A convergent, modular access to α-chloro-trifluoromethyl derivatives and to 1,1-difluoroalkenes

Article abstract of DOI:10.1016/j.tet.2014.11.021

Abstract An efficient protocol for the preparation of S-(1-chloro-2,2,2-trifluoroethyl)-O-ethyl xanthate is reported. This reagent serves as a versatile precursor of highly functionalized gem-difluoroalkenes through various inter- and intramolecular radical reactions and subsequent reduction with activated magnesium metal.

Full text of DOI:10.1016/j.tet.2014.11.021

Tetrahedron xxx (2014) 1e10
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A convergent, modular access to
a-chloro-trifluoromethyl
derivatives and to 1,1-difluoroalkenes
*
Pierre Salomon, Wioletta Kosnik, Samir Z. Zard
ꢀ
ꢁ
ꢁ
Laboratoire de Synthese Organique associe au C. N. R. S., Departement de Chimie, Ecole Polytechnique, F-91128 Palaiseau, France
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient protocol for the preparation of S-(1-chloro-2,2,2-trifluoroethyl)-O-ethyl xanthate is reported.
This reagent serves as a versatile precursor of highly functionalized gem-difluoroalkenes through various
inter- and intramolecular radical reactions and subsequent reduction with activated magnesium metal.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 6 September 2014
Received in revised form 23 October 2014
Accepted 6 November 2014
Available online xxx
This article is dedicated with respect to the
memory of Professor Alan R. Katritzky
Keywords:
Radical addition
Xanthates
Fluorine
1. Introduction
coupling14 and SN20 type reactions15 can offer suitable and powerful
alternatives. Most of these sequences exploit the presence of re-
Over the last two decades, the proportion of useful fluorine
containing molecules has substantially increased. It is presently in
about a third of all compounds on the pharmaceutical and agro-
chemical markets.1 Indeed, the ability of fluorine to deeply alter the
chemical and physical properties of organic molecules is now well
established,2 and provides a unique and formidable tool for drug
designers. Of all valuable fluorinated groups, terminal gem-difluoro
alkenes exhibit broad applicability, for they can be easily used and
transformed into important fluorinated derivatives.3 In addition,
they have an exclusive isosteric property to act as a carbonyl group
mimic,4 and are in some cases responsible for the biological activity
of certain enzyme inhibitors and pesticides.5
active functions, such as ketones or alkyl halides. However, there
remains a dearth of methods starting from much less reactive
groups, such as terminal alkenes.
2. Result and discussion
A few years ago, we reported the synthesis of S-(1-chloro-2,2,2-
trifluoroethyl)-O-ethyl xanthate 1 and its use in a limited number of
radical addition reactions.16 This work also involved the prepara-
tion and study of the acetate and benzoate analogs 2 and 3. How-
ever, it seemed to us that the synthetic potential of 1 had remained
largely underexploited (Fig. 1).
To date, there are various methods to prepare terminal gem-
difluoroalkenes. Several pathways, such as the Wittig,6 the Horner-
Wadsworth-Emmons,7 the Julia type reaction8 or the Julia-
Kociensky olefinations,9 start from ketones or aldehydes. Others
rely on elimination reactions, such as metal induced eliminations,10
base induced elimination of sulfones11 or the thermal elimination of
S
S
S
S
OEt
S
OEt
S
OEt
F3C OAc
F3C OBz
F3C Cl
1
2
3
sulfoxides and b
-hydroxy sulfoxides.12 Finally, the use of difluor-
Fig. 1. A few fluorinated xanthates.
ovinyl metal derivatives, such as difluorovinyllithium,13 or cross-
With the aim of extending this work, we considered using this
xanthate as a unique precursor to highly functionalized -chloro-
a
trifluoromethyl derivatives, as well as to heterocycles bearing
a gem-difluorovinyl motif on the side chain. The pathway envisaged
* Corresponding author. Tel.: þ33 169335971; fax: þ33 169335972; e-mail
address: samir.zard@polytechnique.edu (S.Z. Zard).
http://dx.doi.org/10.1016/j.tet.2014.11.021
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Salomon, P.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.11.021

2
P. Salomon et al. / Tetrahedron xxx (2014) 1e10
to access these heterocycles would begin with simple radical ad-
ditions of xanthate 1 onto olefins bearing an aromatic ring 7, then
harness the ability of xanthates to promote radical cyclizations onto
aromatic rings to form bicyclic compounds 5.17 The desired difluoro
alkene 4 would finally be brought about by a metal induced formal
elimination of ‘CleF’ (Scheme 1).
Cl
F
F
F
F
F
n
n
Y
X
Y
S
Y
X
4
5
EtO
X
S
F
F
F
n
Cl
6
Cl
S
n
Y
F3C
S
OEt
X
7
1
Scheme 1. A route to difluoroalkenes.
Our investigations began with an optimization of the synthesis
of xanthate 1 because, unfortunately, we were unable to duplicate
the earlier reported protocol. The desired substance was obtained,
but in a very poor yield. Furthermore, we found that, contrary to
what had been previously stated, compound 1 is totally stable to
chromatographic purification. We therefore considered revising
the experimental conditions for the whole sequence.
We rapidly identified trifluoroacetic acid as a much better acid/
solvent than the originally used sulfuric acid in acetone (Scheme 2).
Indeed, the xanthate intermediate 9 could be easily removed from
the medium by simple extraction with pentane. Moreover, pentane
appeared to be a suitable solvent for the next step. While we were
screening conditions for the second step using PCl5 as a chlorinat-
ing reagent, we noticed that the evaporation of the solvent from
crude mixture before purification was mainly responsible for the
yield loss. Finally, by conducting the first reaction in trifluoroacetic
acid and the second in pentane, followed by direct purification of
the crude mixture, we were able to isolate xanthate 1 in a good 42%
overall yield from commercially available hemiacetal 8. This re-
producible protocol is very straightforward and was easily scaled
up. Alcohol 9 may also be readily acetylated to give acetate 2, which
is also a useful xanthate for additions to alkenes (Scheme 2).16
Scheme 3. Addition of xanthate 1 to alkenes.
S
excellent yields, up to 99%. A substantial increase was for instance
observed with allylphosphonate, where the yield of the adduct 11h
was raised from 27% to 77%. As usual, xanthate chemistry showed
a great tolerance towards several functional groups such as ke-
tones, amides, ethers or pyridine rings. A small excess of xanthate 1
was used in these additions (typically 1.5 equiv) but it could be
easily recovered at the end of the reaction.
Xanthate adducts 11aeg were next transformed into their cor-
responding polycyclic aromatic or heteroaromatic derivatives by
subsequent treatment with a stoichiometric amount of lauroyl
peroxide. The reactions were performed in either refluxing ethyl
acetate or refluxing chlorobenzene, following literature protocols,18
and ultimately produced bicyclic compounds 12aeg in good yields
relative to their complexity. For instance, azaindoline, tetrahy-
dronaphthyridin-2-one and tetrahydroisoquinolin-1-one de-
rivatives were readily obtained in only two steps from easily
accessible precursors (Scheme 4). The cyclization of compound 12f
represents a new feature, as it is one of the very rare examples of
radical cyclizations leading to dihydronaphthyridin-2-ones not
substituted on the lactam nitrogen.19
OH
S
OEt
KSC(S)OEt
CF3COOH
F3C OR
F3C OH
9
8, R = Me, Et
Ac2O
Pyridine
PCl5, 1.25 equiv
pentane, 0 °C, 1 h
then rt, 2 h
S
S
S
OEt
S
OEt
F3C Cl
1 (42% overall; scale > 5 g)
F3C OAc
2 (90% overall)
Scheme 2. Synthesis of xanthates 1 and 2.
With the desired xanthate 1 in hand, we were able to validate its
good reactivity towards several olefins, using lauroyl peroxide
(DLP) as a thermal radical initiator. The results are displayed in
Scheme 3 [Xa¼ꢀSC(¼S)OEt]. In contrast to the moderate yields
reported in the previous publication where 1 was mainly used
without purification, we isolated the xanthate adducts 11aej in
Please cite this article in press as: Salomon, P.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.11.021

P. Salomon et al. / Tetrahedron xxx (2014) 1e10
3
Table 1
S
CF3
Optimization trials for the reductive elimination
S
OEt
CF3
Cl
DLP
Cl
F
n
n
EtOAc or PhCl
reflux
?
CF3
12a
Y
Cl
Y
F
X
N
X
11a-g
12a-g
N
Ms
N
Ms
14a
Cl
CF3
ꢁC
Conversion
CF3
Entry
Reagent
Solvent
T
Zn,a Cul cat.
Zn,b Cul cat.
Zna
DMF
DMF
AcOEt
EtCO2H
THF
THF
THF
THF
MeOH
MeOH
MeOH
THF
20e50 ꢁC
20e50 ꢁC
Reflux
0%
Cl
1
2
3
4
5
6
7
8
Cl
0%
Ms
12a (48%)
0e100%c
Me
N
N
H
O
CF3
Me
Zna
Reflux
0
0
8%c
MeO
ꢁCdrt
ꢁCdrt
ꢀ78 ꢁCdrt
ꢀ78 ꢁCdrt
Reflux, 2 h
Reflux, 24 h
Reflux
0%
0%
0%
12b (43%)
i-PrMgCl
i-PrMgCl, LiCl
n-BuLi
t-BuLi
Mg
Mg
Mg, I2
Mg
N
Cl
40e75%c
0e30%c
0e30%c
0%
O
CF3
CF3
12c (51%)
9
Cl
10
11
12
13
14
15
16
17
F
N
N
F
N
N
O
Me
12d (47%)
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
0e5%
0%
0%
0%
50e85%
100%
Mg
Mg
Mg
EtOH
O
Me
Cl
Cl
CF3CH2OH
MeOH/PhMe
THF
12e (50%)
CF3
CF3
Cl
Mg, Br(CH2)2Br
MeO
Mg, Br(CH2)2Brd
THF
N
O
a
Zinc flakes.
Zinc powder.
Reactions not reproducible.
H
b
c
Cl
O
12g (64%)
12f (46%)
d
Periodic addition of 1,2-dibromoethane during the reaction.
Scheme 4. Ring-closure onto aromatic and heteroaromatic rings.
For compounds 11hej, we proceeded to the simple reductive
removal of the xanthate moiety, by using either the hypophos-
phorous salt of triethylamine20 or tris(trimethylsilyl)silane21 as the
hydrogen atom donor (Scheme 5).
out to be unreliable. Finally, magnesium, activated in situ by a sub-
stoichiometric amount of 1,2-dibromoethane, promoted the elimi-
nation efficiently. After a few trials, we concluded that the periodic
addition of 1,2-dibromoethane permitted a quantitative conversion
systematically. The optimized protocol is easy to implement, and
a standard work-up yields the desired 1,1-difluoroalkene essentially
quantitatively.
S
EtO
S
Cl
Cl
a) or b)
We were further pleased to find that the same conditions were
equally efficient for most of the other derivatives (Scheme 6).
Compound 14f and 14j were obtained in only 50% yield, because of
the competing cleavage of the amide functions. Indeed, in the case
of 14j, besides the desired product, diphenylamine resulting from
the cleavage of the amide was isolated in 33% yield.
As far as compound 14d and 14e are concerned, we assumed
that the degradation observed came from the hydrolytic instability
of the acetyl moiety. We therefore proceeded with the quantitative
removal of the acetyl protecting group by treatment with potas-
sium carbonate in methanol and subjected the naked substrates
15a and 15b to the elimination conditions. To our delight, the de-
sired terminal gem-difluoroalkenes 16a and 16b were formed in
very good yield (Scheme 7).
In a further variation, we found that xanthate 1 is able to un-
dergo a radical allylation reaction we recently developed. It in-
volves the use of 2-fluoropyridyl derivatives of allylic alcohols as
the allylating agents and overcomes the activation barrier resulting
from the strong and difficult to homolyze carboneoxygen bond.22
As depicted in Scheme 8, the reaction of xanthate 1 with sub-
R
CF3
Cl
R
O
CF3
13a-c
11h-j
MeO
MeO
MeO
CF3
Cl
CF3
((a): <30%; b): 47%)
P
O
13a (a): 93%)
13b
N
CF3
O
7
13c (a): 78%; b): 98%)
Cl
Conditions a) : H3PO2, TEA, AIBN, dioxane, reflux
Conditions b) : (Me3Si)3SiH, AIBN, toluene/cyclohexane 1:1,
reflux
Scheme 5. Reductive dexanthylations of adducts 11hej.
More synthetically interesting is the conversion of b-chlorotri-
fluoromethyl derivatives into 1,1-difluoroalkenes using dissolving
metal reductions. Such transformations are already known; how-
ever, only bromides10c or activated chlorides10b have been employed
in this reaction. In our case, the issue was to induce the insertion of
a metal into the un-activated carbon-chloride bond to promote the
elimination. Taking compound 12a as a model substrate, we
screened several experimental conditions. The first promising result
was obtained by treatment with zinc flakes in refluxing ethyl acetate
(Table 1, entry 3) so that we were able to isolate the desired com-
pound in a quantitative yield. Unfortunately, this reaction proved
non-reproducible and forced us to examine other more reducing
metals such as lithium and magnesium. Promising results were
obtained with tert-butyl lithium but, to our dismay, it again turned
strate 17 gave the desired product in a good 75% yield. The
chlorotrifluoromethyl derivative 18, bearing a double bond at the
position and a masked aldehyde, would be very tedious to make
b-
d
by more conventional methods. Interestingly, base induced elimi-
nation of HCl from compound 18 would lead in principle to the
formation of a trifluoromethyl-substituted diene.
3. Conclusion
In conclusion, we now have in hand a unified, flexible, and
convergent strategy for the synthesis of various acyclic and
Please cite this article in press as: Salomon, P.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.11.021

4
P. Salomon et al. / Tetrahedron xxx (2014) 1e10
heterocyclic substances bearing a terminal difluoro alkene side
Cl
chain. The methodology is based on the use of S-1-chloro-2,2,2-
trifluoroethyl-O-ethyl xanthate 1 as a fluorinated precursor, the
synthesis of which has been re-examined and is now easily re-
producible and scalable. Reagent 1 represents in fact the synthetic
equivalent of a 2,2-difluorovinyl radical (F2C]CHꢂ), which is too
reactive to undergo cleanly intermolecular additions to un-
activated alkenes.
F
CF3
Mg, Br(CH2)2Br
THF, reflux
F
n
n
Y
Y
X
N
X
14
12
F
F
F
F
F
MeO
F
F
N
Me
N
N
H
O
4. Experimental
Ms
O
14c (95%)
14a (95%)
14b (99%)
4.1. General experimental methods
F
F
F
Purification procedures were in accordance with the in-
structions in D. D. Perrin and W. L. F. Armarego, ‘Purification of
Laboratory Chemicals’, Fourth Edition, The Bath Press, Bath, 2002.
All reactions were carried out under dry, oxygen free nitrogen.
F
Cl
F
F
N
N
F
N
N
N
O
O
Me
H
Cl
O
Me
ꢂ
Flash chromatography was performed on silica gel (SDS, 60 A C. C.
14d (0%)a
14e (0%)a
14f (50%)
40e63 mm) as the stationary phase. Thin Layer Chromatography
(TLC) was performed on alumina plates pre-coated with silica gel
(Merck silica gel, 60 F254), which were visualized by the quenching
of UV fluorescence when applicable (lmax¼254 nm and/or 366 nm)
and/or by staining with vanillin or anisadehyde in acidic ethanol
followed by heating. Infrared spectra were recorded as solutions
in CH2Cl2 using NaCl cells, on a PerkineElmer FT 2000. Absorption
maxima (nmax) are reported in wavenumbers (cmꢀ1) and only
selected peaks are reported. Magnetic resonance spectra
were recorded at room temperature on a Bruker Avance DPX
400 instrument. Proton magnetic resonance spectra (1H NMR)
were recorded at 400 MHz and coupling constants (J) are reported
to ꢃ0.5 Hz. The following abbreviations were utilized to describe
peak patterns when appropriate: br¼broad, s¼singlet,
d¼doublet, t¼triplet, q¼quartet, quint¼quintuplet, hex¼hexuplet,
hept¼heptuplet, oct¼octuplet and m¼multiplet. Carbon magnetic
resonance spectra (13C NMR) were recorded in the same in-
F
O
P
F
MeO
F
MeO
OMe
F
14g (0%)a
14h (80%)
O
O
F
N
F
F
O
F
MeO
14i (90%)
7
14j (50%)b
a) degradation of the crude mixture
b) Ph2NH (33%) also isolated, see text
Scheme 6. Synthesis of difluoroalkenes.
Cl
Cl
CF3
K2CO3
CF3
strument at 100.6 MHz. Chemical shifts (dH, dC) are quoted in parts
F
F
N
N
N
F
N
N
H
MeOH
per million (ppm) and are referenced to TMS (0 ppm). Low-
resolution mass spectra (m/z) were recorded by chemical ioniza-
tion (CI/NH3) on a HewlettePackard HP 5989B and only report
molecular species ([MþH]þ, [MþNH4]þ) and other major frag-
ments. High-resolution mass spectra were recorded by positive
electron impact ionization (EIþ) at 70 e.V. on a JEOL JMS-GCmate II
mass spectrometer. The quoted masses are accurate to ꢃ5 ppm. The
names of the molecules that appear in the following pages were
generated using either Beilstein AutoNom 2000 (CAS) or Chem-
BioDraw Ultra 11.0.
O
Me
Cl
15a (99%)
12d
Mg, Br(CH2)2Br
THF, reflux
F
F
N
H
16a (89%)
Cl
CF3
15b (99%)
CF3
K2CO3
MeOH
F
N
N
H
F
N
N
4.2. General procedures
O
Me
12e
Mg, Br(CH2)2Br
THF, reflux
F
F
4.2.1. General procedure A for the addition reaction. A solution of
olefin (n mmol) and xanthate (between 1.3 n and 2 n mmol) in
AcOEt (n mL) was refluxed under a flow of nitrogen for 15 min.
Lauroyl peroxide (DLP) 5 mol % was then added every hour until
total conversion of the starting olefin was observed. The mixture
was cooled to room temperature and the solvent evaporated under
reduced pressure. Flash column chromatography afforded the de-
sired adduct as a mixture of two diastereoisomers.
16b (83%)
F
N
N
H
Scheme 7. Synthesis of azaindolines and tetrahydroazaquinolines.
S
Me
O
N
Me
S
F3C Cl
DLP
OEt
Me
O
4.2.2. General procedure B for the cyclization reaction. A solution
of the xanthate adduct (n mmol) in either AcOEt or chlorobenzene
(50 n mL) was refluxed under a flow of nitrogen for 15 min.
Lauroyl peroxide (DLP) 20 mol % was then added every 15 min
(chlorobenzene) or every hour (ethyl acetate) until total conversion
of the starting olefin was observed. The mixture was cooled
to room temperature and the solvent evaporated under reduced
Me
Me
O
F
1
Cl
O
F3C
O
EtOAc, reflux
Me
17
18 (75%; E:Z = 3.5:1)
Scheme 8. Radical allylation of xanthate 1.
Please cite this article in press as: Salomon, P.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.11.021

P. Salomon et al. / Tetrahedron xxx (2014) 1e10
5
pressure. Flash column chromatography afforded the desired
product as a mixture of two diastereoisomers.
chromatography (petroleum ether/ethyl acetate 80:20) to afford the
corresponding xanthate adduct 11a (2592 mg, 96%) as a mixture of
two diastereoisomers 80:20 and as a colorless oil. 1H NMR
(400 MHz; CDCl3): dH 7.50e7.35 (m, 5H), 4.60e4.51 (m, 2H),
4.47e4.39 (m, 0.2H), 4.39e4.29 (m, 0.8H), 4.10e4.00 (m, 1.2H),
3.98e3.82 (m, 1.8H), 2.90 (s, 2.4H), 2.89 (s, 0.6H), 2.75 (ddd, J¼15.1,
6.9, 5.3 Hz, 0.2H), 2.56 (ddd, J¼14.7, 11.9, 2.6 Hz, 0.8H), 2.19 (ddd,
J¼15.3,11.9, 2.1 Hz, 0.8H), 2.19e2.12 (m, 0.2H),1.34 (t, J¼7.1 Hz, 0.6H),
1.32 (t, J¼7.1 Hz, 2.4H); 13C NMR (100 MHz; CDCl3): dC major di-
astereoisomer: 210.5, 137.9, 129.7 (2C), 128.9 (2C), 128.8, 123.8 (q,
J¼279 Hz), 70.6, 54.9 (d, J¼33.7 Hz), 53.6, 44.9, 37.1, 31.4, 13.6; minor
diastereoisomer: 211.0, 138.3, 129.7, 128.9, 128.7, 123.8 (q, J¼279 Hz),
70.4, 54.4 (q, J¼33 Hz), 52.76, 45.9, 37.0, 33.1, 13.6; IR (CCl4): nmax
4.2.3. General procedure C for the elimination reaction. A magneti-
cally round bottom flask was charged with the corresponding tri-
fluorochloro compound (n mmol), freshly activated magnesium
(20 n mmol), and dry THF (33 n mL) and the suspension was heated
up to reflux. 1,2-Dibromoethane (0.5 n mmol) was then added ev-
ery two hours until total conversion of the starting material was
observed by NMR. The mixture was cooled to room temperature
and a saturated solution of citric acid (15 n mL) was added. After
total disappearance of solid magnesium, Et2O was added, the layers
were partitioned and the aqueous one was extracted twice with
Et2O. The combined organic layers were washed with brine and
dried over anhydrous MgSO4. Removal of the solvent and flash
chromatography if necessary yielded to the desired difluoro olefin.
2987, 1493, 1357, 1267, 1225, 1185, 1161, 1132, 1052; HRMS (EIþ):
35
calculated (found) for C
H ClF3NO2: 328.0386 (328.0390).
12 10
4.3.4. 5-Chloro-3-[(ethoxymethanethioyl)sulfanyl]-6,6,6-trifluoro-N-
(6-methylpyridin-2-yl)hexanamide (11b). Following general pro-
cedure A, the reaction was carried out using N-(6-methylpyridin-2-
4.3. Experimental procedures and spectroscopic data
4.3.1. [(1-Chloro-2,2,2-trifluoroethyl)sulfanyl](ethoxy)methanethione
(1). A magnetically stirred round bottom flask was charged with
potassium ethyl xanthate salt (8 g, 50 mmol), 100 mL of trifluoro-
acetic acid and cooled to 0 ꢁC. 2,2,2-Trifluoro-1-methoxyethan-1-ol
(8.19 g, 63 mmol) was added slowly and the solution was stirred
30 min at 0 ꢁC and 1 h at room temperature. Pentane (100 mL) and
water (100 mL) were added, the layers were separated and the
aqueous layer was extracted twice with pentane (100 mL). The
combined organic layers were washed with brine and dried over
anhydrous MgSO4. The solution was concentrated to 100 mL in
vacuo, was cooled to 0 ꢁC and phosphorus pentachloride (13.10 g,
63 mmol) was added. The solution was stirred at 0 ꢁC for 30 min
and at room temperature for 2 h. The solution was then directly
purified by silica gel column chromatography23 (pentane 100%) and
concentrated under reduced pressure at 20 ꢁC to afford 1 (5.01 g,
42%) as a pale yellow liquid. 1H NMR (400 MHz; CDCl3): dH 6.26 (q,
J¼6.9 Hz, 1H), 4.74 (q, J¼7.1 Hz, 2H), 1.47 (t, J¼7.1 Hz); 13C NMR
(100 MHz; CDCl3): dC 206.4, 122.7 (q, J¼279 Hz), 72.0, 63.6 (q,
J¼37 Hz), 13.6. The spectral data were incorrectly reported in the
original communication (Ref. 16).
yl)but-3-enamide (500 mg, 2.83 mmol), xanthate 1 (1.0 g,
4.5 mmol). The residue was purified by silica gel column chroma-
tography (petroleum ether/ethyl acetate 85:15) to afford the xan-
thate adduct 11b (850 mg, 72%) as a mixture of two diastereoisomers
60:40 and as a colorless oil. 1H NMR (400 MHz; CDCl3): dH 9.25 (br s,
0.4H), 9.11 (br s, 0.6H), 8.04e7.88 (m, 1H), 7.56 (t, J¼7.8 Hz, 1H), 6.87
(d, J¼7.4 Hz, 1H), 4.66e4.52 (m, 2H), 4.48e4.29 (m, 2H), 3.04e2.80
(m, 2H), 2.71e2.52 (m,1H), 2.39 (s, 3H), 2.35e2.20 (m,1H),1.41e1.33
(m, 3H); 13C NMR (100 MHz; CDCl3): dC major diastereoisomer: 211.7,
168.0, 156.5, 150.3, 138.7, 123.7 (q, J¼279 Hz), 119.5, 111.3, 70.4, 55.3
(q, J¼33 Hz), 43.5, 41.8, 34.6, 23.7,13.5; minor diastereoisomer: 211.6,
168.0, 156.5, 150.2, 138.7, 123.7 (q, J¼279 Hz), 119.6, 111.4, 70.3, 54.8
(q, J¼33 Hz), 43.1, 39.2, 34.4, 23.7, 13.5; IR (CCl4): nmax 3419, 2928,
1702,1456,1267,1230,1128,1051; HRMS (EIþ): calculated (found) for
35
C
H
ClF3N2O2S2: 414.0450 (414.0448).
15 18
4.3.5. Ethyl ({4-chloro-5,5,5-trifluoro-1-[1-(4-methoxyphenyl)-N-meth-
ylformamido]pentan-2-yl}sulfanyl)carbothioate (11c). Following gen-
eral procedure A, the reaction was carried out with 4-methoxy-N-
methyl-N-(prop-2-en-1-yl)benzamide18b (609 mg, 3.0 mmol), xan-
thate 1 (928 mg, 3.9 mmol). The residue was purified by silica gel
column chromatography (petroleum ether/diether ether 80:20 to
20:80) to afford the xanthate adduct 11c (620 mg, 47%) as a mixture of
two diastereoisomers 65:35 and as a colorless oil. 1H NMR (400 MHz;
CDCl3): dH 7.36 (d, J¼8.6 Hz, 2H), 6.90 (d, J¼8.7 Hz, 2H), 4.71e4.58 (m,
2.35H), 4.53e4.12 (m, 2H), 3.90e3.75 (m, 4H), 3.57e3.39 (m, 0.65H),
3.12 (s, 1.95H), 3.09 (s, 1.05H), 2.53e2.08 (m, 2H), 1.44e1.39 (m, 3H);
13C NMR (100 MHz; CDCl3): dC major diastereoisomer: 211.6, 172.1,
160.7, 128.9 (2C), 127.8, 123.7 (q, J¼279 Hz), 113.7 (2C), 70.7, 55.3,
55.7e54.2(m), 50.5, 45.3, 38.4, 32.4, 13; minor diastereoisomer: 211.8,
171.9, 160.8, 128.9 (2C), 127.6, 123.6 (q, 279 Hz), 113.7 (2C), 70.5, 55.3,
55.7e54.2 (m), 49.5, 45.9, 39.5, 34.1, 13.6; IR (CCl4): nmax 2933, 1642,
4.3.2. 1-(Ethoxycarbonothioylthio)-2,2,2-trifluoroethyl acetate (2). A
magnetically stirred round bottom flask was charged with potassium
ethyl xanthate salt (0.8 g, 5 mmol), 10 mL of trifluoroacetic acid and
cooled to
7.5 mmol) was added slowly and the solution was stirred 30 min at
ꢁC and 1 h at room temperature. Acetic anhydride (0.47 mL,
0
ꢁC. 2,2,2-trifluoro-1-methoxyethan-1-ol (0.72 mL,
0
5 mmol) and pyridine (0.4 mL, 5 mmol) were then added drop-wise
and the solution was stirred 30 min. DCM (30 mL) and water (30 mL)
were added, the layers were separated and the aqueous layer was
extracted twice with DCM (30 mL). The combined organic layers
were washed with HCl (1%), water, brine, and dried over anhydrous
MgSO4. The solution was concentrated in vacuo (cold bath water)
and the residue was purified by silica gel column chromatography
(petroleum ether/ethyl acetate 98:2) to afford 2 (1.2 g, 90%) as
a yellow oil. 1H NMR (400 MHz; CDCl3): dH 7.19 (q, J¼6.8 Hz,1H), 4.69
(dq, J¼7.2, 1.6 Hz, 2H), 2.18 (s, 3H), 1.44 (t, J¼7.2 Hz, 3H); 13C NMR
(100 MHz; CDCl3): dC 205.7, 167.6, 122.4 (q, J¼278 Hz), 76.5 (q,
J¼36 Hz), 71.4, 20.3, 13.5; IR (CCl4): nmax 2987, 1780, 1443, 1371, 1345,
1231, 1131, 1112, 1030. The spectral data were incorrectly reported in
the original communication (Ref. 16).
1610, 1483, 1393, 1303, 1252, 1223, 1173, 1130, 1052; HRMS (EIþ):
35
calculated (found) for C
H
ClF3NO2: 322.0822 (322.0832).
14 16
4.3.6. N-{4-Chloro-2-[(ethoxymethanethioyl)sulfanyl]-5,5,5-
trifluoropentyl}-N-(6-fluoropyridin-2-yl)acetamide (11d). Following gen-
eral procedure A, the reaction was carried out with N-(6-fluoropyridin-
2-yl)-N-(prop-2-en-1-yl)acetamide18a (2.00 g, 10.3 mmol), xanthate 1
(4.17 g, 17.5 mmol). The residue was purified by silica gel column
chromatography (petroleum ether/ethyl acetate 75:25) to afford the
xanthate adduct 11d (3.86 mg, 84%) as a mixture of two di-
astereoisomers 60:40 and as a yellow oil. 1H NMR (400 MHz; CDCl3): dH
major diastereoisomer: 7.93 (m, 1H), 7.24e7.15 (m, 1H), 6.99e6.93 (m,
1H), 4.66e4.55 (m, 2H), 4.49 (dd, J¼13.7, 8.5 Hz, 1H), 4.43e4.35 (m, 1H),
4.22e4.06 (m, 1H), 4.03 (dd, J¼13.7, 6.2 Hz, 1H), 2.31 (dd, J¼8.4, 5.9 Hz,
2H), 2.12 (s, 3H), 1.40 (t, J¼7.1 Hz, 3H); minor diastereoisomer: 7.93 (m,
4.3.3. N-{4-Chloro-2-[(ethoxymethanethioyl)sulfanyl]-5,5,5-
trifluoropentyl}-N-phenylmethanesulfonamide (11a). Following gen-
eral procedure A, the reaction was carried out using N-phenyl-N-
(prop-2-en-1-yl)methanesulfonamide24 (1.27 g, 6.0 mmol), xanthate
1 (1.86 g, 7.8 mmol). The residue was purified by silica gel column
Please cite this article in press as: Salomon, P.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.11.021

6
P. Salomon et al. / Tetrahedron xxx (2014) 1e10
1H), 7.24e7.15 (m, 1H), 6.99e6.93 (m, 1H), 4.66e4.55 (m, 3H), 4.28 (dd,
J¼6.1, 4.6 Hz, 2H), 4.22e4.06 (m, 1H), 2.53 (ddd, J¼14.8, 8.7, 4.1 Hz, 1H),
3.29e3.10 (m, 2H), 2.47e2.09 (m, 3.6H), 1.96 (ddt, J¼14.0, 10.4,
6.7 Hz, 0.4H), 1.49e1.41 (m, 3H); 13C NMR (100 MHz; CDCl3): dC
major diastereoisomer: 212.0, 197.1, 163.6, 130.3 (2C), 129.8, 124.0 (q,
J¼279 Hz), 113.8 (2C), 70.5, 55.5, 55.4 (q, J¼33 Hz), 47.4, 36.3, 35.1,
30.0, 13.6; minor diastereoisomer: 211.9, 197.05, 163.68, 130.3 (2C),
129.7, 124.0 (q, J¼279 Hz), 113.8 (2C), 70.3, 55.5, 54.7 (q, J¼33 Hz),
46.6, 36.8, 35.0, 26.1,13.6; IR (CCl4): nmax 2937, 1682, 1602, 1510, 1263,
2.23 (ddd, J¼15.1, 9.8, 5.5 Hz, 1H), 2.11 (s, 3H), 1.41 (t, J¼7.1 Hz, 3H); 13
C
NMR (100 MHz; CDCl3): dC major diastereoisomer: 211.1, 170.6, 162.5 (d,
J¼244 Hz), 152.8 (d, J¼13 Hz), 143.0 (d, J¼7 Hz), 123.8 (q, J¼279 Hz),
118.8 (d, J¼5 Hz), 108.2 (d, J¼36 Hz), 70.5, 55.2 (q, J¼33 Hz), 49.9, 45.9,
32.3, 23.0, 13.6; minor diastereoisomer: 211.3, 170.8, 162.4 (d, J¼244 Hz),
152.9 (d, J¼13 Hz), 143.0 (d, J¼7 Hz), 123.9 (q, J¼279 Hz), 118.8 (d,
J¼5 Hz),108.2 (d, J¼36 Hz), 70.4, 54.6 (q, J¼33 Hz), 48.4, 46.3, 33.9, 23.0,
1223, 1170, 1127, 1052; HRMS (EIþ): calculated (found) for
35
C
H
ClF3O3S2: 428.0494 (428.0504).
17 20
13.6; IR (CCl4): nmax 2928, 1684, 1600, 1452, 1378, 1311, 1267, 1226, 1131,
35
1049; HRMS (EIþ): calculated (found) for C12H ClF4N2O: 311.0574
4.3.10. N,N-Diphenylundec-10-enamide (10j). A magnetically round
bottom flask was charged with N-phenylaniline (13.50 g, 80 mmol),
undec-10-enoyl chloride (4.04 g, 20 mmol), and 20 mL of toluene
and the solution was heated up to reflux. After 3 h, 37% HCl solution
(6.7 mL, 80 mmol) was added slowly, the salts filtered off and the
solvent evaporated under reduced pressure. The residue was
recrystallized from petroleum ether to afford the desired olefin 10j
(6.7 g,100%) as white crystals. Mp: 51 ꢁC. 1H NMR (400 MHz; CDCl3):
dH 7.44e7.30 (m, 4H), 7.29e7.18 (m, 6H), 5.80 (ddt, J¼16.9, 10.2,
6.7 Hz, 1H), 4.98 (dd, J¼17.1, 1.7 Hz, 1H), 4.92 (d, J¼10.2, 1H), 2.25 (t,
J¼7.5 Hz, 2H), 2.02 (m, 2H),1.64 (m, 2H),1.44e1.17 (m,10H); 13C NMR
(100 MHz; CDCl3): dC 172.8, 142.6 (2C), 138.6, 129.7e124.8 (10C),
113.8, 37.9, 33.4, 28.9, 28.9, 28.8, 28.6, 28.5, 25.13; IR (CCl4): nmax
12
(311.0576).
4.3.7. N-{5-Chloro-3-[(ethoxymethanethioyl)sulfanyl]-6,6,6-
trifluorohexyl}-N-(6-fluoropyridin-2-yl)acetamide
(11e). Following
general procedure A, the reaction was carried out with N-(but-3-en-
1-yl)-N-(6-fluoropyridin-2-yl)acetamide18e (370 g, 1.78 mmol), xan-
thate 1 (550 g, 2.31 mmol). The residue was purified by silica gel
column chromatography (petroleum ether/ethyl acetate 80:20 to
60:40) to afford the xanthate adduct 11e (740 mg, 93%) as a mixture
of two diastereoisomers 60:40 and as a colorless oil. 1H NMR
(400 MHz; CDCl3): dH 7.87e7.77 (m,1H), 7.25e7.11 (m,1H), 6.87e6.76
(m, 1H), 4.60 (q, J¼6.8 Hz, 2H), 4.47e4.37 (m, 0.45H), 4.33 (dqd,
J¼11.0, 6.6, 2.3 Hz, 0.55H), 4.05e3.77 (m, 3H), 2.38e2.20 (m, 2H),
2.19e2.08 (m, 2H), 2.07 (s, 1.35H), 2.06 (s, 1.65H), 1.38 (t, J¼7.1 Hz,
3H); 13C NMR (100 MHz; CDCl3): dC major diastereoisomer: 211.7,
170.1, 162.2 (d, J¼243 Hz), 153.2 (d, J¼13.3 Hz), 142.7 (d, J¼7.7 Hz),
123.8 (q, J¼279 Hz), 117.7 (d, J¼5 Hz), 107.3 (d, J¼36 Hz), 70.4, 55.1 (q,
J¼33 Hz), 45.2, 45.1, 35.4, 33.9, 23.2, 13.5; minor diastereoisomer:
211.6, 170.2, 162.1 (d, J¼243 Hz), 153.2 (d, J¼13.3 Hz), 142.8 (d,
J¼7.7 Hz), 123.8 (q, J¼279 Hz), 117.4 (d, J¼5 Hz), 107.2 (d, J¼36 Hz),
70.2, 54.4 (q, J¼33 Hz), 45.2, 44.2, 35.4, 30.0, 23.2,13.5; IR (CCl4): nmax
2928, 2856, 1679, 1493, 1370, 1274; HRMS (EIþ): calculated (found)
35
for C
H
ClF3O2S2: 335.2249 (335.2249).
15 18
4.3.11. Dimethyl 4-chloro-2-[(ethoxymethanethioyl)sulfanyl]-5,5,5-
trifluoropentane-1-phosphonate (11h). Following general procedure
A, the reaction was carried out using dimethyl (prop-2-en-1-yl)
phosphonate (150 mg, 1 mmol), xanthate 1 (476 mg, 2 mmol). The
residue was purified by silica gel column chromatography (petro-
leum ether/ethyl acetate 30:70) to afford the corresponding xan-
thate adduct 11h (300 mg, 77%) as a mixture of two diastereoisomers
65:35 and as a pale yellow oil. 1H NMR (400 MHz; CDCl3): dH
4.72e4.61 (m, 2H), 4.48e4.18 (m, 2H), 3.83e3.74 (m, 6H), 2.69 (ddd,
J¼14.8, 8.7, 4.1 Hz, 0.35H), 2.59e2.46 (m,1.3H), 2.41e2.21 (m, 2.35H),
1.44 (t, J¼7.1 Hz, 1.95H), 1.43 (t, J¼7.1 Hz, 1.05H); 13C NMR (100 MHz;
CDCl3): dC major diastereoisomer: 211.0, 123.8 (q, J¼279 Hz), 70.5,
55.2 (q, J¼34 Hz), 52.8e52.6 (m, 2C), 42.1 (d, J¼2 Hz), 34.6, 31.5 (d,
J¼137 Hz), 13.7; minor diastereoisomer: 211.5, 123.9 (q, J¼279 Hz),
70.4, 54.8 (q, J¼34 Hz), 52.8e52.6 (m, 2C), 41.4 (d, J¼4 Hz), 35.3 (d,
2985, 1682, 1600, 1453, 1376, 1268, 1224, 1130, 1050; HRMS (EIþ):
35
calculated (found) for C
H
ClF4N2O2S2: 446.0513 (446.0514).
16 19
4.3.8. 5-Chloro-N-(2,4-dichlorophenyl)-3-[(ethoxymethanethioyl)sul-
fanyl]-6,6,6-trifluorohexanamide (11f). Following general procedure
A, the reaction was carried out with N-(2,4-dichlorophenyl)but-3-
enamide18d (690 mg, 3.0 mmol), xanthate 1 (928 mg, 3.9 mmol).
The residue was purified by silica gel column chromatography (pe-
troleum ether/ethyl acetate 90:10 to 60:40) to afford the xanthate
adduct 11f (1.37 g, 98%) as a mixture of two diastereoisomers 65:35
and as a yellow oil. 1H NMR (400 MHz; CDCl3): dH 8.33 (br s, 0.35H),
8.25 (br s, 0.65H), 7.40e7.36 (m, 2H), 7.06 (s, 1H), 4.68e4.58 (m, 2H),
4.45e4.32 (m, 2H), 3.01 (dd, J¼15.7, 5.2 Hz, 0.65H), 2.89 (dd, J¼15.7,
7.5 Hz, 1.35H), 2.61 (ddd, J¼14.7, 8.9, 3.7 Hz, 0.35H), 2.53 (ddd, J¼13.7,
11.6, 1.9 Hz, 0.65H), 2.35 (ddd, J¼15.1, 10.3, 5.4 Hz, 0.35H), 2.24 (ddd,
J¼14.9, 11.6, 3.2 Hz, 0.65H), 1.45e1.36 (m, 3H); 13C NMR (100 MHz;
CDCl3): dC major diastereoisomer: 212.0, 168.4, 138.8, 135.1 (2C),
124.7, 123.7 (q, J¼279 Hz), 118.5 (2C), 70.9, 55.1 (q, J¼33 Hz), 43.7,
42.3, 34.8,13.6; minor diastereoisomer: 211.8,168.4,138.7,135.1 (2C),
124.7, 123.7 (q, J¼279 Hz), 118.6 (2C), 70.7, 54.7 (q, J¼33 Hz), 43.3,
39.9, 34.9, 13.6; IR (CCl4): nmax 3434, 2987, 1709, 1586, 1518, 1444,
J¼3 Hz), 28.9 (d, J¼141 Hz), 13.7; IR (CCl4): nmax 2954, 1269, 1227,
35
1127, 1048; HRMS (EIþ): calculated (found) for C10
387.9946 (Found: 387.9950).
H ClF3O4PS2:
17
4.3.12. Ethyl {[4-chloro-5,5,5-trifluoro-1-(4-methoxyphenoxy)pentan-2-
yl]sulfanyl}methanethioate (11i). Following general procedure A, the
reaction was carried out using 1-methoxy-4-(prop-2-en-1-yloxy)ben-
zene (164 mg, 1.0 mmol), xanthate 1 (357 mg, 1.5 mmol). The residue
was purified by silica gel column chromatography (petroleum ether/
diethyl ether 98:2) to afford the xanthate adduct 11i (358 mg, 89%) as
a mixture of two diastereoisomers 60:40 and as a colorless oil. 1H NMR
(400 MHz; CDCl3): dH 6.90e6.80 (m, 4H), 4.68 (q, J¼7.1 Hz, 2H),
4.50e4.32 (m, 2H), 4.29e4.24 (m, 1H), 4.18e4.07 (m, 1H), 3.78 (s, 3H),
2.71 (ddd, J¼13.5, 9.7, 3.6 Hz, 0.4H), 2.47e2.40 (m, 1H), 2.35 (ddd,
J¼14.6, 10.7, 5.2 Hz, 0.6H), 1.44 (t, J¼7.1 Hz, 3H); 13C NMR (100 MHz;
CDCl3): dC major diastereoisomer: 211.5, 154.3, 152.1, 123.9 (q,
J¼278 Hz), 115.7 (2C), 114.5 (2C), 70.6, 70.4, 55.7e54.3 (m, 2C), 46.5,
32.4, 13.5; minor diastereoisomer: 211.8, 154.4, 152.0, 123.8 (q,
J¼278 Hz), 115.6 (2C), 114.5 (2C), 70.5, 69.9, 55.7e54.3 (m, 2C), 45.8,
1406, 1268, 1228, 1129, 1050; HRMS (EIþ): calculated (found) for
35
C
H
Cl3F3NO2S2: 466.9562 (466.9557).
15 15
4.3.9. 6-Chloro-4-[(ethoxymethanethioyl)sulfanyl]-7,7,7-trifluoro-1-
(4-methoxyphenyl)heptan-1-one (11g). Following general procedure
A, the reaction was carried out using 1-(4-methoxyphenyl)pent-4-
en-1-one (380 mg, 2.0 mmol), xanthate 1 (619 mg, 2.6 mmol). The
residue was purified by silica gel column chromatography (petro-
leum ether/ethyl acetate 90:10) to afford the corresponding xanthate
adduct 11g (850 mg, 99%) as a mixture of two diastereoisomers
60:40 and as a colorless oil. 1H NMR (400 MHz; CDCl3): dH 7.99 (d,
J¼8.9 Hz, 2H), 6.99 (d, J¼8.9 Hz, 2H), 4.76e4.57 (m, 2H), 4.50e4.40
(m, 1H), 4.23e4.14 (m, 0.6H), 4.14e4.06 (m, 0.4H), 3.92 (s, 3H),
32.8,13.5; IR (CCl4): nmax 2935,1508,1267,1228,1183,1130,1049; HRMS
35
(EIþ): calculated (found) for C15
H
ClF3O2S2: 402.0338 (402.0349).
18
4.3.13. 12-Chloro-10-[(ethoxymethanethioyl)sulfanyl]-13,13,13-trifluoro-
N,N-diphenyltridecanamide (11j). Following general procedure A, the
reaction was carried out using N,N-diphenylundec-10-enamide (1.10 g,
Please cite this article in press as: Salomon, P.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.11.021

P. Salomon et al. / Tetrahedron xxx (2014) 1e10
7
3.3 mmol), xanthate 1 (1.19 g, 5.0 mmol). The residue was purified by
silica gel column chromatography (petroleum ether/diethyl ether
80:20) to afford the xanthate adduct 11j (1768 mg, 92%) as a mixture of
two diastereoisomers 55/45 and as a yellow oil. 1H NMR (400 MHz;
CDCl3): dH 7.45e7.30 (m, 4H), 7.30e7.14 (m, 6H), 4.72e4.59 (m, 2H),
4.42e4.32 (m, 0.55H), 4.27e4.18 (m, 0.45H), 4.06e3.93 (m, 1H),
2.37e2.29 (m, 1H), 2.29e2.22 (m, 2H), 2.22e2.06 (m, 1H), 1.83e1.51
(m, 4H), 1.51e1.35 (m, 5H), 1.35e1.17 (m, 8H); 13C NMR (100 MHz;
CDCl3): dC major diastereoisomer: 212.5, 173.2, 142.9 (2C), 130.3e125.4
(m, 10C), 123.9 (q, J¼279 Hz), 70.24, 55.5 (q, J¼33 Hz), 47.4, 35.7,
35.2, 31.5, 29.3e28.9 (m, 4C), 26.5, 25.4, 13.7; minor diastereoisomer:
212.5, 173.2, 142.9 (2C), 130.3e125.4 (m, 10C), 123.9 (q, J¼279 Hz),
70.0, 54.6 (q, J¼33 Hz), 46.7, 35.9, 35.7, 35.2, 29.3e28.9 (m, 4C), 26.3,
4H), 3.24 (dd, J¼12.7, 1.6 Hz, 1H), 3.20e3.15 (m, 1H), 3.15 (s, 3H), 2.39
(ddd, J¼13.8, 11.3, 2.4 Hz, 1H), 2.03 (ddd, J¼14.2, 12.1, 3.9 Hz, 1H); 13
C
NMR (100 MHz; CDCl3): dC major diastereoisomer: 164.0, 162.2,
140.3, 131.3, 123.9 (q, J¼279 Hz), 121.3, 113.0, 112.3, 56.1 (q, J¼33 Hz),
55.5, 53.6, 35.4, 34.9, 34.2; IR (CCl4): nmax 2930, 1662, 1609, 1325,
35
1260, 1170, 1131; HRMS (EIþ): calculated (found) for C14
321.0743 (321.0750).
H ClF3NO2:
15
4.3.17. 1-[3-(2-Chloro-3,3,3-trifluoropropyl)-6-fluoro-1H,2H,3H-pyr-
rolo[2,3-b]pyridin-1-yl]ethan-1-one (12d). Following general pro-
cedure B with 11d (3.45 mg, 7.7 mmol) in chlorobenzene. The
residue was purified by silica gel column chromatography (DCM)
and recrystallized from an EP/Et2O mixture to afford the product 12d
(895 mg, 36%) as a mixture of two diastereoisomers 55:45 and as an
amorphous white solid. Mp¼120 ꢁC. 1H NMR (400 MHz; CDCl3): dH
major diastereoisomer: 7.67e7.58 (m, 1H), 6.58 (dd, 8.0, 1.9 Hz, 1H),
4.36e4.26 (m, 1H), 4.27e4.15 (m, 1H), 4.02 (dd, J¼12.4, 4.0 Hz, 1H),
3.58e3.48 (m, 1H), 2.68 (s, 3H), 3.32e2.13 (m, 2H); minor di-
astereoisomer: 7.67e7.58 (m, 1H), 6.58 (dd, 8.0, 1.9 Hz, 1H),
4.36e4.26 (m, 1H), 4.27e4.15 (m, 1H), 3.86 (dd, J¼12.2, 5.9 Hz, 1H),
3.69e3.58 (m, 1H), 2.68 (s, 3H), 3.32e2.13 (m, 2H); 13C NMR
(100 MHz; CDCl3): dC major diastereoisomer: 169.8, 163.0 (d,
J¼239 Hz), 154.0 (d, J¼17 Hz), 137.2 (d, J¼9 Hz), 123.8 (q,
J¼279 Hz), 123.3 (d, J¼5 Hz), 101.9 (d, J¼37 Hz), 55.1 (q, J¼33 Hz),
53.0, 36.3, 32.5, 24.9; minor diastereoisomer: 169.8, 163.0 (d,
J¼239 Hz), 153.8 (d, J¼17 Hz), 136.9 (d, J¼9 Hz), 123.8 (q, J¼279 Hz),
123.9 (d, J¼5 Hz),102.1 (d, J¼37 Hz), 54.9 (q, J¼33 Hz), 51.0, 36.6, 32.1,
25.4, 13.7; IR (CCl4): nmax 2928, 2856, 1680, 1493, 1370, 1267, 1220,
35
1052; HRMS (EIþ): calculated (found) for C25
(452.1968).
H
ClF3NO: 452.1968
30
4.3.14. 3-(2-Chloro-3,3,3-trifluoropropyl)-1-methanesulfonyl-2,3-
dihydro-1H-indole (12a). A solution of xanthate adduct 11a
(5.76 mmol) in DCE (30 mL) was refluxed under a flow of nitrogen for
15 min. Lauroyl peroxide (DLP) (756 mg, 33 mol %) was then added
every hour until total conversion of the starting olefin was observed.
The mixture was cooled to room temperature and the solvent
evaporated under reduced pressure. Recrystallization using petro-
leum ether and AcOEt afforded the desired compound 12a (950 mg,
48%) as a mixture of two diastereoisomers 65:35 and as white
crystals. 1H NMR (400 MHz; CDCl3): dH 7.47e7.39 (m, 1H), 7.33e7.19
(m, 2H), 7.12e7.06 (m, 1H), 4.21e4.12 (m, 1H), 4.12e4.02 (m, 1H),
3.82 (dd, J¼10.3, 3.4 Hz, 0.65H), 3.79e3.72 (m, 0.35H), 3.71e3.65 (m,
0.65H), 3.65e3.57 (m, 0.35H), 2.91 (s, 3H), 2.37e2.07 (m, 2H); 13C
NMR (100 MHz; CDCl3): dC major diastereoisomer: 141.6,131.9,129.3,
123.9 (q, J¼279 Hz), 124.9, 123.7, 113.7, 56.7, 55.6 (q, J¼34 Hz), 36.6,
35.6, 34.3; minor diastereoisomer: 141.6, 132.7, 129.0, 123.8 (q,
J¼279 Hz), 124.5, 124.0, 113.6, 55.3 (q, J¼34 Hz), 54.8, 36.4, 35.8, 34.6;
24.8; IR (CCl4): nmax 2928, 1681, 1605, 1483, 1386, 1297, 1262, 1132;
35
HRMS (EIþ): calculated (found) for C12
(310.0497).
H
ClF4N2O: 310.0496
11
4.3.18. 1-[4-(2-Chloro-3,3,3-trifluoropropyl)-7-fluoro-1,2,3,4-
tetrahydro-1,8-naphthyridin-1-yl]ethan-1-one (12e). Following gen-
eral procedure B with 11e (500 mg, 1.15 mmol) in chlorobenzene.
The residue was purified by silica gel column chromatography (pe-
troleum ether/diethyl ether 80:20 to 50:50) to afford the product 12e
(187 mg, 50%) as a mixture of two diastereoisomers 60:40 and as
a colorless oil. 1H NMR (400 MHz; CDCl3): dH 7.69e7.53 (m, 1H),
6.70e6.62 (m, 1H), 4.20 (dqd, J¼12.6, 6.3, 2.8 Hz, 0.6H), 4.06e3.71
(m, 2.4H), 3.34e3.16 (m, 1H), 2.56 (s, 1.8H), 2.55 (s, 1.2H), 2.26e1.93
(m, 3.4H), 1.77e1.67 (m, 0.6H); 13C NMR (100 MHz; CDCl3): dC major
diastereoisomer: 171.3, 160.1 (d, J¼239 Hz), 149.3 (d, J¼15 Hz), 141.4
(d, J¼8 Hz), 123.9 (q, J¼279 Hz), 122.3 (d, J¼5 Hz), 104.3 (d, J¼37 Hz),
55.0 (q, J¼33 Hz), 40.1, 36.1, 32.0, 26.1, 26.0; minor diastereoisomer:
171.7, 160.8 (d, J¼239 Hz), 149.1 (d, J¼15 Hz), 141.3 (d, J¼8 Hz), 123.9
(q, J¼279 Hz), 121.6 (d, J¼5 Hz), 103.9 (d, J¼37 Hz), 55.8 (q, J¼33 Hz),
40.7, 34.3, 32.7, 27.5, 26.2; IR (CCl4): nmax 2934, 1682, 1585, 1465,
IR (CCl4): nmax 1480, 1366, 1276, 1263, 1168, 1132; HRMS (EIþ): cal-
35
culated (found) for C
H
ClF3NO2: 327.0308 (327.0318).
12 13
4.3.15. 4-(2-Chloro-3,3,3-trifluoropropyl)-7-methyl-1,2,3,4-tetrahydro-
1,8-naphthyridin-2-one (12b). Following general procedure B with
11b (830 mg, 2 mmol) in chlorobenzene. The residue was purified by
silica gel column chromatography (petroleum ether/ethyl acetate
80:20 to 50:50) to afford the product 12b (250 mg, 43%) as a mixture
of two diastereoisomers 60:40 and as an amorphous white solid. 1H
NMR (400 MHz; CDCl3): dH 9.97 (br s, 0.4H), 9.95 (br s, 0.6H), 7.47 (d,
J¼7.6 Hz, 0.6H), 7.41 (d, J¼7.6 Hz, 0.4H), 6.94 (d, J¼7.6 Hz, 1H), 4.26
(dqd, J¼12.3, 6.2, 3.6 Hz, 0.4H), 3.74 (dqd, J¼12.5, 6.3, 2.4 Hz, 0.6H),
3.38e3.28 (m, 1H), 2.90 (dd, J¼16.5, 6.4 Hz, 0.6H), 2.79 (dd, J¼16.5,
6.9 Hz, 0.4H), 2.61e2.54 (m, 1H), 2.53 (s, 1.8H), 2.52 (s, 1.2H),
2.25e2.12 (m, 1H), 2.05 (ddd, J¼14.9, 11.3, 4.6 Hz, 0.4H), 1.94 (ddd,
J¼14.9, 11.3, 4.6 Hz, 0.6H); 13C NMR (100 MHz; CDCl3): dC major di-
astereoisomer: 170.4, 157.7, 149.7, 136.7, 123.7 (q, J¼279 Hz), 118.3,
115.3, 55.5 (q, J¼33 Hz), 36.7, 34.2, 31.1, 23.5; minor diastereoisomer:
169.7, 157.7, 149.7, 136.7, 123.8 (q, J¼279 Hz), 118.5, 117.4, 54.4 (q,
1435, 1370, 1274, 1131; HRMS (EIþ): calculated (found) for
35
C
H ClF4N2O2: 324.0653 (not found).
13 13
4.3.19. 6,8-Dichloro-4-(2-chloro-3,3,3-trifluoropropyl)-1,2,3,4-
tetrahydroquinolin-2-one (12f). Following general procedure B with
11f (830 mg,1.77 mmol) in chlorobenzene. The residue was purified
by silica gel column chromatography (petroleum ether/diethyl
ether 80:20 to 50:50) to afford the product 12f (282 mg, 46%) as
a mixture of two diastereoisomers 65:35 and as an amorphous
white solid. Mp¼192 ꢁC. 1H NMR (400 MHz; CDCl3): dH 9.87 (br s,
0.35H), 9.81 (s, 0.65H), 7.13 (d, J¼2.0 Hz, 0.65H), 7.12 (d, J¼2.0 Hz,
0.35H), 6.88 (d, J¼2.0 Hz, 0.65H), 6.86 (d, J¼2.0 Hz, 0.35H),
4.33e4.23 (m, 0.35H), 4.16e4.04 (m, 0.65H), 3.85e3.78 (m, 0.35H),
3.78e3.72 (m, 0.65H), 2.87e2.64 (m, 2H), 2.27 (ddd, J¼14.7, 8.6,
3.0 Hz, 0.7H), 2.13e1.96 (m, 1.3H); 13C NMR (100 MHz; CDCl3): dC
major diastereoisomer: 170.9, 138.9, 134.6, 133.9, 124.3, 123.7 (q,
J¼279 Hz), 122.3, 115.5, 55.3 (q, J¼34 Hz), 36.2, 35.8, 30.2; minor
diastereoisomer: 170.2, 138.7, 134.5, 133.9, 124.3, 123.8 (q,
J¼279 Hz), 122.1, 115.0, 54.3 (q, J¼34 Hz), 32.7, 31.9, 29.8; IR (CCl4):
J¼33 Hz), 34.4, 34.0, 31.0, 23.4; IR (CCl4): nmax 3406, 2929, 1711, 1455,
35
1268, 1131; HRMS (EIþ): calculated (found) for C12
292.0590 (292.0603).
H
ClF3N2O:
12
4.3.16. 4-(2-Chloro-3,3,3-trifluoropropyl)-6-methoxy-2-methyl-
1,2,3,4-tetrahydroisoquinolin-1-one (12c). Following general pro-
cedure B with 11c (500 mg, 1.13 mmol) in chlorobenzene. The resi-
due was purified by silica gel column chromatography (petroleum
ether/ethyl acetate 80:20) to afford the product 12c (190 mg, 51%) as
a mixture of two diastereoisomers 85:15 and as an amorphous white
solid. Mp¼98e102 ꢁC. 1H NMR (400 MHz; CDCl3): dH major di-
astereoisomer: 8.09 (d, J¼8.7 Hz, 1H), 6.92 (dd, J¼8.7, 2.5 Hz, 1H),
6.78 (d, J¼2.5 Hz, 1H), 3.99 (dd, J¼12.7, 4.1 Hz, 1H), 3.92e3.80 (m,
Please cite this article in press as: Salomon, P.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.11.021

8
P. Salomon et al. / Tetrahedron xxx (2014) 1e10
nmax 3409, 1716, 1693, 1600, 1575, 1260, 1174, 1129; HRMS (EIþ):
silica gel column chromatography (petroleum ether/diethyl ether
80:20) to afford the product 13c (625 mg, 98%) as an orange oil. 1H
NMR (400 MHz; CDCl3): dH 7.46e7.32 (m, 4H), 7.31e7.17 (m, 6H),
4.07 (dqd, J¼10.0, 6.7, 3.3 Hz, 1H), 2.27 (t, J¼7.5 Hz, 2H), 2.04e1.93
35
calculated (found) for C
H Cl3F3NO: 344.9702 (344.9711).
9
12
4.3.20. 4-(2-Chloro-3,3,3-trifluoropropyl)-6-methoxy-1,2,3,4-
tetrahydronaphthalen-1-one (12g). Following general procedure B
with 11g (850 mg, 2 mmol) in ethyl acetate. The residue was pu-
rified by silica gel column chromatography (petroleum ether/ethyl
acetate 90:10) to afford the product 12g (390 mg, 64%) as a mixture
of two diastereoisomers 85:15 and as an amorphous white solid. 1H
NMR (400 MHz; CDCl3): dH 8.03 (d, J¼8.7 Hz, 1H), 6.87 (dd, J¼8.7,
2.4 Hz, 1H), 6.78 (d, J¼2.4 Hz, 1H), 4.01 (dqd, J¼12.8, 6.5, 2.7 Hz, 1H),
3.86 (s, 3H), 3.31e3.22 (m, 1H), 2.73e2.56 (m, 2H), 2.46e2.25 (m,
2H), 2.13e2.00 (m, 2H); 13C NMR (100 MHz; CDCl3): dC 195.6, 163.6,
146.9, 130.8, 125.3, 124.0 (q, J¼279 Hz), 133.3, 112.9, 56.1 (q,
J¼33 Hz), 55.4, 35.8, 34.1, 33.6, 28.2; IR (CCl4): nmax 2929, 1685,
(m,1H),1.86e1.72 (m, 1H),1.72e1.58 (m, 3H),1.49e1.19 (m,13H); 13
C
NMR (100 MHz; CDCl3): dC 173.2, 142.9 (2C), 130.4e125.3 (m, 10C),
124.1 (q, J¼280 Hz), 57.6 (q, J¼33 Hz), 35.2, 30.8, 29.3 (3C), 29.1 (2C),
28.6, 25.5 (2C); IR (CCl4): nmax 2928, 2856, 1680, 1493, 1371, 1269,
35
1178, 1129; HRMS (EIþ): calculated (found) for C25
453.2046 (453.2035).
H
ClF3NO:
31
4.3.24. 3-(3,3-Difluoroprop-2-en-1-yl)-1-methanesulfonyl-2,3-
dihydro-1H-indole (14a). Following general procedure C with 12a
(80 mg, 0.24 mmol). 14a (64 mg, 95%) was obtained as a white solid
without purification. 1H NMR (400 MHz; CDCl3): dH 7.45 (d, J¼8.1 Hz,
1H), 7.33e7.22 (m, 2H), 7.11 (td, J¼7.5, 0.9 Hz, 1H), 4.21 (dtd, J¼24.7,
8.0, 2.2 Hz, 1H), 4.10 (dd, J¼10.4, 9.2 Hz, 1H), 3.69 (dd, J¼10.4, 5.9 Hz,
1H), 3.50e3.41 (m, 1H), 2.93 (s, 3H), 2.50e2.40 (m, 1H), 2.36e2.26
(m, 1H); 13C NMR (100 MHz; CDCl3): dC 157.1 (t, J¼288 Hz), 141.8,
133.3, 128.7, 124.6, 123.7, 113.5, 74.7 (dd, J¼23, 20 Hz), 55.3, 39.7 (t,
J¼2 Hz), 34.5, 27.3 (d, J¼4 Hz); IR (CCl4): nmax 1746, 1480, 1460, 1364,
1166; HRMS (EIþ): calculated (found) for C12H13F2NO2: 273.0635
(273.0640).
1599, 1269, 1256, 1129; HRMS (EIþ): calculated (found) for
35
C
H ClF3O2: 306.0634 (306.0638).
14 14
4.3.21. Dimethyl (4-chloro-5,5,5-trifluoropentyl)phosphonate (13a). A
magnetically round bottom flask was charged with 11h (300 mg,
0.77 mmol), an aqueous solution of hypophosphorous acid (50% wt)
(504 mg, 3.85 mmol), triethylamine (429 mg, 4.25 mmol), 7.6 mL of
dioxane. The solution was refluxed under a flow of nitrogen for 5 min
then AIBN (13 mg, 0.08 mmol) was added every hour until TLC
showed total conversion of the starting xanthate. The mixture was
cooled to room temperature and ethyl acetate was added. The layers
were partitioned and the aqueous one was extracted twice with
ethyl acetate. The combined organic layers were washed with brine
and dried over anhydrous MgSO4. The residue was purified by silica
gel column chromatography (DCM/methanol 95:5) to afford the
product 13a (188 mg, 93%) as an orange oil. 1H NMR (400 MHz;
CDCl3): dH 4.06 (dqd, J¼9.8, 6.6, 3.2 Hz, 1H), 3.74 (s, 3H), 3.71 (s, 3H),
2.14e1.68 (m, 6H); 13C NMR (100 MHz; CDCl3): dC 124.0 (q,
J¼279 Hz), 56.9 (q, J¼33 Hz), 52.4 (d, J¼7 Hz), 52.4 (d, J¼7 Hz), 31.4
(d, J¼15 Hz), 23.8 (d, J¼143 Hz), 19.0 (d, J¼5 Hz); IR (CCl4): nmax 3685,
4.3.25. 4-(3,3-Difluoroprop-2-en-1-yl)-7-methyl-1,2,3,4-tetrahydro-
1,8-naphthyridin-2-one (14b). Following general procedure C with
12b (50.0 mg, 0.17 mmol). 14b (40.4 mg, 100%) was obtained as
a colorless oil without purification. 1H NMR (400 MHz; CDCl3): dH
8.51 (br s, 1H), 7.35 (d, J¼7.6 Hz, 1H), 6.82 (d, J¼7.6 Hz, 1H), 4.12 (dtd,
J¼24.5, 8.0, 2.0 Hz, 1H), 3.01e2.93 (m, 1H), 2.77 (dd, J¼16.4, 6.3 Hz,
1H), 2.56 (dd, J¼16.4, 4.6 Hz, 1H), 2.48 (s, 3H), 2.33e2.20 (m, 2H); 13
C
NMR (100 MHz; CDCl3): dC 170.1, 158.4 (t, J¼287 Hz), 156.6, 149.5,
136.12, 118.2, 117.4, 74.6 (dd, J¼24, 21 Hz), 35.8, 34.9 (t, J¼2 Hz), 27.0
(d, J¼4 Hz), 23.6; IR (CCl4): nmax 3408, 2927, 1745, 1709, 1608, 1456,
1350, 1275, 1156; HRMS (EIþ): calculated (found) for C12H12F2N2O:
238.0918 (238.0925).
3453, 2953, 1267, 1180, 1126, 1062; HRMS (EIþ): calculated (found)
35
for C7H ClF3O3P: 268.0243 (not found).
13
4.3.26. 4-(3,3-Difluoroprop-2-en-1-yl)-6-methoxy-2-methyl-1,2,3,4-
tetrahydroisoquinolin-1-one (14c). Following general procedure C
with 12c (95 mg, 0.29 mmol). 14c (75.1 mg, 97%) was obtained as
a pale yellow oil without purification. 1H NMR (400 MHz; CDCl3): dH
8.02 (d, J¼8.7 Hz, 1H), 6.84 (dd, J¼8.7, 2.5 Hz, 1H), 6.63 (d, J¼2.5 Hz,
1H), 4.17 (dddd, J¼24.8, 9.3, 7.2, 2.2 Hz, 1H), 3.82 (s, 3H), 3.73 (dd,
J¼12.6, 4.4 Hz, 1H), 3.28 (dd, J¼12.6, 3.3 Hz, 1H), 3.10 (s, 3H),
2.84e2.76 (m, 1H), 2.42e2.31 (m, 1H), 2.30e2.19 (m, 1H); 13C NMR
(100 MHz; CDCl3): dC 164.25, 162.21, 157.0 (dd, J¼288, 287 Hz), 142.7,
130.5, 121.5, 112.5, 111.8, 75.4 (dd, J¼23, 21 Hz), 55.3, 51.3, 37.9 (t,
J¼2 Hz), 35.14, 26.5 (d, J¼4 Hz); IR (CCl4): nmax 2930,1745,1660,1608,
1485, 1259; HRMS (EIþ): calculated (found) for C14H15F2NO2:
267.1071 (267.1069).
4.3.22. 1-[(4-Chloro-5,5,5-trifluoropentyl)oxy]-4-methoxybenzene
(13b). A magnetically round bottom flask was charged with 11i
(670 mg, 1.66 mmol), tris(trimethylsilyl)silane (496 mg, 2 mmol) in
16 mL of a 1:1 solution of toluene and cyclohexane. The solution was
refluxed under a flow of nitrogen for 5 min then AIBN (26 mg,
0.16 mmol) was added. After 30 min, the mixture was cooled to room
temperature and the solvent evaporated under reduced pressure.
The residue was purified by silica gel column chromatography (pe-
troleum ether/diethyl ether 96:4) to afford the product 13b (230 mg,
47%) as a colorless oil. 1H NMR (400 MHz; CDCl3): dH 6.84 (s, 4H),
4.25e4.14 (m, 1H), 4.03e3.91 (m, 2H), 3.77 (s, 3H), 2.33e2.22 (m,
1H), 2.17e2.05 (m, 1H), 2.03e1.88 (m, 2H); 13C NMR (100 MHz;
CDCl3): dC 154.0, 152.9, 124.14 (q, J¼279 Hz), 115.4 (2C), 114.7 (2C),
67.3, 57.4 (q, J¼33 Hz), 55.8, 28.1, 25.6; IR (CCl4): nmax 2935, 1508,
4.3.27. 6,8-Dichloro-4-(3,3-difluoroprop-2-en-1-yl)-1,2,3,4-
tetrahydroquinolin-2-one (14f). Following general procedure C with
12f (130 mg, 0.38 mmol). The residue was purified by silica gel col-
umn chromatography (petroleum ether/diethyl ether 70:30) to afford
14f (55 mg, 50%) as an amorphous white solid. Mp: 136e138 ꢁC. 1H
NMR (400 MHz; CDCl3): dH 9.65 (br s, 1H), 7.09 (d, J¼2.0 Hz, 1H), 6.82
(d, J¼2.0 Hz, 1H), 4.18 (dtd, J¼24.5, 8.2, 2.1 Hz, 1H), 3.47e3.40 (m, 1H),
2.77e2.64 (m, 2H), 2.32e2.13 (m, 2H); 13C NMR (100 MHz; CDCl3): dC
171.0, 155.8 (q, J¼288 Hz), 138.7, 134.1, 133.9, 124.0, 122.5, 114.9, 74.5
(dd, J¼23, 21 Hz), 34.2, 33.4, 25.7; IR (CCl4): nmax 2952, 1745, 1691,
1272, 1231, 1172, 1131; HRMS (EIþ): calculated (found) for
35
C
H
ClF3O2S2: 282.0634 (282.0632).
15 18
4.3.23. 12-Chloro-13,13,13-trifluoro-N,N-diphenyltridecanamide
(13c). A magnetically round bottom flask was charged with 11j
(803 mg, 1.4 mmol), an aqueous solution of hypophosphorous acid
(50% wt) (924 mg, 7.0 mmol), triethylamine (777 mg, 7.7 mmol) in
14 mL of dioxane. The solution was refluxed under a flow of nitrogen
for 5 min then AIBN (23 mg, 0.14 mmol) was added every hour until
TLC showed total conversion of the starting xanthate. The mixture
was cooled to room temperature and ethyl acetate was added. The
layers were partitioned and the aqueous one was extracted twice
with ethyl acetate. The combined organic layers were washed with
brine and dried over anhydrous MgSO4. The residue was purified by
1601, 1578, 1394, 1373, 1317; HRMS (EIþ): calculated (found) for
35
C
12
H
Cl2F2NO: 291.0029 (291.0024).
9
4.3.28. 3-(3,3-Difluoroprop-2-en-1-yl)-6-fluoro-1H,2H,3H-pyrrolo
[2,3-b]pyridine (16a). Following general procedure C with 15a25a
Please cite this article in press as: Salomon, P.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.11.021

P. Salomon et al. / Tetrahedron xxx (2014) 1e10
9
(110 mg, 0.41 mmol). The residue was purified by silica gel column
chromatography (petroleum ether/diethyl ether 70:30) to afford 16a
(75 mg, 88%) as a colorless oil. 1H NMR (400 MHz; CDCl3): dH
7.30e7.22 (m, 1H), 6.07 (dd, J¼7.7, 1.0 Hz, 1H), 4.67 (br s, 1H), 4.17
(dtd, J¼24.9, 8.0, 2.4 Hz, 1H), 3.82e3.72 (m, 1H), 3.40e3.29 (m, 2H),
2.41e2.22 (m, 2H); 13C NMR (100 MHz; CDCl3): dC 163.9 (d,
J¼236 Hz), 163.1 (d, J¼18 Hz), 157.0 (dd, J¼288, 287 Hz), 134.6 (d,
J¼9 Hz), 120.1 (d, J¼5 Hz), 95.3 (d, J¼37 Hz), 75.0 (dd, J¼23, 21 Hz),
50.3, 39.1 (t, J¼2 Hz), 27.2 (d, J¼4 Hz); 13C NMR (100 MHz; CDCl3): dC
163.9 (d, J¼236 Hz), 163.1 (d, J¼18 Hz), 157.0 (dd, J¼288, 287 Hz),
134.6 (d, J¼9 Hz), 120.1 (d, J¼5 Hz), 95.3 (d, J¼37 Hz), 75.0 (dd, J¼23,
21 Hz), 50.3, 39.1 (t, J¼2 Hz), 27.2 (d, J¼4 Hz); IR (CCl4): nmax 3444,
with 17 (205 mg, 0.73 mmol), xanthate 1 (260.0 mg, 1.09 mmol),
ethyl acetate (1.1 mL) and the solution was heated to reflux. DLP
(58 mg, 0.14 mmol) was then added by portion every hour until total
consumption of the starting olefin was observed. The crude mixture
was passed through a pad of basic Al2O3, the solvent evaporated and
the residue was purified on flash column chromatography (petro-
leum ether/ethyl acetate 95:5) to afford compound 18 (158 mg, 75%)
as two isomers in a 3.5:1 ratio. 1H NMR (400 MHz; CDCl3): dH major
isomer: 5.68 (t, J¼6.8 Hz,1H), 4.74 (s,1H), 4.14e4.04 (m,1H), 3.66 (d,
J¼11.2 Hz, 2H), 3.50 (d, J¼10.8 Hz, 2H) 2.79 (ddd, J¼15.6, 6.8, 3.6 Hz,
1H), 2.58 (ddd, J¼15.6, 9.6, 7.2 Hz, 1H), 2.10 (s, 3H), 1.76 (s, 3H), 1.22
(s, 3H), 0.74 (s, 3H); minor isomer: 5.45 (t, J¼7.2 Hz,1H), 5.05 (s, 1H),
4.16e4.05 (m, 1H), 3.69e3.62 (m, 2H), 3.50 (d, J¼11.2 Hz, 2H), 2.91
(dddd, J¼15.2 Hz, 7.6, 3.6, 1.2 Hz, 1H), 2.57 (dddd, J¼15.2, 10.0, 7.6
1.2 Hz, 1H), 1.85 (d, J¼1.2 Hz, 3H), 1.22 (s, 3H), 0.75 (s, 3H); 13C NMR
(100 MHz; CDCl3): dC major isomer: 137.6, 124.0 (q, J¼277 Hz), 121.7,
104.1, 77.2 (2C), 56.9 (q, J¼33 Hz), 30.1, 29.5, 22.9, 21.8, 11.7; minor
isomer: 137.8, 124.0 (q, J¼277 Hz), 122.5, 99.4, 77.3 (2C), 57.4 (q,
J¼32 Hz), 30.1, 29.5, 22.9, 21.9, 18.6; IR (CCl4): nmax major isomer:
2958, 2848, 1469, 1394, 1261, 1185, 1128, 1016, 983; minor isomer:
2959, 2851, 1470, 1395, 1365, 1262, 1183, 1127, 1016, 983.
2927, 1746, 1620, 1595, 1445; HRMS (EIþ): calculated (found) for
35
C
10
H
ClF3N2: 214.0718 (214.0722).
9
4.3.29. 1-[4-(3,3-Difluoroprop-2-en-1-yl)-7-fluoro-1,2,3,4-tetrahydro-
1,8-naphthyridin-1-yl]ethan-1-one (16b). Following general pro-
cedure C with 15b26(b) (52 mg, 0.18 mmol). 16b (35 mg, 83%) was
obtained as an amorphous white solid without purification.
Mp¼64e66 ꢁC. 1H NMR (400 MHz; CDCl3): dH 7.25 (t, J¼8.0 Hz, 1H),
6.06 (dd, J¼7.9, 2.4 Hz, 1H), 5.29 (br s,1H), 4.18 (dddd, J¼25.1, 8.6, 7.5,
2.4 Hz,1H), 3.44e3.37 (m, 2H), 2.80e2.73 (m,1H), 2.33e2.15 (m, 2H),
1.94e1.84 (m, 1H), 1.83e1.74 (m, 1H); 13C NMR (100 MHz; CDCl3): dC
162.0 (d, J¼235 Hz), 156.9 (dd, J¼287, 288 Hz), 154.3 (d, J¼17 Hz),
140.0 (d, J¼9 Hz), 114.2 (d, J¼4 Hz), 95.0 (d, J¼37 Hz), 75.5 (dd, J¼23,
21 Hz), 37.7, 34.8, 28.1 (d, J¼4 Hz), 25.0; IR (CCl4): nmax 3447, 3272,
2931,1745,1618,1462,1355,1224; HRMS (EIþ): calculated (found) for
Acknowledgements
We thank Ecole Polytechnique for a scholarship to P.S. and
ꢁ
L’Oreal for a post-doctoral grant to W.K.
C11H11F3N2: 228.0874 (228.0881).
Supplementary data
4.3.30. Dimethyl (5,5-difluoropent-4-en-1-yl)phosphonate (14h).
Following general procedure C with 13a (150 mg, 0.57 mmol). The
residue was purified by silica gel column chromatography (DCM/
methanol 95:5) to afford 14h (98 mg, 80%) as a colorless oil. 1H
NMR (400 MHz; CDCl3): dH 4.10 (dtd, J¼25.2, 7.9, 2.4 Hz, 1H), 3.73
(s, 3H), 3.70 (s, 3H), 2.13e1.98 (m, 2H), 1.79e1.59 (m, 4H); 13C NMR
(100 MHz; CDCl3): dC 156.6 (t, J¼287 Hz), 76.9e76.3 (m), 52.3 (d,
J¼6 Hz, 2C), 23.9 (d, J¼142 Hz), 22.9 (dd, J¼18, 4 Hz), 22.2; IR
(CCl4): nmax 2953, 1747, 1248, 1064, 1036; HRMS (EIþ): calculated
(found) for C7H13F2O3P: 214.0570 (214.0567).
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.11.021.
References and notes
1. (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37,
320; (b) Thayer, A. M. Chem. Eng. News 2006, 84, 15.
2. (a) Cho, E. J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.; Watson, D. A.; Buchwald, S. L.
Science 2010, 328, 1679; (b) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317,
1881; (c) Hiyama, T. Organofluorine Compounds: Chemistry and Applications;
Springer: Berlin, Germany, 2000.
3. (a) Hayashi, S.; Nakai, T.; Ichikawa, N.; Burton, D. J.; Naae, D. G.; Kesling, H. S.
Chem. Lett. 1979, 983; (b) Hayashi, S.; Nakai, T.; Ichikawa, N. Chem. Lett. 1980,
651; (c) Ichikawa, J.; Wada, W.; Okauchi, T.; Minami, T. J. Chem. Soc., Chem.
Commun. 1997, 1537; (d) Yokota, M.; Fujita, D.; Ichikawa, J. Org. Lett. 2007, 9,
4639; (e) Ichikawa, J.; Yokota, M.; Kudo, T.; Umezaki, S. Angew. Chem., Int. Ed.
2008, 47, 4870.
4.3.31. 1-[(5,5-Difluoropent-4-en-1-yl)oxy]-4-methoxybenzene
(14i). Following general procedure C with 13b (210 mg, 0.74 mmol).
The residue was purified by silica gel column chromatography
(petroleum ether/diethyl ether 97:3) to afford the product 14i
(153 mg, 90%) as a colorless oil. 1H NMR (400 MHz; CDCl3): dH 6.83
(s, 4H), 4.19 (dtd, J¼25.3, 7.9, 2.5 Hz, 1H), 3.92 (t, J¼6.2 Hz, 2H), 3.77
(s, 3H), 2.21e2.13 (m, 2H), 1.84 (m, 2H); 13C NMR (100 MHz; CDCl3):
dC 156.4 (dd, J¼287, 285 Hz), 153.9, 153.1, 115.5 (2C), 114.7 (2C),
77.5e77.0 (m), 67.6, 55.8, 29.1 (t, J¼2 Hz), 19.0 (d, J¼4 Hz); IR (CCl4):
4. Motherwell, W. B.; Tozer, M. J.; Ross, B. C. J. Chem. Soc., Chem. Commun. 1989,
1437.
5. (a) McDonald, I. A.; Lacoste, J. M.; Bey, P.; Palfreyman, M. G.; Zreika, M. J. Med.
Chem. 1985, 28, 186; (b) Weintraub, P. M.; Holland, A. K.; Gates, C. A.; Moore, W.
R.; Resvick, R. J.; Bey, P.; Peet, N. P. Biorg. Med. Chem. 2003, 11, 427; (c)
Altenburger, J. M.; Lassalle, G. Y.; Matrougui, M.; Galtier, D.; Jetha, J. C.; Bocskei,
Z.; Berry, C. N.; Lunven, C.; Lorrain, J.; Herault, J. P.; Schaeffer, P.; O’Connor, S. E.;
nmax 2951, 1746, 1509, 1231; HRMS (EIþ): calculated (found) for
Herbert, J. M. Biorg. Med. Chem. 2004, 12, 1713; (d) Pitterna, T.; Boger, M.;
€
35
Maienfisch, P. Chimia 2004, 58, 108.
C
H ClF3O2S2: 228.0962 (228.0964).
15 18
6. (a) Faqua, S. A.; Duncan, W. G.; Silverstein, R. M. Tetrahedron Lett. 1964, 5, 1461;
(b) Faqua, S. A.; Duncan, W. G.; Silverstein, R. M. J. Org. Chem. 1965, 30, 1027; (c)
Naae, D. G.; Burton, D. J. J. Fluorine Chem. 1971, 1, 123.
7. (a) Obayashi, M.; Ito, E.; Matsui, K.; Kondo, K. Tetrahedron Lett. 1982, 23, 2323;
(b) Edwards, M. L.; Stemerick, D. M.; Jarvi, E. T.; Matthews, D. P.; McCarthy, J. R.
Tetrahedron Lett. 1990, 31, 5571.
8. (a) Sabol, J. S.; McCarthy, J. R. Tetrahedron Lett. 1992, 33, 3101; (b) Prakash, G. K.
S.; Wang, Y.; Hu, J.; Olah, G. A. J. Fluorine Chem. 2005, 126, 1361.
9. Zhao, Y.; Huang, W.; Zhu, L.; Hu, J. Org. Lett. 2010, 12, 1444.
10. (a) Cohen, S. G.; Wolosinski, H. T.; Scheuer, P. J. J. Am. Chem. Soc. 1949, 71, 3439;
(b) Polishchuk, V. R.; German, L. S.; Knunyants, I. L. Russ. Chem. Bull. 1971, 20,
715; (c) Hagooly, A.; Ben-David, I.; Rozen, S. J. Org. Chem. 2002, 67, 8430; (d)
Hagooly, A.; Rozen, S. J. Fluorine Chem. 2005, 126, 1239.
4.3.32. 13,13-Difluoro-N,N-diphenyltridec-12-enamide (14j). Following
general procedure C with 13c (225 mg, 0.5 mmol). The residue was
purified by silica gel column chromatography (petroleum ether/
diethyl ether 80:20) to afford the product 14j (100 mg, 50%) as a col-
orless oil. 1H NMR (400 MHz; CDCl3): dH 7.47e7.31 (m, 4H), 7.31e7.19
(m, 6H), 4.13 (dtd, J¼25.6, 7.9, 2.7 Hz, 1H), 2.27 (t, J¼7.5 Hz, 2H),
2.00e1.93 (m, 2H), 1.66 (q, J¼7.2 Hz, 2H), 1.40e1.19 (m, 14H); 13C NMR
(100 MHz; CDCl3): dC 173.2,156.1 (t, J¼285 Hz),142.9 (2C),131.5e123.7
(10C), 78.0 (t, J¼21 Hz), 35.2, 29.4, 29.3 (2C), 29.2 (2C), 28.8, 25.5, 22.1
(2C); IR (CCl4): nmax 2928, 2856, 1746, 1680, 1594, 1493, 1369, 1271;
HRMS (EIþ): calculated (found) for C25H31F2NO: 399.2374 (399.2371).
11. Prakash, G. K. S.; Hu, J.; Wang, Y.; Olah, G. A. Angew. Chem., Int. Ed. 2004, 43,
5203.
12. (a) Reutrakul, V.; Thongpaisanwong, T.; Tuchinda, P.; Kuhakarn, C.; Pohmakotr,
M. J. Org. Chem. 2004, 69, 6913; (b) Reutrakul, V.; Rukachaisirikul, V. Tetrahe-
dron Lett. 1983, 24, 725; (c) Kim, K.-I.; McCarthy, J. R. Tetrahedron Lett. 1996, 37,
3223; (d) Pohmakotr, M.; Boonkitpattarakul, K.; Ieawsuwan, W.; Jarussophon,
S.; Duangdee, N.; Tuchinda, P.; Reutrakul, V. Tetrahedron 2006, 62, 5973.
4.3.33. 2-(5-Chloro-6,6,6-trifluorohex-2-en-2-yl)-5,5-dimethyl-1,3-
dioxane(18). A magnetically stirred round bottom flask was charged
Please cite this article in press as: Salomon, P.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.11.021

10
P. Salomon et al. / Tetrahedron xxx (2014) 1e10
^
13. (a) Sauvetre, R.; Normant, J. F. Tetrahedron Lett. 1981, 22, 957; (b) Tanaka, K.;
Nakai, T.; Ishikawa, N. Tetrahedron Lett. 1978, 19, 4809; (c) Ichikawa, J.; Sonoda,
T.; Kobayashi, H. Tetrahedron Lett. 1989, 30, 1641; (d) Ichikawa, J.; Minami, T.;
Sonoda, T.; Kobayashi, H. Tetrahedron Lett. 1992, 33, 3779; (e) Ichikawa, J. J.
Fluorine Chem. 2000, 105, 257; (f) Percy, J. M. Tetrahedron Lett. 1990, 31, 3931; (g)
Patel, S. T.; Percy, J. M. J. Chem. Soc., Chem. Commun. 1992, 1477; (h) Bennet, A. J.;
Percy, J. M.; Rock, M. H. Synlett 1992, ; (i) Lee, J.; Tsukazaki, M.; Snieckus, V.
Tetrahedron Lett. 1993, 34, 415.
Commun. 1996, 2511; (j) Gagosz, F.; Zard, S. Z. Org. Lett. 2003, 5, 2655; (k) Gagosz,
F.; Zard, S. Z. Org. Synth. 2007, 84, 32; (l) Salomon, P.; Zard, S. Z. Org. Lett. 2014, 16,
1482; (m) Jean-Baptiste, L.; Yemets, S.; Legay, R.; Lequeux, T. J. Org. Chem. 2006, 71,
2352; (n) Salomon, P.; Zard, S. Z. Org. Lett. 2014, 16, 2926.
18. (a) Qacemi, M. E.; Ricard, L.; Zard, S. Z. Chem. Commun. 2006, 4422; (b)
Cholleton, N.; Zard, S. Z. Tetrahedron Lett. 1998, 39, 7295; (c) Binot, G.; Zard, S. Z.
Tetrahedron Lett. 2005, 46, 7503; (d) Quiclet-Sire, B.; Tran, N. D. M.; Zard, S. Z.
ꢁ
Org. Lett. 2012, 14, 5514; (e) Bacque, E.; El Qacemi, M.; Zard, S. Z. Org. Lett. 2004,
^
14. (a) Gillet, J. P.; Sauvetre, R.; Normant, J. F. Synthesis 1986, 1986, 538; (b) Tellier,
6, 3671; (f) Petit, L.; Zard, S. Z. Chem. Commun. 2010, 5148.
^
ꢁ
F.; Sauvetre, R.; Normant, J. F.; Dromzee, Y.; Jeannin, Y. Organomet. Chem. 1987,
19. Bacque, E.; El Qacemi, M.; Zard, S. Z. Heterocycles 2012, 84, 291.
331, 281; (c) Raghavanpillai, A.; Burton, D. J. J. Org. Chem. 2004, 69, 7083; (d) Shi,
G.-q.; Huang, X.-h.; Zhang, F.-J. Tetrahedron Lett. 1995, 36, 6305.
20. (a) Boivin, J.; Jrad, R.; Juge, S.; Nguyen, V. T. Org. Lett. 2003, 5, 1645; (b) Barton,
D. H. R.; Jang, D. O.; Jaszberenyi, J. Cs. Tetrahedron Lett. 1992, 33, 5709; (c)
Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. Cs. J. Org. Chem. 1993, 58, 6838; (d)
Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. Cs. Tetrahedron Lett. 1992, 33, 2311;
(e) Barton, D. H. R.; Parekh, S. I.; Tse, C.-L. Tetrahedron Lett. 1993, 34, 2733.
21. Chatgilialoglu, C. Chem. Rev. 1995, 95, 1229.
ꢁ
ꢁ
ꢁ
ꢁ
15. (a) Begue, J.-P.; Bonnet-Delpon, D.; Rock, M. H. Synlett 1995, 659; (b) Begue, J.-P.;
Bonnet-Delpon, D.; Rock, M. H. Tetrahedron Lett. 1995, 36, 5003; (c) Begue, J.-P.;
Bonnet-Delpon, D.; Rock, M. H. J. Chem. Soc., Perkin Trans. 11996, 1409; (d) Tellier,
^
F.; Baudry, M.; Sauvetre, R. Tetrahedron Lett. 1997, 38, 5989; (e) Uneyama, K.;
Kato, T. Tetrahedron Lett. 1998, 39, 587; (f) Ichikawa, J.; Fukui, H.; Ishibashi, Y. J.
Org. Chem. 2003, 68, 7800.
16. Tournier, L.; Zard, S. Z. Tetrahedron Lett. 2005, 46, 455.
22. (a) Charrier, N.; Quiclet-Sire, B.; Zard, S. Z. J. Am. Chem. Soc. 2008, 130, 8898; (b)
Braun, M.-G.; Quiclet-Sire, B.; Zard, S. Z. J. Am. Chem. Soc. 2011, 133, 15954; (c)
Debien, L.; Quiclet-Sire, B.; Zard, S. Z. Org. Lett. 2011, 13, 5676; (d) Debien, L.;
Quiclet-Sire, B.; Zard, S. S. Org. Lett. 2012, 14, 5118; (e) Debien, L.; Braun, M.-G.;
Quiclet-Sire, B.; Zard, S. Z. Org. Lett. 2013, 15, 6250.
17. For reviews, see: (a) Zard, S. Z. Angew. Chem., Int. Ed. 1997, 36, 672; (b) Quiclet-Sire,
B.; Zard, S. Z. Chem.dEur. J. 2006, 12, 6002; (c) Quiclet-Sire, B.; Zard, S. Z. Top. Curr.
Chem. 2006, 264, 201; (d) Quiclet-Sire, B.; Zard, S. Z. Pure Appl. Chem. 2011, 83, 519;
(e) For an account of the discovery of this process, see: Zard, S. Z. Aust. J. Chem.
2006, 59, 663; (f) For applications to the synthesis of heteroaromatics, see: El
Qacemi, M.; Petit, L.; Quiclet-Sire, B.; Zard, S. Z. Org. Biomol. Chem. 2012, 10, 5707
For the synthesis of organofluorine compounds, see; (g) Bertrand, F.; Pevere, V.;
Quiclet-Sire, B.; Zard, S. Z. Org. Lett. 2001, 3, 1069; (h) Li, S.; Zard, S. Z. Org. Lett.
2013, 15, 5898; (i) Denieul, M.-P.; Quiclet-Sire, B.; Zard, S. Z. J. Chem. Soc., Chem.
23. Evaporation of the crude mixture leads to decomposition of the desired
product.
24. Ly, T.-M.; Quiclet-Sire, B.; Sortais, B.; Zard, S. Z. Tetrahedron Lett. 1999, 40, 2533.
25. (a) Obtained from 12d after deacetylation with K2CO3 (3 equiv) in refluxing
methanol (3 M) for 1 h (98% yield). (b) Obtained from 12e after deacetylation
with K2CO3 (3 equiv) in refluxing methanol (3 M) for 1 h (100% yield).
Please cite this article in press as: Salomon, P.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.11.021