSF5), 2.81–2.66 (m,
1.64H, CHaHCH, CHaCH3, CHbCH3), 2.35–2.26 (m, 0.45H, CHbHCH),
2.26–2.17 (m, 0.47H, CHHbCH), 1.64 (app. q, J = 11.5 Hz, 0.59H,
CHHaCH), 1.34 (d, J = 7.4 Hz, 1.26H, CH3b) 1.32 (d, J = 7.4 Hz, 1.66H,
CH3a) ppm. 13C NMR (125 MHz, CDCl3): δC = 177.6 (2 × C, Ca=O,
Cb=O), 73.7–72.7 (m, 2 × CH2, CH2aSF5, CH2bSF5), 72.6–72.2 (m,
2 × CH, CHaCH2SF5, CHbCH2SF5), 36.6 (CH2, CH2aCH), 35.2 (CH,
CHaCH3), 34.8 (CH2, CH2bCH), 33.4 (CH, CHbCH3), 15.8 (CH3, CH3b),
14.8 (CH3, CH3a) ppm. 19F NMR (470 MHz, CDCl3): δF = 83.3–81.4 (m,
1F, SFF4), 68.0–66.7 (m, 4F, SFF4) ppm. HRMS (ESI-TOF, m/z): Calcd
for C6H10F5O2S [M + H]+ 241.0316, found 241.0333.
(s) cm–1 1H NMR (500 MHz, CDCl3): δH = 4.62 (dd, J = 9.1, 2.0 Hz,
.
0.85H, CH(7b)CH2SF5), 4.59 (dd, J = 12.3, 4.4 Hz, 0.15H, CH(8)HCHCl),
4.37 (dd, J = 12.3, 7.2 Hz, 0.15H, CHH(8)CHCl), 4.03 (dd, J = 7.2,
4.6 Hz, 0.14H, CH(8)Cl), 3.86–3.67 (m, 1.77H, CH2(7b)SF5), 2.70 (d, J =
17.7 Hz, 0.15H, CH(8)HC(O)), 2.51 (app. dq, J = 17.7, 0.7 Hz, 0.86H,
CH(7b)HC(O)), 2.38 (d, J = 17.2 Hz, 0.15H, CHbHC(O)), 2.36 (d, J =
16.7 Hz, 0.85H, CHH(7b)C(O)), 1.25 (s, 2.76H, CH3(7b)), 1.17 (s, 0.47H,
CH3(8)), 1.14 (s, 0.46H, CH3(8)), 1.02 (s, 2.62H, CH3(7b)) ppm. 13C NMR
(125 MHz, CDCl3): δC = 174.2 (C, C(7b)=O), 168.6 (C, C(8)=O), 82.0 (p,
J = 3.3 Hz, CH, CH(7b)CH2SF5), 70.4 (CH2, CH2(8)CHCl), 70.1 (p, J =
15.7 Hz, CH2, CH2SF5), 61.1 (CH, CH(8)Cl), 44.2 (CH2, CH2(7b)C(O)), 42.1
(CH2, CH2(8)C(O)), 40.3 (C, C(7b)(CH3)2), 34.9 (C, C(8)(CH3)2), 27.2 (CH3,
CH3(8)), 24.2 (CH3, CH3(7b)), 23.0 (CH3, CH3(8)), 21.0 (CH3, CH3(7b)) ppm.
19F NMR (470 MHz, CDCl3): δF = 88.1–72.3 (m, 1F, SFF4), 66.6 (dt, J =
146.7, 7.7 Hz, 4F, SFF4) ppm. HRMS (ESI-TOF, m/z): Calcd for
C7H12F5O2S [M + H]+ 255.0473, found 255.0471; Calcd for C7H12ClO2
[M + H]+ 163.0520, found 163.0525.
3-Ethyl-5-((pentafluoro-λ6-sulfanyl)methyl)dihydrofuran-2(3H)-
one (7f): Following the general procedure on 100 mg scale of 2f,
the desired product was isolated as a white solid (83.1 mg,
0.327 mmol, 96 %) in a 77:23 mixture of diastereoisomers after puri-
fication by AFP (30–100 % EtOAc/hexanes, 1–15–2 CV). Mp: 63.1–
64.3 °C. FT-IR: ν = 3018 (w), 2980 (w), 2947 (w), 2887 (w), 1749 (s),
1456 (w), 1468 (w), 1391 (w), 1362 (w), 1188 (m), 1171 (m), 1043
3,3-Dimethyl-5-((pentafluoro-λ6-sulfanyl)methyl)dihydrofuran-
2(3H)-one (7c): Following the general procedure on 100 mg scale
of 2c, the desired product was isolated as a white solid (75.8 mg,
0.298 mmol, 88 %) after purification by AFP (30–100 % EtOAc/hex-
(m) cm–1 1H NMR (500 MHz, CDCl3): δH = 5.06–4.97 (m, 0.23H,
.
CHbCH2SF5), 4.88 (app. ddt, J = 10.5, 7.0, 5.2, 0.77H, CHaCH2SF5),
4.06–3.89 (m, 1.08H, CHaHSF5, CHbHSF5), 3.84–3.70 (m, 1.07H,
anes, 1–15–2 CV). Mp: 99.1–100.3 °C. FT-IR: ν = 2980 (w), 2970 (w), CHHaSF5, CHHbSF5), 2.69–2.58 (m, 1.80H, CHaHCH, CHaEt, CHbEt),
2939 (w), 1767 (s), 1456 (w), 1356 (w), 1207 (w), 1155 (m), 1124 (m), 2.31–2.20 (m, 0.51H, CHbHCH, CHHbCH), 2.02–1.84 (m, 1.11H,
1045 (m) cm–1 1H NMR (500 MHz, CDCl3): δH = 4.99–4.90 (m, 1H, CHaHCH3, CHbHCH3), 1.71–1.46 (m, 2.10H, CHHaCH, CHHaCH3,
CHCH2SF5), 4.04–3.92 (m, CHHSF5), 3.85–3.70 (m, 1H, CHHSF5), 2.35 CHHbCH3), 1.05 (t, J = 7.5 Hz, 0.64H, CH2CH3b) 1.02 (d, J = 7.5 Hz,
.
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2.30H, CH2CH3a) ppm. 13C NMR (125 MHz, CDCl3): δC = 176.9 (2 × C,
Ca=O, Cb=O), 73.7–73.2 (m, 2 × CH2, CH2aSF5, CH2bSF5), 72.8–72.4
(m, 2 × CH, CHaCH2SF5, CHbCH2SF5), 41.6 (CH, CHaEt), 40.1 (CH,
1200 (m), 1176 (m), 1130 (w), 1090 (w) cm–1
CDCl3): δH = 7.42–7.30 (m, 4.58H, 5 × ArHa, 5 × ArHb), 5.20 (dddd,
J = 8.4, 7.1, 6.0, 5.2 Hz, 0.75H, CHaCH2SF5), 4.96 (d, J = 11.8 Hz,
.
1H NMR (500 MHz,
CHbEt), 34.1 (CH2, CH2aCH), 32.5 (CH2, CH2bCH), 23.9 (CH2, CH2bCH3), 0.28H, CHbHAr), 4.95–4.87 (m, 0.30H, CHbCH2SF5), 4.87 (d, J =
23.1 (CH2, CH2aCH3), 11.6 (CH3, CH2CH3b), 11.5 (CH3, CH2CH3a) ppm.
19F NMR (470 MHz, CDCl3): δF = 83.4–81.3 (m, 1F, SFF4), 68.0–67.0
(m, 4F, SFF4) ppm. HRMS (ESI-TOF, m/z): Calcd for C7H12F5O2S [M +
H]+ 255.0473, found 255.0488.
11.7 Hz, 0.80H, CHaHAr), 4.74 (d, J = 11.8 Hz, 0.27H, CHHbAr), 4.67
(d, J = 11.7 Hz, 0.73H, CHHaAr), 4.24 (app. t, J = 8.0 Hz, 0.29H,
CHbOBn), 4.13 (dd, J = 6.8, 2.6 Hz, 0.71H, CHaOBn), 4.05–3.97 (m,
0.33H, CHbHSF5), 3.96–3.89 (m, 0.81H, CHaHSF5), 3.87–3.79 (m,
0.32H, CHHbSF5), 3.79–3.69 (m, 0.85H, CHHaSF5), 2.71 (ddd, J = 13.8,
8.0, 6.6 Hz, 0.34H, CHbHCH), 2.53 (ddd, J = 14.0, 6.1, 2.6 Hz, 0.79H,
CHaHCH), 2.11 (ddd, J = 14.5, 8.3, 6.7 Hz, 0.83H, CHHaCH), 2.08–1.98
(m, 0.41H, CHHbCH) ppm. 13C NMR (125 MHz, CDCl3): δC = 173.3 (C,
Cb=O), 172.6 (C, Ca=O), 136.6 (C, CbAr), 136.5 (C, CaAr), 128.80 (CH,
CHAr), 128.76 (CH, CHAr), 128.51 (CH, CHAr), 128.49 (CH, CHAr), 128.44
(CH, CHAr), 128.36 (CH, CHAr), 73.8 (p, J = 4.6 Hz, CH, CHaCH2SF5),
73.5–72.9 (m, 2 × CH2, CH2aSF5, CH2bSF5), 72.60 (CH, CHaOBn), 72.59
(CH2, OCH2bAr), 72.3 (CH, CHbOBn), 72.2 (CH2, OCH2aAr), 71.8 (p, J =
4.7 Hz, CH, CHbCH2SF5), 35.8 (CH2, CH2aCH), 35.0 (CH2, CH2bCH)
ppm. 19F NMR (470 MHz, CDCl3): δF = 83.0–81.2 (m, 1F, SFF4), 68.0–
67.0 (m, 4F, SFF4) ppm. HRMS (ESI-TOF, m/z): Calcd for C12H14F5O3S
[M + H]+ 333.0578, found 333.0583.
5-((Pentafluoro-λ6-sulfanyl)methyl)-4-phenyldihydrofuran-
2(3H)-one (7g): Following the general procedure on 100 mg scale
of 2g, the desired product was isolated as a white solid (42.0 mg,
0.14 mmol, 47 %) in a 91:9 mixture of diastereoisomers after purifi-
cation by flash column chromatography (15 % EtOAc/hexanes). Mp:
99.8–102.2 °C. FT-IR: ν = 3020 (w), 2968 (w), 1782 (w), 1501 (s), 1410
1
(w), 1192 (w), 1149 (w), 1040 (m), 806 (m) cm–1. H NMR (500 MHz,
CDCl3): δH = 7.46–7.33 (m, 3.06H, 3 × ArHa, 3 × ArHb), 7.28–7.23 (m,
2.08H, 2 × ArHa), 7.15–7.12 (m, 0.18H, 2 × ArHb), 5.27 (app. q, J =
6.0 Hz, 0.09H, CHbCH2SF5), 4.98 (app. td, J = 8.9, 2.4 Hz, 0.91H,
CHaCH2SF5), 3.98–3.83 (m, 0.92H, CHaHSF5), 3.85–3.74 (m, 1.01H,
CHHaSF5, CHbPh), 3.48–3.39 (m, 0.19H, CHbHSF5, CHHbSF5), 3.34–
3.27 (m, 0.92H, CHaPh), 3.12 (dd, J = 17.7, 8.7 Hz, 0.10H, CHbHC(O)),
3.00 (dd, J = 17.7, 8.7 Hz, 0.93H, CHaHC(O)), 2.80–2.74 (m, 1.06H,
CHHaC(O), CHHbC(O)) ppm. 13C NMR (125 MHz, CDCl3): δC = 175.3
(C, Cb=O), 173.8 (C, Ca=O), 136.6 (C, CbAr), 136.4 (C, CaAr), 129.8 (CH,
3-Fluoro-5-((pentafluoro-λ6-sulfanyl)methyl)dihydrofuran-
2(3H)-one (7j): Following the general procedure on 100 mg scale
of 2j, the desired product was isolated as a white solid (45.0 mg,
CHaAr), 129.7 (CH, CHbAr), 129.4 (CH, CHbAr), 128.9 (CH, CHaAr), 127.7 0.18 mmol, 52 %) in a 63:37 mixture of diastereoisomers after purifi-
(CH, CHbAr), 127.3 (CH, CHaAr), 80.8 (p, J = 3.6 Hz, CH, CHaCH2SF5),
77.8 (p, J = 3.9 Hz, CHbCH2SF5), 72.2 (p, J = 15.4 Hz, CH2aSF5,
CH2bSF5), 46.9 (CH, CHaPh), 44.6 (CH, CHbPh), 36.8 (CH2, CH2aC(O)),
36.5 (CH2, CH2bC(O)) ppm. 19F NMR (470 MHz, CDCl3): δF = 83.3–
80.7 (m, 1F, SFaF4, SFbF4), 67.3 (dt, J = 147.0, 7.7 Hz, 0.37F, SFF4b),
66.8 (dt, J = 147.4, 8.1 Hz, 3.62F, SFF4a) ppm. HRMS (ESI-TOF, m/z):
Calcd for C11H12F5O2S [M + H]+ 303.0473, found 303.0470.
cation by flash column chromatography (CH2Cl2). Mp: 76.3–78.2 °C.
FT-IR: ν = 2970 (w), 1782 (s), 1414 (m), 1211 (m), 1190 (m), 1026
(m), 918 (m), 804 (s) cm–1 1H NMR (500 MHz, CDCl3): δH = 5.35–
.
5.20 (m, 1H, CHaCH2SF5, CHbF), 5.14 (ddd, J = 50.9, 6.4, 2.7 Hz, 0.63H,
CHaF), 4.99 (ddd, J = 12.5, 8.4, 5.8 Hz, 0.35H, CHbCH2SF5) 4.10–3.93
(m, 1H, CHaHSF5, CHbHSF5), 3.89–3.74 (m, 1H, CHHaSF5, CHHbSF5),
2.97 (dddd, J = 14.0, 10.6, 8.0, 6.1 Hz, 0.37H, CHbHCHF), 2.79 (dddd,
J = 23.6, 15.0, 6.3, 2.7 Hz, 0.63H, CHaHCHF), 2.41–2.22 (m, 1H,
CHHaCHF, CHHbCHF) ppm. 13C NMR (125 MHz, CDCl3): δC = 169.6
(d, J = 21.2 Hz, C, Cb=O), 169.3 (d, J = 20.3 Hz, C, Ca=O), 85.4 (dd,
J = 185.0, 2.5 Hz, CH, CHaF), 85.0 (d, J = 193.0 Hz, CH, CHbF), 73.6
(p, J = 4.8 Hz, CH, CHaCH2SF5), 73.2 (p, J = 15.5 Hz, CH2, CH2bSF5),
72.8 (p, J = 14.8 Hz, CH2, CH2aSF5), 71.4–71.0 (m, CH, CHbCH2SF5),
35.2 (d, J = 21.6 Hz, CH2, CH2aCHF), 34.7 (d, J = 20.0 Hz, CH2,
CH2bCHF) ppm. 19F NMR (470 MHz, CDCl3): δF = 82.3–80.1 (m, 1.21F,
SFaF4, SFbF4), 68.5–66.9 (m, 4.22F, SFF4a, SFF4b), –191.4 (ddd, J = 50.8,
31.6, 23.1 Hz, 0.63F, CHFa), –192.9 (ddd, J = 51.0, 22.5, 10.6 Hz, 0.37F,
CHFb) ppm. HRMS (ESI-TOF, m/z): Calcd for C5H7F6O2S [M + H]+
245.0065, found 245.0050.
5-((Pentafluoro-λ6-sulfanyl)methyl)-3-phenyldihydrofuran-
2(3H)-one (7h): Following the general procedure on 100 mg scale
of 2h, the desired product was isolated as a white solid (87.1 mg,
0.288 mmol, 96 %) in a 63:37 mixture of diastereoisomers after puri-
fication by AFP (30–100 % EtOAc/hexanes, 1–15–2 CV). Mp: 93.3–
95.1 °C. FT-IR: ν = 3067 (w), 2970 (w), 1776 (s), 1605 (w), 1501 (w),
1456 (w), 1414 (w), 1346 (w), 1273 (w), 1173 (m), 1151 (m), 1047 (m)
cm–1. 1H NMR (500 MHz, CDCl3): δH = 7.42–7.37 (m, 1.77H, 2 × ArHa,
2 × ArHb), 7.36–7.31 (m, 0.96H, ArHa, ArHb), 7.29–7.26 (m, 1.74H,
2 × ArHa, 2 × ArHb), 5.14 (app. qd, J = 6.8, 5.8 Hz, 0.37H, CHbCH2SF5),
5.03 (app. ddt, J = 10.5, 7.0, 5.3 Hz, 0.63H, CHaCH2SF5), 4.15–3.99
(m, 1.09H, CHaHSF5, CHbHSF5), 3.99–3.92 (m, 0.96H, CHaPh, CHbPh),
3.92–3.77 (m, 1.03H, CHHaSF5, CHHbSF5), 2.96 (ddd, J = 13.7, 8.7,
5.5 Hz, 0.66H, CHaHCH), 2.70 (app. dt, J = 13.2, 6.5 Hz, 0.39H,
CHbHCH), 2.54 (ddd, J = 13.6, 9.5, 6.8 Hz, 0.41H, CHHbCH3), 2.16
(app. td, J = 12.7, 10.4 Hz, 0.64H, CHHaCH) ppm. 13C NMR (125 MHz,
CDCl3): δC = 175.5 (C, Cb=O), 175.1 (C, Ca=O), 135.9 (C, CbAr), 135.3
(C, CaAr), 129.4 (CH, CHAr), 129.2 (CH, CHAr), 128.24 (CH, CHAr), 128.22
(CH, CHAr), 128.1 (CH, CHAr), 127.5 (CH, CHAr), 73.7–73.0 (m, 2 × CH2,
CH, CH2aSF5, CH2bSF5, CHbCH2SF5), 72.6 (p, J = 4.1 Hz, CH,
CHaCH2SF5), 46.5 (CH, CHaPh), 45.0 (CH, CHbPh), 37.5 (CH2, CH2aCH),
4-Chloro-5-(pentafluoro-λ6-sulfanyl)pentanenitrile (12): Follow-
ing the general procedure on 50 mg scale of 2k, 4-chloro-5-(penta-
fluoro-λ6-sulfanyl)pentanenitrile (12) was isolated as a yellow oil
(24 mg, 0.099 mmol, 57 %) after purification by AFP (30–100 %
EtOAc/hexanes, 1–15–2 CV). FT-IR: ν = 3009 (w), 1736 (s), 1458 (w),
1366 (m), 1211 (m) cm–1. 1H NMR (500 MHz, CDCl3): δH = 4.47 (dddd,
J = 10.2, 7.0, 5.5, 2.6 Hz, 1H, CHCl), 4.16–4.00 (m, 1H, CHHSF5), 3.99–
3.77 (m, 1H, CHHSF5), 2.75–2.58 (m, 2H, CH2CN), 2.48–2.38 (m, 1H,
CHHCHCl), 2.02 (dddd, J = 14.4, 10.5, 7.1, 5.4 Hz, 1H, CHHCHCl) ppm.
35.7 (CH2, CH2bCH) ppm. 19F NMR (470 MHz, CDCl3): δF = 83.0–81.4 13C NMR (125 MHz, CDCl3): δC = 117.9 (C, CN), 75.9 (p, J = 14.6 Hz,
(m, 1F, SFF4), 68.0–67.3 (m, 4F, SFF4) ppm. HRMS (ESI-TOF, m/z): Calcd
CH2, CH2SF5), 53.9 (p, J = 4.7 Hz, CH, CHCl), 33.2 (p, J = 1.7 Hz, CH2,
CH2CHCl), 14.9 (CH2, CH2CN) ppm. 19F NMR (470 MHz, CDCl3): δF =
85.6–79.5 (m, 1F, SFF4), 66.8 (dt, J = 146.6, 8.1 Hz, 4F, SFF4) ppm.
HRMS (ESI-TOF, m/z): Calcd for C5H11ClF5N2S [M + NH4]+ 261.0246,
found 261.0246.
for C11H12F5O2S [M + H]+ 303.0473, found 303.0484.
3-(Benzyloxy)-5-((pentafluoro-λ6-sulfanyl)methyl)dihydrofuran-
2(3H)-one (7i): Following the general procedure on 100 mg scale
of 2i, the desired product was isolated as a white solid (72.7 mg,
0.219 mmol, 81 %) in a 73:27 mixture of diastereoisomers after puri-
fication by AFP (30–100 % EtOAc/hexanes, 1–15–2 CV). Mp: 80.6–
82.8 °C. FT-IR: ν = 2932 (w), 2255 (w), 1792 (m), 1456 (w), 1338 (w),
Ethyl 4-Chloro-5-(pentafluoro-λ6-sulfanyl)pentanoate (13): Fol-
lowing the general procedure on 100 mg scale of 2l, ethyl 4-chloro-
5-(pentafluoro-λ6-sulfanyl)pentanoate (13) was isolated as a yellow
Eur. J. Org. Chem. 2019, 6655–6665
www.eurjoc.org
6663
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
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oil (18.8 mg, 0.065 mmol, 22 %) after purification by AFP (30–100 %
EtOAc/hexanes, 1–15–2 CV). FT-IR: ν = 2986 (w), 2874 (w), 1666 (s),
1
1547 (w), 1493 (m), 1445 (m), 1421 (m), 1286 (m), 1097 (s) cm–1. H
NMR (500 MHz, CDCl3): δH = 4.47 (app. ddt, J = 12.7, 5.7, 3.0 Hz, 1H,
CHCl), 4.17 (q, J = 7.2 Hz, 2H, OCH2CH3), 4.10–3.99 (m, 1H, CHHSF5),
3.98–3.85 (m, 1H, CHHSF5), 2.68–2.51 (m, 2H, CH2CO2Et), 2.36 (app.
dtd, J = 15.2, 7.7, 3.1 Hz, 1H, CHHCHCl), 2.02–1.88 (m, 1H, CHHCHCl),
1.28 (t, J = 7.1 Hz, 3H, OCH2CH3) ppm. 13C NMR (125 MHz, CDCl3):
δC = 172.1 (C, CO2Et), 76.6 (p, J = 13.8 Hz, CH2, CH2SF5), 60.8 (CH2,
OCH2CH3), 54.9 (p, J = 4.4 Hz, CH, CHCl), 32.5 (CH2CHCl), 30.7 (CH2,
CH2CO2Et), 14.1 (CH3, OCH2CH3) ppm. 19F NMR (470 MHz, CDCl3):
δF = 85.7–81.8 (m, 1F, SFF4), 66.5 (app. dq, J = 146.6, 7.4 Hz, 4F,
SFF4) ppm. HRMS (ESI-TOF, m/z): Calcd for C7H16ClF5NO2S [M +
NH4]+ 308.0505, found 308.0507.
[7]
[8]
Reduction of 7a
a) D. S. Lim, J. S. Choi, C. S. Pak, J. T. Welch, J. Pestic. Sci. 2007, 32, 255–
259; b) O. S. Kanishchev, W. R. Dolbier Jr., Chem. Eur. J. 2017, 23, 7677–
7681.
5-(Pentafluoro-λ6-sulfanyl)pentane-1,4-diol (14): To a solution of
7a (100 mg, 0.442 mmol) in dry Et2O (4.40 mL) at 0 °C was added
LiAlH4 (33.4 mg, 0.884 mg). After 17 h at r.t., a 10 % solution of HCl
was added and the aqueous phase was separated and extracted
with Et2O (3 ×). The organic phases were combined, dried with
MgSO4 and carefully concentrated in vacuo to afford the product
(61.9 mg, 0.269 mmol, 61 %) as a colorless oil. FT-IR: ν = 3348 (w),
For recent examples, see: a) N. Iida, E. Tokunaga, N. Saito, N. Shibata, J.
Fluorine Chem. 2015, 171, 120–123; b) N. Lida, K. Tanaka, E. Tokunaga, S.
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Philp, Tetrahedron 2000, 56, 3399–3408.
2943 (w), 1715 (m), 1269 (m), 1049 (w) cm–1 1H NMR (500 MHz,
.
CDCl3): δH = 4.32 (app. tt, J = 8.4, 3.1 Hz, 1H, CHOH), 3.83–3.66
(m, 4H, CH2SF5, CH2OH), 2.45 (br s, 2H, 2 × OH), 1.81–1.66 (m, 3H,
CHHCHOH, CH2CH2OH), 1.65–1.54 (m, 1H, CHHCHOH) ppm. 13C
NMR (125 MHz, CDCl3): δC = 77.9 (p, J = 10.3 Hz, CH2, CH2OH), 67.9
(p, J = 3.9 Hz, CH, CHOH), 62.6 (CH2, CH2OH), 33.2 (p, J = 1.4 Hz,
CH2, CH2CHOH), 28.5 (CH2, CH2CH2OH) ppm. 19F NMR (470 MHz,
CDCl3): δF = 85.3 (p, J = 145.3 Hz, 1F, SFF4), 66.6 (dt, J = 145.6,
8.4 Hz, 4F, SFF4) ppm. HRMS (ESI-TOF, m/z): Calcd for C5H12F5O2S
[M + H]+ 231.0473, found 231.0478.
[9]
[10]
a) S. Altomonte, G. L. Baillie, R. A. Ross, J. Riley, M. Zanda, RSC Adv. 2014,
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This work was supported by the Natural Sciences and Engineer-
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[12]
[13]
[14]
Keywords: Pentafluorosulfanyl · Lactones · Silver ·
Cyclization · Heterocycles
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Received: August 6, 2019
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