Highly stereoselective approach to 3-fluoroalkylated (E)-hex-3-ene-1,5- diyne derivatives via an addition-elimination reaction

Article abstract of DOI:10.1016/j.jfluchem.2013.09.010

Palladium(0)-catalyzed Sonogashira cross-coupling reaction of 2-fluoroalkylated (Z)-2-fluoro-1-iodoethene, which is easily prepared from commercially available polyfluorinated alcohols in facile three steps, with terminal alkynes in DMF at room temperature for 24 h took place stereospecifically to give the corresponding 1-fluoroalkylated (Z)-1-fluorobut-1-en-3-yne derivatives in good to excellent yield. Thus obtained fluoroalkylated 1-fluoroenynes were effectively subjected to addition-elimination reaction with various alkynyllithiums at room temperature, leading to 3-fluoroalkylated hex-3-ene-1,5-diyne derivatives in good to high yields with an excellent E selectivity.

Full text of DOI:10.1016/j.jfluchem.2013.09.010

Accepted Manuscript
Title: Highly stereoselective approach to 3-fluoroalkylated
(E)-hex-3-ene-1,5-diyne derivatives via an
addition-elimination reaction
Author: Tsutomu Konno Misato Kishi Takashi Ishihara
Shigeyuki Yamada
PII:
S0022-1139(13)00322-9
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2013.09.010
FLUOR 8197
To appear in:
FLUOR
Received date:
Revised date:
Accepted date:
4-9-2013
19-9-2013
19-9-2013
Please cite this article as: T. Konno, M. Kishi, T. Ishihara, S. Yamada, Highly
stereoselective approach to 3-fluoroalkylated (E)-hex-3-ene-1,5-diyne derivatives
via an addition-elimination reaction, Journal of Fluorine Chemistry (2013),
http://dx.doi.org/10.1016/j.jfluchem.2013.09.010
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Graphical Abstract
Research Highlights
•
Fluoroalkylated cis-enediynes are prepared via the highly stereoselective addition-elimination
reaction.
•
•
The stereoselectivity is approximately (E)/(Z) = >95/5
Various cis-enediynes are prepared only in 5 steps.
Page 1 of 19

Highly stereoselective approach to 3-fluoroalkylated (E)-hex-3-ene-1,5-
diyne derivatives via an addition-elimination reaction
Tsutomu Konno,*a Misato Kishi,a Takashi Ishihara,a and Shigeyuki Yamadab
aDepartment of Chemistry and Materials Technology, Kyoto Institute of Technology,
Matsugasaki, Sakyo-ku, Kyoto 606-0962, Japan
bDepartment of Applied Chemistry, Graduate School of Engineering, Tokyo University of
Agriculture and Technology, 2-24-16, Nakamachi, Koganei 184-8588, Japan
Abstract: Palladium(0)-catalyzed Sonogashira cross-coupling reaction of 2-fluoroalkylated (Z)-2-
fluoro-1-iodoethene, which is easily prepared from commercially available polyfluorinated alcohols
in facile three steps, with terminal alkynes in DMF at room temperature for 24 h took place
stereospecifically to give the corresponding 1-fluoroalkylated (Z)-1-fluorobut-1-en-3-yne
derivatives in good to excellent yield. Thus obtained fluoroalkylated 1-fluoroenynes were
effectively subjected to addition-elimination reaction with various alkynyllithiums at room
temperature, leading to 3-fluoroalkylated hex-3-ene-1,5-diyne derivatives in good to high yields
with an excellent E selectivity.
Keyword : Addition-elimination reaction, Fluorinated alkenes, Fluoroalkylated enediyne
compounds, Fluorine-containing enyne compounds, Alkynyllithiums
Page 2 of 19

1. Introduction
cis-Enediyne structures have been frequently found in natural products as antitumor active
compounds, such as Esperamicin A1 and Dynemicin A [1], whose biological activity is derived
from the formation of p-benzyne (1,4-dehydrobenzene diradical) via Bergman cycloaromatization
of the enediyne unit [2]. Thus, the generated diradical can abstract hydrogen atoms from the two
strands of the DNA duplex, causing double strand DNA cleavage and subsequent apoptosis, that is,
self-programmed cell death [3]. In addition, the cis-isomers are also recognized in a synthetic
organic chemistry as extremely useful precursors for the construction of aromatic ring by an
electrocyclization, which are frequently used for the preparation of polyaromatic hydrocarbons
(PAHs) [4]. Therefore, it is not surprising that numerous synthetic approaches to non-fluorinated
enediyne compounds have been developed so far. Nevertheless, there have been quite a limited
number of studies on the synthesis of fluoroalkylated enediyne molecules (Figure 1) [5, 6], though
the introduction of fluorine atom(s) into organic molecules very often changes their physical as well
as chemical characteristics significantly, resulting in the discovery of new materials with unique
physical properties [7].
Rf
H
Figure 1. cis-3-Fluoroalkyl-hex-3-ene-1,5-diyne compounds
Very recently, we developed efficient synthetic approaches to stereo-defined CF3-substituted
trans- and cis-enediyne compounds from the CF3-containing diyne via a highly regio- and
stereoselective carbocupration and hydrostannation reactions (Scheme 1, Path A) [8]. In the course
of our continuous studies on more practical synthesis of such fluoroalkylated enediynes, we wish to
report herein an alternative and facile synthetic methods for the preparation of such fluoroalkylated
enediyne compounds through
a
nucleophilic addition-elimination reaction of various
alkynyllithiums toward fluorinated alkenes in detail (Scheme 1, Path B) [9].
Page 3 of 19

R1
Previous works
(Path A)
F3C
trans-
via
RfCF2CH2OH
Carbocupration
enediynes
R2
H
Elimination
of HF
F3C
R1
3 steps
(Ref. [10])
R3
F3C
(Rf = CF3)
via
cis-
enediynes
Hydrostannation
Rf
H
R1
H
Rf
H
I
Sonogashira
Cross-coupling
F
F
R3
R1
R1
R1
R4
Li
Rf
H
Rf
and/or
Addition-elimination
reaction
H
R4
R1
R4
Minor isomer
This work
(Path B)
Major isomer
Scheme 1. Synthetic outline for fluoroalkylated enediyne derivatives
2. Results and discussion
Initially, we started with a preparation of precursors for fluoroalkylated enediyne derivatives, i.e. 1-
fluoroalkylated (Z)-1-fluoro-1-en-3-ynes 3-5, through Pd(0)-catalyzed Sonogashira cross-coupling
reaction of polyfluorinated vinyl iodide 1 with terminal alkynes 2 according to the method
developed by our research group [8, 10], and the results are shown in Scheme 2. Thus,
commercially available polyfluorinated alcohols [11] were treated with p-toluenesulfonyl chloride
and NaOH at room temperature to give the corresponding tosylates in quantitative yields, which
were subjected to NaI/diethyleneglycol at room temperature, followed by distillation, affording
polyfluoroalkyl iodides. Then, the iodides underwent a smooth stereoselective ! -elimination
reaction by KOH in DMSO, leading to the 2-fluoroalkylated 2-fluoro-1-iodoethenes 1 in good
yields. Finally, on treating the iodides 1 with 1.2 equiv of terminal acetylene 2 in the presence of 5
mol% of Pd(OAc)2, 10 mol% each of PPh3 and CuI, and 1.5 equiv of Et3N in N,N-
dimethylformamide (DMF) at room temperature for 24 h, the Sonogashira cross-coupling reaction
proceeded smoothly to give the corresponding (Z)-fluoroalkylated enyne 3a-c, 4a, 5a in good to
high isolated yields as a single stereoisomer without any interconversion of Z to E configuration
[12].
Page 4 of 19

Scheme 2. Preparation of polyfluorinated enynes 3-5
With various substrates in hand, our interest was focused on the synthesis of 3-fluoroalkylated
hex-3-ene-1,5-diyne derivatives 7-9 via addition-elimination reaction of various alkynyllithiums 6
toward 1-fluoroalkylated (Z)-1-fluoro-1-en-3-ynes 3-5. Thus, the reaction of fluoroalkylated enynes
3-5 with 2.0 equiv of lithium acetylides 6, readily prepared from terminal alkynes 6 and n-
butyllithium, was conducted in THF at room temperature for 2 h. The results are listed in Table 1.
Page 5 of 19

Table 1. Addition-elimination reaction of fluoroalkylated enynes 3-5 with various alkynyllithiums 6
Page 6 of 19

The addition-elimination reaction of trifluoromethylated enyne 3a with 2.0 equiv of
(phenylethynyl)lithium (6A) in THF at room temperature for 2 h took place very smoothly to form
the corresponding enediyne derivative 7Aa in 73% isolated yield. We were very delighted to find
an excellent E selective formation of 7Aa (E:Z = 98:2). Various alkynyllithiums having an
aromatic ring on the terminus, such as 1-naphthyl (6D), 3-thienyl (6F), ferrocenyl (6G), as R2 could
effectively take part in the addition-elimination reaction, the corresponding products 7Da, 7Fa, and
7Ga being obtained in 56-77% yields in a highly E selective fashion. The alkyl or alkenyl
substituents like n-hexyl (6B) or cyclohex-1-enyl (6H) on alkynyllithium did not cause any
significant influence on the addition-elimination reaction though the substituent such as 2-pyridyl
(6E) and trimethylsilyl (6I) resulted in a significant decrease of the yield and stereoselectivity.
Trifluoromethylated enynes 3b or 3c carrying a n-hexyl or a (benzyloxy)dimethylmethyl group on
the alkyne terminus also underwent the smooth addition-elimination reaction with acetylide 6A,
giving rise to the corresponding 7Ab and 7Ac in good yields with an excellent E selectivity (E:Z =
>96:4).
Other fluoroalkylated enyne compounds, such as difluoromethylated and
hexafluoropropylated enynes, 4a and 5a, was also subjected to the stereoselective addition-
elimination reaction, yielding the corresponding addition-elimination products 8Aa and 9Aa in 74%
(E/Z = 92/8) and 44% (E/Z = 94/6) yields, respectively.
The stereochemistry of the obtained enediynes was made as follows (Scheme 3 and Figure 2).
Thus, the major product of 7Aa is a known compound, which can be prepared from CF3-containing
diyne 10 via a highly regio- and stereoselective hydrostannation reaction in six steps, as shown in
Scheme 3 [8]. Thus, on treating 10 with 1.2 equiv of n-Bu3SnH in the presence of 20 mol% of Et3B
in toluene at ! 78 °C for 1 h, fortunately, the hydrostannation reaction proceeded quite smoothly to
afford the corresponding trans-vinylstannane in 75% isolated yield as a sole product. Then, the
stereoselectively obtained CF3-substituted vinylstannane 10 was converted to the corresponding
vinyl iodide by treating 10 with iodine in CH2Cl2 at room temperature, which underwent quite
smoothly Sonogashira cross-coupling reaction with phenylacetylene, giving rise to the
corresponding stereo-defined CF3-substituted cis-enediyne compound in 74% isolated yields.
Finally, the terminal functional group, i.e. BnOC(Me)2, in enediyne was easily convertible to the
corresponding (E)-7Aa enediyne through the deprotection and the subsequent Sonogashira cross-
coupling reaction. The comparison of the NMR spectra of the major product in 7Aa starting from
3a with the one starting from 10 made it possible to determine the double bond configuration of the
Page 7 of 19

1
major product in 7Aa as E. Additionally, it was observed in H NMR spectra that the signal of Ha
could be barely observed as quartet/multiplet (Rf = CF3 and HCF2CF2CF2), or triplet (Rf = HCF2) in
almost all of the major isomers, as shown in Figure 2. This fact strongly indicates that the spin-spin
splitting of Ha signal might be derived from the interaction between Ha and a fluoroalkyl group,
suggesting that the addition-elimination products have an E configuration.
Scheme 3. Determination of the stereochemistry
Page 8 of 19

Figure 2. Interaction between Ha and a fluoroalkyl group
Page 9 of 19

The excellent E selectivity on the addition-elimination reaction could be rationalized by the
formation of stable carbanion intermediates, followed by the anti-elimination of LiF. The possible
reaction mechanism is illustrated in Scheme 4 [6a].
R1
F
F
R1
! F!
H
H
Z-isomer
Electronic
repulsion
Rf
Rf
R2
R2
Int-C'
Int-A'
R2
R2
R1
R1
H
H
Rf
R2
Li
from top face
Rf
Rf
F
F
Rf
H
Int-C
Int-A
!
!
Rf
F
H
R1
R2
E-isomer
R1
Rf
F
F
R2
from bottom face
Li
H
H
R1
R1
Int-D
Int-B
R2
R2
R2
R2
Electronic
repulsion
Rf
Rf
Z-isomer
! F!
H
H
R1
F
F
R1
Int-D'
Int-B'
Scheme 4. A possible reaction mechanism for E-selective addition-elimination reaction (Li cation was omitted for
clarification.)
A nucleophilic attack of alkynyllithium to an ! -carbon on the enyne substrate could form
conformational intermediates Int-A (attacked from top face) or Int-B (attacked from bottom face),
which is in equilibrium with either Int-C or Int-D due to a resonance effect. Their intermediates
Int-A to Int-D would rotate 60° so that an elimination of LiF proceeds via anti-elimination, giving
rise to an intermediate Int-A’ to Int-D’. Among them, Int-C’ and Int-D’ would be much more
favorable than the others because there is no electronic gauche repulsion between an alkynyl and an
Page 10 of 19

electronic bulkyl fluoroalkyl groups. As a consequence, an immediate anti-elimination of LiF from
preferentially formed Int-C’ and Int-D’ proceeds to give enediyne compounds with an excellent E
selectivity.
3. Conclusion
In conclusion, we have described an effective preparation of (Z)-1-fluoroalkylated 1-fluoroenyne
compounds by Pd(0)-catalyzed cross-coupling reaction of 2-fluoroalkylated 2-fluoro-1-iodoethene
with terminal alkynes. Thus obtained 1-fluoroalkylated 1-fluoroenynes were subjected to the
addition-elimination reaction with various types of alkynyllithiums, leading to the corresponding 3-
fluoroalkylated hex-3-ene-1,5-diyne derivatives in good yields with an excellent E selectivity. We
believe that the present E-selective synthetic procedure for fluoroalkylated enediyne delivatives
would facilitate to open avenues to fluorine-containing biologically active compounds.
4. Experimental
4.1. General procedures
Infrared spectra (IR) were determined in a liquid film on a NaCl plate or KBr disk method with a
JASCO FT/IR-4100 typeA spectrometer. 1H and 13C NMR spectra were measured with a JEOL
JNM-AL400 NMR spectrometer in a chloroform-d (CDCl3) solution with tetramethylsilane (Me4Si)
as an internal reference. A JEOL JNM-EX90A (84.21 MHz) FT-NMR spectrometer and a JEOL
JNM-AL400 NMR spectrometer were used for determining the yields of the products with
hexafluorobenzene (C6F6). 19F NMR (376.05 MHz) spectra were measured with a JEOL JNM-AL
400 NMR spectrometer in a chloroform-d (CDCl3) solution with trichlorofluoromethane (CFCl3) as
an internal standard. High-resolution mass spectra (HRMS) were taken on a JEOL JMS-700MS
spectrometer by electron impact (EI), chemical ionization (CI), and fast atom bombardment (FAB)
methods.
All reactions were routinely monitored by 19F NMR spectroscopy or TLC, and carried out under an
atmosphere of argon.
4.1.1. Materials
Page 11 of 19

N,N-Dimethylformamide (DMF), triethylamine (Et3N), and hexamethylphosphoric triamide
(HMDS) were fleshly distilled from calcium hydride (CaH2). All chemicals were of reagent grade
and, if necessary, were purified in the usual manner prior to use. Thin-layer chromatography (TLC)
was done with Merck silica gel 60 F254 plates, and column chromatography was carried out using
Wako gel C-200 as adsorbent.
4.2. General procedure for the preparation of 2-fluoroalkylated 1-iodo-2-fluoroethene 1
The starting polyfluorinated vinyl iodides 1 were prepared from easily available polyfluorinated
alcohols with 3 steps according to the reported procedure, as follows: Polyfluorinated alcohol (1.0
mol) and p-toluenesulfonyl chloride (1.2 mol) was dissolved in H2O (350 mL), and dropwise the
whole was heated at 50 °C. To the solution was added slowly a NaOH solution (150 mL, 1.2 mol).
After stirring of the reaction mixture for 3 h, the reaction mixture was cooled to room temperature,
followed by extraction with Et2O three times. The combined organic layers were washed with NH3
aq. (twice), ten H2O (three times), and dried over anhydrous Na2SO4. After evaporation of the
organic materials, the residue and NaI (180 g, 1.2 mol) was dissolved in diethyleneglycol (350 mL).
The solution was heated (bath temperature ca. 170 °C/760 mmHg) to distill the desired iodide,
which was washed with water six times. The crude materials were dissolved in DMSO (250 mL),
and to this reaction mixture was added a KOH solution (100 mL, 0.9 mol) at 0-10 °C. After stirring
of the reaction mixture for 24 h, the reaction mixture was heated at 80-100 °C to obtain the light-red
oil, which was washed with H2O, dried over anhydrous Na2SO4, then filtered to afford the desired
polyfluorinated vinyl iodide 1. The characterization data for 1 were in accordance with a previously
reported data, see: Ref. [10].
4.3. Typical procedure for the preparation of (Z)-1,1,1,2-tetrafluoro-5-phenyl-2-penten-4-yne (3a)
In a two-necked round-bottomed flask equipped with a magnetic stirrer bar, a rubber septum, and
an inlet tube for Ar, was charged with a solution of Pd(OAc)2 (224 mg, 1.0 mmol) and PPh3 (525
mg, 2.0 mmol) in DMF (133 mL). To a solution of prepared Pd(0) catalyst in advance was added 1-
iodo-2,3,3,3-tetrafluoroprop-1-ene (4.80 g, 20 mmol), followed by continuous stirring for 20 min at
room temperature. After that, ethynylbenzene (2.6 mL, 2.45 g, 24 mmol), Et3N (4.2 mL, 3.07 g, 30
mmol), and CuI (381 mg, 2 mmol) was added in this order into the above mixture. The whole was
Page 12 of 19

stirred for 24 h before quenching with saturated aqueous NH4Cl solution. The mixture was
extracted with Et2O three times, and the combined organic layers were dried over anhydrous
Na2SO4, then filtered. The filtrate was evaporated to give the corresponding crude materials, which
was purified by silica gel column chromatography, affording the 1,1,1,2-tetrafluoro-5-phenyl-2-
penten-4-yne (3a, 2.71 g, 12.65 mmol, 76% yield).
4.3.1. (Z)-1,1,1,2-Tetrafluoro-5-phenylpent-2-en-4-yne (3a)
1H NMR (CDCl3) ! 5.93 (d, J = 28.8 Hz, 1H), 7.36 – 7.40 (m, 3H), 7.49 – 7.51 (m, 2H); 13C NMR
(CDCl3) ! 77.5, 95.1 (dq, J = 3.9, 4.1 Hz), 100.1 (dq, J = 6.5, 1.7 Hz), 118.4 (qd, J = 271.1, 39.8
Hz), 121.8, 128.5, 129.5, 131.9, 152.1 (dq, J = 273.1, 39.3 Hz); 19F NMR (CDCl3) ! ! 120.82 (dq, J
= 28.8, 9.8 Hz, 1F), ! 72.99 (d, J = 9.8 Hz, 3F); IR (neat) ! 3074, 2927, 2213, 1685, 1367, 1200,
1149, 1030, 1009, 756 cm-1; HRMS calcd for C11H6F4 (M+) 214.0406, found 214.0396.
4.3.2. (Z)-1,1,1,2-Tetrafluoroundec-2-en-4-yne (3b)
1H NMR (CDCl3) ! 0.90 (t, J = 6.80 Hz, 3H), 1.24 – 1.44 (m, 6H), 1.52 – 1.60 (m, 2H), 2.38 (t, J =
7.2 Hz, 2H), 5.68 (d, J = 29.2 Hz, 1H); 13C NMR (CDCl3) ! 14.0, 19.7, 22.5, 28.2, 28.5, 31.3, 69.1,
95.5 (dq, J = 13.7, 3.6 Hz), 102.6 (dq, J = 6.6, 1.6 Hz), 118.5 (qd, J = 271.1, 39.7 Hz), 151.9 (dq, J
= 270.4, 38.9 Hz); 19F NMR (CDCl3) ! ! 123.76 (dq, J = 29.2, 9.8 Hz, 1F), ! 73.08 (d, J = 9.8 Hz,
3F) ; IR (neat) ! 3078, 2935, 2862, 2339, 2224, 1685, 1469, 1431, 1372, 1155, 959 cm-1; HRMS
calcd for C11H14 F4Na (M+Na) 245.0929, found 245.0940.
4.3.3. (Z)-6-Benzyloxy-1,1,1,2-tetrafluoro-6-methylhept-2-en-4-yne (3c)
1H NMR (CDCl3) ! 1.59 (s, 6H), 4.63 (s, 2H), 5.76 (d, J = 28.8 Hz, 1H), 7.27 – 7.36 (m, 5H); 13C
NMR (CDCl3) ! 28.5, 66.8, 71.0, 81.7, 94.5 – 94.6 (m), 103.0 (d, J = 5.7 Hz), 118.2 (qd, J = 271.2,
39.7 Hz), 127.4, 127.7, 128.3, 138.5, 152.5 (dq, J = 272.6, 39.3 Hz); 19F NMR (CDCl3) ! ! 120.71
(dq, J = 28.8, 9.8 Hz, 1F), ! 73.19 (d, J = 9.8 Hz, 3F); IR (neat) ! 3069, 2988, 2868, 2229, 1684,
1455, 1301, 1111, 929, 846, 697, 661 cm-1; HRMS calcd for C15H14F4O (M+) 286.0981, found
286.0977.
4.3.4. (Z)-1,1,2-Trifluoro-5-phenylpent-2-en-4-yne (4a)
1H NMR (CDCl3) ! 5.70 (d, J = 30.4 Hz, 1H), 6.14 (td, J = 53.4, 4.9 Hz, 1H), 7.32 – 7.37 (m, 3H),
7.37 – 7.51 (m, 2H); 13C NMR (CDCl3) ! 78.4 – 78.5 (m, 1C), 93.8 (dt, J = 9.0, 6.6 Hz), 98.3-98.5
Page 13 of 19

(m, 1C), 108.7 (td, J = 230.8, 37.2 Hz), 122.1, 128.4, 129.2, 131.8, 157.0 (dt, J = 272.7, 25.2 Hz);
19F NMR (CDCl3) ! –124.04 (dd, J =53.4, 19.1 Hz, 2F), –117.85 to –117.65 (m, 1F); IR (neat) !
3061, 2975, 2867, 2373, 2213, 1955, 1683, 1598, 1491, 1402, 1274, 1109, 895 cm-1; HRMS calcd
for C11H7F3 (M+) 196.0500, found 196.0508.
4.3.5. (Z)-1,1,2,2,3,3,4-Heptafluoro-7-phenylhept-4-en-6-yne (5a)
1H NMR (CDCl3) ! 5.94 (d, J = 29.2 Hz, 1H), 6.05 (tt, J = 52.0, 5.2 Hz, 1H), 7.34 – 7.39 (m, 3H),
7.49 – 7.55 (m, 2H); 13C NMR (CDCl3) δ = 77.8, 97.3 (dt, J = 8.2, 6.2 Hz), 100.4 (m, 1C), 104 –
115 (m, 3C), 121.8, 128.5, 129.5, 131.8, 152.8 (dt, J = 272.8, 28.7 Hz); 19F NMR (CDCl3) ! –137.5
to –137.2 (m, 2F), –130.7 to –130.6 (m, 2F), ! 119.8 to ! 119.6 (m, 2F), ! 116.18 to ! 116.00 (m, 1F);
IR (neat) ! 3069, 2212, 1674, 1348, 1222, 1163, 1126, 949, 827, 756 cm-1; HRMS calcd for
C13H8F7 (M+H) 297.0514, found 297.0527.
4.4. Typical procedure for the synthesis of 1,6-diphenyl-3-(trifluoromethyl)hex-3-en-1,5-diyne (7Aa)
In a two-necked round-bottomed flask equipped with a magnetic stirrer bar, a rubber septum, and an
inlet tube for Ar, was charged with a solution of ethynylbenzene (82 mg, 0.80 mmol) in THF (2.0
mL). To the solution was added n-BuLi (0.5 mL, 0.80 mmol) at 0 °C, followed by stirring at that
temperature for 30 min. To the resultant solution was added the 1,1,1,2-tetrafluoro-5-phenylpent-2-
en-4-yne (82 mg, 0.37 mmol) at 0 °C. The whole was allowed to warm to room temperature, then
being stirred for another 2 h. The reaction was quenched with saturated aqueous NH4Cl solution
and the resultant was extracted with Et2O three times. The combined organic layers were dried over
anhydrous Na2SO4, followed by filtered. The filtrate was evaporated to give the crude materials,
which was purified by silica gel column chromatography, affording the 1,6-diphenyl-3-
(trifluoromethyl)hex-3-en-1,5-diyne (7Aa, 83 mg, 0.28 mmol, 73% yield, Isomer ratio, E/Z =98/2).
4.4.1. (E)-1,6-Diphenyl-3-(trifluoromethyl)hex-3-en-1,5-diyne (7Aa)
Yield: 73% (E:Z = 98:2); 1H NMR (CDCl3) ! = 6.60 – 6.64 (m, 1H), 7.35 – 7.42 (m, 6H), 7.52 –
7.57 (m, 4H); 13C NMR (CDCl3) ! = 81.7 (q, J = 2.2 Hz), 85.2, 100.2, 102.8, 120.4 (q, J = 5.50 Hz),
121.9, 122.9 (q, J = 34.7 Hz), 121.6 (q, J = 273.1 Hz), 122.1, 128.5, 128.6, 129.5, 129.6, 131.9,
132.0; 19F NMR (CDCl3) ! = –66.55 (s, 3F); IR (neat) ! 3054, 2926, 2244, 2209, 2189, 1952, 1729,
1490, 1391, 916, 864, 754, 687 cm-1; HRMS calcd for C19H11F3 (M+) 296.0813, found 296.0807.
4.4.2. (E)-1-(1-Naphthyl)-6-phenyl-3-(trifluoromethyl)hex-3-en-1,5-diyne (7Da)
Page 14 of 19

Yield: 56% (E:Z = 97:3); 1H NMR (CDCl3) ! 6.71 (s, 1H), 7.34 – 7.57 (m, 8H), 7.80 – 7.92 (m,
3H), 8.40 – 8.45 (m, 1H); 13C NMR (CDCl3) ! 85.5, 86.5 (q, J = 2.1 Hz), 98.6, 102.90, 102.92,
119.4, 120.2 (q, J = 5.5 Hz), 121.7 (q, J = 273.2 Hz), 122.0, 123.1 (q, J = 34.4 Hz), 125.2, 126.0,
126.7, 128.3, 128.5, 129.6, 127.4, 130.1, 130.3, 132.3, 133.1; 19F NMR (CDCl3) ! ! 66.34 (s, 3F, E-
isomer), ! 62.71 (s, 3F, Z-isomer); IR (neat) ! 3057, 2206, 2184, 1587, 1410, 1375, 1307, 1135,
1106, 1023, 863 cm-1; HRMS calcd for C23H13F3 (M+) 346.0969, found 346.0977.
4.4.3. (E)-6-Phenyl-1-(2-pyridyl)-3-(trifluoromethyl)hex-3-en-1,5-diyne (7Ea)
Yield: 35% (E:Z = 83:17); 1H NMR (CDCl3) ! 6.72 – 6.73 (m, 1H), 7.29 – 7.40 (m, 4H), 7.55 –
7.60 (m, 3H), 7.66 – 7.74 (m, 1H), 8.66 – 8.72 (m, 1H); 13C NMR (CDCl3) ! 80.7 (q, J = 3.0 Hz),
85.0, 98.5, 104.0, 120.1, 121.5 (q, J = 273.0 Hz), 122.5 (q, J = 34.2 Hz), 122.6 (q, J = 5.5 Hz),
123.7, 127.7, 128.5, 129.8, 132.2, 136.1, 142.3, 150.4; 19F NMR (CDCl3) ! ! 66.22 (s, 3F, E-
isomer), ! 62.74 (s, 3F, Z-isomer); IR (neat) ! 3054, 2926, 2191, 1733, 1581, 1464, 1181, 1136, 987,
919, 870 cm-1; HRMS calcd for C18H11F3N (M+H) 298.0844, found 298.0848.
4.4.4. (E)-6-Phenyl-1-(3-thienyl)-3-(trifluoromethyl)hex-3-en-1,5-diyne (7Fa)
Yield: 69% (E:Z = 95:5); 1H NMR (CDCl3) ! 6.62 (q, J = 1.6 Hz, 1H), 7.20 – 7.22 (m, 1H), 7.32 –
7.39 (m, 4H), 7.51 – 7.53 (m, 2H), 7.62 – 7.63 (m, 1H); 13C NMR (CDCl3) ! 81.4 (q, J = 2.2 Hz),
85.2, 95.3, 102.7, 120.2 (q, J = 5.6 Hz), 121.0, 122.1, 123.9 (q, J = 34.7 Hz), 124.4 (q, J = 284.5
Hz), 125.8, 128.6, 129.6, 129.7, 130.5, 132.0; 19F NMR (CDCl3) ! ! 66.51 (s, 3F, E-isomer), ! 62.91
(s, 3F, Z-isomer); IR (neat) ! 3110, 3052, 2213, 2191, 1726, 1603, 1426, 1307, 1136, 1066, 931,
871 cm-1; HRMS calcd for C17H9F3S (M+) 302.0377, found 302.0376.
4.4.5. (E)-1-Ferrocenyl-6-phenyl-3-(trifluoromethyl)hex-3-en-1,5-diyne (7Ga)
Yield: 77% (E:Z = 95:5); 1H NMR (CDCl3) ! 4.24 – 4.36 (m, 7H), 4.50 – 4.57 (m, 2H), 6.58 (q, J =
1.6 Hz, 1H), 7.35 – 7.40 (m, 3H), 7.53 – 7.58 (m, 2H); 13C NMR (CDCl3) ! 66.9, 69.2, 69.7, 70.1,
70.2, 70.3, 71.9, 72.1, 78.17, 78.19, 85.6, 87.0, 100.7, 104.6, 118.7 (q, J = 5.3 Hz), 121.5 (q, J =
270.5 Hz), 122.3, 123.5 (q, J = 33.6 Hz), 128.5, 129.4, 131.9; 19F NMR (CDCl3) ! ! 66.60 (s, 3F, E-
isomer), ! 62.93 (s, 3F, Z-isomer); IR (neat) ! 3097, 2210, 2192, 1602, 1306, 1135, 1081, 918, 822
cm-1; HRMS calcd for C23H15F3Fe (M+) 404.0475, found 404.0472.
4.4.6. (E)-1-Phenyl-4-(trifluoromethyl)dodec-3-en-1,5-diyne (7Ba)
Page 15 of 19

Yield: 56% (E:Z = 96:4); 1H NMR (CDCl3) ! 0.86 (t, J = 6.99 Hz, 3H), 1.25 – 1.30 (m, 4H), 1.42 –
1.50 (m, 2H), 1.59 – 1.66 (m, 2H), 2.49 (t, J = 6.39 Hz, 2H), 6.52 (m, 1H), 7.35 – 7.39 (m, 3H),
7.48 – 7.50 (m, 2H); 13C NMR (CDCl3) ! 14.0, 19.8, 22.5, 28.3, 28.5, 31.3, 73.2 (q, J = 2.0 Hz),
85.0, 101.2, 102.7, 119.3 (q, J = 5.8 Hz), 121.6 (q, J = 268.7 Hz), 123.0, 123.3 (q, J = 34.3 Hz),
128.4, 129.4, 132.0; 19F NMR (CDCl3) ! ! 67.13 (s, 3F, E-isomer), ! 63.36 (s, 3F, Z-isomer); IR
(neat) ! 3055, 2932, 2860, 2197, 1604, 1382, 1305, 1136, 1034, 864 cm-1; HRMS calcd for
C19H19F3 (M+H) 304.1439, found 304.1431.
4.4.7. (E)-1-(Cyclohex-1-enyl)-6-phenyl-3-(trifluoromethyl)hex-3-en-1,5-diyne (7Ha)
Yield: 82% (E:Z = 96:4); 1H NMR (CDCl3) ! 1.60 – 1.71 (m, 4H), 2.10 – 2.30 (m, 4H), 6.32 – 6.37
13
(m, 1H), 6.51 (q, J = 2.0 Hz, 1H), 7.36 – 7.38 (m, 3H), 7.49 – 7.51 (m, 2H); C NMR (CDCl3) !
21.3, 22.1, 25.9, 28.7, 79.4 (q, J = 2.5 Hz), 85.3, 102.0, 102.5, 119.0 (q, J = 5.8 Hz), 120.2, 121.6
(q, J = 272.8 Hz), 123.3 (q, J = 34.7 Hz), 128.5, 129.4, 132.0, 138.3; 19F NMR (CDCl3) ! ! 66.78
(s, 3F, E-isomer), ! 63.12 (s, 3F, Z-isomer); IR (neat) ! 2933, 2861, 2181, 1577, 1394, 1307, 1138,
1061, 788 cm-1; HRMS calcd for C19H15F3 (M+) 300.1126, found 300.1130.
4.4.8. (E)-6-Phenyl-3-(trifluoromethyl)-1-(trimethysilyl)hex-3-en-1,5-diyne (7Ia)
Yield: 21% (E:Z = 93:7); 1H NMR (CDCl3) ! 0.27 (s, 9H), 6.60 (q, J = 1.6 Hz), 7.35 – 7.40 (m,
3H), 7.49 – 7.51 (m, 2H); 13C NMR (CDCl3) ! -0.38, 85.0, 95.9 (q, J = 2.2 Hz), 102.8, 107.3, 121.5
(q, J = 273.1 Hz), 121.7 (q, J = 5.8 Hz), 122.1, 122.9 (q, J = 33.9 Hz), 128.5, 129.6, 132.1; 19F
NMR (CDCl3) ! ! 66.64 (s, 3F, E-isomer), ! 63.04 (s, 3F, Z-isomer); IR (neat) ! 2963, 2201, 1603,
1584, 1367, 1306, 1139, 1006, 868 cm-1; HRMS calcd for C16H15F3Si (M+) 292.0895, found
292.0905.
4.4.9. (E)-1-Phenyl-3-(trifluoromethyl)dodec-3-en-1,5-diyne (7Ab)
Yield: 65% (E:Z = 96:4); 1H NMR (CDCl3) ! 0.86 (t, J = 6.99 Hz, 3H), 1.24 – 1.62 (m, 8H), 2.46 –
13
2.50 (m, 2H), 6.41 – 6.42 (m, 1H), 7.33 – 7.38 (m, 3H), 7.50 – 7.53 (m, 2H); C NMR (CDCl3) !
14.0, 20.1, 22.5, 28.4, 28.5, 31.3, 81.4, 81.5, 98.8, 105.8 (q, J = 1.6 Hz), 121.5 (q, J = 5.5 Hz),
19
122.01 (q, J = 272.8 Hz), 122.02, 122.3 (q, J = 33.3 Hz), 128.4, 129.3, 131.9; F NMR (CDCl3) !
! 66.63 (s, 3F, E-isomer), ! 63.05 (s, 3F, Z-isomer); IR (neat) ! 2932, 2860, 2219, 1589, 1396, 1289,
1138, 1039, 869 cm-1; HRMS calcd for C19H19F3O (M+) 304.1439, found 304.1443.
Page 16 of 19

4.4.10. (E)-7-Benzyloxy-7-methyl-1-phenyl-3-(trifluoromethyl)oct-3-en-1,5-diyne (7Ac)
Yield: 68% (E:Z = 97:3); 1H NMR (CDCl3) ! = 1.65 (s, 6H), 4.69 (s, 2H), 6,49 (q, J = 1.60 Hz, 1H),
7.26 – 7.47 (m, 10H); 13C NMR (CDCl3) ! = 28.7, 66.9, 71.2, 80.1, 81.2 (q, J = 2.2 Hz), 99.8, 105.3,
120.0 (q, J = 5.5 Hz), 121.5 (q, J = 273.3 Hz), 121.6, 123.7 (q, J = 34.7 Hz), 127.4, 127.7, 128.3,
19
128.4, 129.4, 131.9, 138.6 ; F NMR (CDCl3) ! = –66.83 (s, 3F); IR (neat) ! 3034, 2986, 2935,
2201, 1589, 1491, 1389, 1292, 1183, 1139, 1030, 867, 756, 689 cm-1; HRMS calcd for C23H18F3O
(M+) 367.1310, found 367.1312.
4.4.11. (E)-3-(Difluoromethyl)-1,6-diphenylhex3-en-1,5-diyne (8Aa)
Yield: 74% (E:Z = 92:8); 1H NMR (CDCl3) ! 6.21 (t, J = 55.8 Hz, 1H), 6.43 (t, J = 2.4 Hz, 1H),
7.35 – 7.38 (m, 6H), 7.52 – 7.57 (m, 4H); 13C NMR (CDCl3) ! 82.9 (t, J = 4.2 Hz), 85.8, 99.9,
101.0 (t, J = 2.5 Hz), 112.7 (t, J = 240.8 Hz), 119.1 (t, J = 9.1 Hz), 122.2, 122.4, 127.0 (t, J = 22.7
Hz), 124.5, 128.5, 129.2, 129.3, 131.87, 131.90; 19F NMR (CDCl3) ! ! 116.17 (d, J = 53.4 Hz, 2F,
Z-isomer), ! 114.64 (d, J = 55.8 Hz, 2F, E-isomer); IR (neat) ! 3061, 2867, 2214, 1955, 1683, 1598,
1491, 1402, 1048, 917, 895 cm-1; HRMS calcd for C19H12F2 (M+) 278.0907, found 278.0909.
4.4.12. (E)-5,5,6,6,7,7-Hexafluoro-1-phenyl-4-(phenylethynyl)hept-3-en-1-yne (9Aa)
Yield: 44% (E:Z = 94:6); 1H NMR (CDCl3) ! 6.12 (tt, J = 52.0, 5.6 Hz, 1H), 6.60 (s, 1H), 7.35 –
7.42 (m, 6H), 7.54 (m, 4H); 13C NMR (CDCl3) ! 82.3 (t, J = 5.0 Hz), 85.7, 100.9, 103.3 (t, J = 1.7
Hz), 108.9 (tt, J = 253.3, 31.4 Hz), 100 – 130 (m, 2C), 121.97, 122.09 (t, J = 25.6 Hz), 122.14,
122.6 (t, J = 8.7 Hz), 128.5, 128.6, 129.5, 129.6, 131.8, 132.0; 19F NMR (CDCl3) ! ! 137.15
(dquint., J = 52.0, 7.3 Hz, 2F), ! 130.31 (q, J = 6.5 Hz, 2F), ! 112.60 (t, J = 7.3 Hz, 2F); IR (neat) !
3517, 3056, 2189, 1491, 1357, 1205, 1154, 1014, 916, 862 cm-1; HRMS calcd for C21H12F6 (M+)
378.0843, found 378.0846.
Page 17 of 19

References
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I. H. Jeong, Tetrahedron Lett. 48 (2007) 627-631. (b) M. Shimizu, T. Fujimoto, X. Liu, H.
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of this manuscript. As for the other reference in the determination of the stereochemistry, see.
(b) J.P. Bégué, D. Bonnet-Delpon, D. Mexureur, M. Ourévitch, Mag. Reson. Chem. 29 (1991)
675-678.
[9] Addition-elimination reaction of fluorinated alkenes are powerful tools for construction of
Page 18 of 19

various types of fluorine-containing organic molecules, see: (a) S. Yamada, T. Takahashi, T.
Konno, T. Ishihara, J. Fluorine Chem. 149 (2013) 95-103. (b) S. Yamada, K. Shimoji, T.
Takahashi, T. Konno, T. Ishihara, Chem. Asian J. 5 (2010) 1846-1853. (c) S. Yamada, E. Ishii,
T. Konno, T. Ishihara, Tetrahedron 64 (2008) 4215-4223. (d) S. Yamada, M. Noma, K. Hondo,
T. Konno, T. Ishihara, J. Org. Chem. 73 (2008) 522-528. (e) S. Yamada, E. Ishii, T. Konno, T.
Ishihara, Org. Biomol. Chem. 5 (2007) 1442-1449. (f) S. Yamada, T. Takahashi, T. Konno, T.
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[11] We thank Daikin Industries, Ltd. for supplying 2,2,3,3,3-pentafluoropropanol, 2,2,3,3-
tetrafluoropropanol, and 2,2,3,3,4,4,5,5-octafluoropentanol.
[12] Assignment of the stereochemistry of 3a was made by NMR spectroscopy. The coupling
constant between vicinal H and F (3JH-F) of 3a was 28.8 Hz, which indicates the 3a possesses Z
configuration. The stereochemistries of the other enynes were determined on the basis of the
vicinal H-F coupling constants.
Page 19 of 19