A novel method for (Z)-stereoselective preparation of CF3-substituted enediynes and their coupling reactions

Article abstract of DOI:10.1016/j.tetlet.2006.11.111

Trifluoromethylated enynyl sulfones 3 were reacted with 2-4 equiv of phenyl, n-hexyl, trimethylsilyl, or triisopropylsilyl substituted ethynyllithium reagents in THF or ether at 0 °C to give trifluoromethylated enediynes 6 (Z)-stereoselectively in 41-96%

Full text of DOI:10.1016/j.tetlet.2006.11.111

Tetrahedron Letters 48 (2007) 627–631
A novel method for (Z)-stereoselective preparation of
CF3-substituted enediynes and their coupling reactions
Hyang Hwa Jeon, Jang Bae Son, Ji Hoon Choi and In Howa Jeong*
Department of Chemistry, Yonsei University, Wonju, Republic of Korea
Received 13 October 2006; revised 9 November 2006; accepted 17 November 2006
Available online 12 December 2006
Abstract—Trifluoromethylated enynyl sulfones 3 were reacted with 2–4 equiv of phenyl, n-hexyl, trimethylsilyl, or triisopropylsilyl
substituted ethynyllithium reagents in THF or ether at 0 °C to give trifluoromethylated enediynes 6 (Z)-stereoselectively in 41–96%
yields. The reactions of b-fluoro-b-trifluoromethylvinyl sulfone 5 with same ethynyllithium reagents (4 equiv) afforded the corre-
sponding enediynes 6 in 41–90% yields. The cross-coupling reactions of 6 bearing TMS group with aryl iodides in the presence
of Pd(PPh3)2Cl2, Ag2CO3, and n-Bu4NBr provided the corresponding enediynes 6 in 20–71% yields. Dimerization of (Z)-6 bearing
TMS group in the presence of CuBr2 and K2CO3 yielded dimer (Z,Z)-7 in good yield.
Ó 2006 Elsevier Ltd. All rights reserved.
Recently, enediyne compounds have attracted much
interest since they can be used not only to study on
the mechanism for their function in antitumor anti-
biotics1–3 such as dynemicin, neocarzinostatin, and espera-
micin, but also utilize in the synthesis of oligoenynes and
oligoenediynes as well as p-conjugated polymers for
electronic and photonic applications.4–7 Although
numerous methods for the preparation of nonfluori-
nated enediyne derivatives and their applications to
the synthesis of benzene derivatives and p-conjugated
oligomers have been well documented in the previous lit-
eratures,8–15 there has been quite limited reports on the
preparation of trifluoromethylated enediynes, which are
valuable building blocks in the synthesis of trifluoro-
methylated oligoenediynes, in which the presence of tri-
fluoromethyl group sometimes causes their properties to
change dramatically as compared to nonfluorinated
ones. Hong prepared (E)-trifluoromethylated enediyne
from the Pd-catalyzed Sonogashira coupling reaction
of (Z)-1,2-dibromo-3,3,3-fluoropropene with terminal
alkynes.16 (Z)-Trifluoromethylated enediyne was also
prepared from the reaction of trifluoromethylated oxira-
nyllithiums with (pinacolato)borane, in which trifluo-
romethylated oxiranyllithiums were synthesized from
the treatment of trifluoromethylated dichlorohydrines
with 2 equiv of alkyllithium at a low temperature.17
However, the previous methods have some drawbacks
such as lack of novelity and generality, and tedious pro-
cedure. Herein, we wish to report a novel and general
preparation of (Z)-stereoselective trifluoromethylated
enediynes and their coupling reactions to give a variety
of trifluoromethylated enediynes and their dimers.
Trifluoromethylated enynyl sulfones 3a–b (E/Z = 9/91)
as precursors to enediynes were prepared in quantitative
yields from the oxidation of trifluoromethylated enynyl
sulfides 2a–b (E/Z = 9/91), which were synthesized from
the reaction of pentafluoroethyl phenyl dithioketal 1
with phenyl or n-hexyl substituted ethynyllithium
reagents (2.5 equiv).18 The assignment of E and Z iso-
mers of 3a–b was made by the comparison of chemical
19
shift of authentic sample in F NMR spectroscopy.19
It has been established that 19F NMR signal
(ꢀÀ55.70 ppm) in the Z-isomer is less shielded than that
(ꢀÀ59.00 ppm) in the E-isomer. Since 1 was not reacted
with trimethylsilyl or triisopropylsilyl substituted
ethynyllithium reagents, enynyl sulfones 3c–d were
prepared from the reaction of b-fluoro-b-trifluoro-
methylvinyl sulfone 5, formed by oxidation of b-fluoro-
b-trifluoromethylvinyl sulfide 4,20 with trimethylsilyl or
triisopropylsilyl substituted ethynyllithium reagents.
Keywords: Trifluoromethylated enynyl sulfones; Trifluoromethylated
enediynes; (Z)-Stereoselectivity; Cross-coupling reaction; Dimeriza-
tion.
*
Further reactions of 3a–b with ethynyllithium reagents
(2–4 equiv) in THF or ether at 0 °C for 1–2 h afforded
Corresponding author. Tel.: +82 33 760 2240; fax: +82 33 763
4323; e-mail: jeongih@yonsei.ac.kr
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.111

628
H. H. Jeon et al. / Tetrahedron Letters 48 (2007) 627–631
CF3
CF3
SPh
R1C CLi (2.5 equiv)
THF, 0 o 15 oC, 16 h
MCPBA (2.2 equiv)
CH2Cl2, rt, 3 h
SPh
SO2Ph
F3CF2C
C
R
C
C
C
C
C
R1
R1
SPh
Ph
Ph
(R = Ph)
3a (R1 = Ph, 98%, E/Z = 9/91)
2a (R1 = Ph, 98%)
1 (R = Me, Ph)
3b (R1 = n-C6H13, 99%, E/Z = 9/91)
2b (R1 = n-C6H13, 89%)
THF,
TiCl4/
LiAlH4
reflux,
3 h
CF3
CF3
CF3
MCPBA (2.2 equiv)
CH2Cl2, reflux, 24 h
R2C CLi (1.5 equiv)
SPh
F
SO2Ph
SO2Ph
C
F
CH2Cl2, 0 oC, 3 h
C
R2
R
R
Ph
3c (R2 = TMS, 72%, E/Z =35/65)
4a (R = Ph, 92%, E/Z = 84/16)
4b (R = Me, 78%, E/Z = 61/39)
5a (R = Ph, 93%, E/Z = 84/16)
5b (R = Me, 90%, E/Z = 61/39)
3d (R2 = TIPS, 64%, E/Z = 35/65)
the corresponding enediynes 6a–f (Z)-stereoselectively in
41–96% yields. The reactions of 3c–d with trimethylsilyl
or triisopropylsilyl substituted ethynyllithium reagents
also yielded enediynes 6g–i (Z)-stereoselectively in high
yields under the same reaction condition. (Z)-Isomers
of enediynes 6f–j were used after isolation by column
chromatography, but the separation of (Z)-isomer of
6a was not successful. We assigned E and Z isomers of
6a–i by the comparison of chemical shift of (Z)-1-phen-
yl-4-phenylethynyl-3-trifluoromethyl-oct-3-en-1-yne in 19F
NMR spectroscopy, in which signal appeared at
À61.1 ppm.17 Since the chemical shift of one isomer of
6a in the 19F NMR spectra is À61.08 ppm, this isomer
should be (Z)-isomer and thus a signal at À57.01 ppm
will be (E)-isomer. The use of ether as a solvent in the
reactions of 3a–d with trimethylsilyl or triisopropylsilyl
substituted ethynyllithium reagent provided a better
result than did the use of THF. The results of these reac-
tions are summarized in Table 1. (Z)-Stereoselectivity in
these reactions can be rationalized by the formation of
stable carbanion intermediates followed by the elimina-
tion of sulfonyl group. The conformational intermedi-
ates [A] and [B] could be formed from top and bottom
attack of the substituted ethynyllithium on (Z)-3,
respectively. Rotation of these two intermediates by
60° would result in two reasonably stable conforma-
tional intermediates [C] and [D], which quickly undergo
the elimination of the sulfonyl group to give (Z)-6 in a
high stereoselectiviy. The other isomer, (E)-3 could pro-
vide (E)-6 in a high stereoselectively in a similar manner.
However, the reaction of 3b with ethynyllithium
reagents showed relatively less stereoselectivity because
of presumably steric effect of flexible hexyl group.
Vinyl sulfones 5a–b are very reactive species to react
with phenyl, n-hexyl or trimethylsilyl ethynyllithium
reagents to give the corresponding enediynes 6a, 6e,
6g, and 6j–m in 41–90% yields whose results are summa-
rized in Table 2. (Z)-Stereoselectivity in these reactions
was decreased dramatically as compared to the reaction
as shown in Table 1. This low stereoselectivity can be
explained by the reaction process involving a different
intermediate. We actually examined the reaction of 5a
with 2.5 equiv of phenylethynyllithium at 0 °C, in which
3a, 3e, and 6a were obtained as a mixture. This result
indicated that the reaction of 5a with ethynyllithium
did not proceed only via intermediate 3a. In other
words, 6a was also obtained via intermediate 3e.
We carried out the palladium-catalyzed cross-coupling
reaction of 6c, 6f, and 6g with aryl iodides to introduce
an aromatic group at the trimethylsilyl (TMS) site.21
Table 1. Preparation of trifluoromethylated enediynes 6 from trifluoromethylated enynyl sulfones 3
R1
CF3
CF3
C
R1C
CLi (X equiv)
SO2Ph
C
C
Solvent, 0 oC, t h
C
C
C
R
R
Ph
Ph
3
6
Compound
R
R1
X
Solvent
t
Yielda (%)
E/Zb
6a
6b
6c
6d
6e
6f
Ph
Ph
Ph
n-C6H13
n-C6H13
n-C6H13
TMS
Ph
2
2
3
4
4
4
3
3
3
THF
THF
Ether
THF
THF
Ether
Ether
Ether
Ether
1
1
2
1
1
2
2
2
2
87
96
92
68
64
41
82
84
73
9/91
9/91
7/93
18/82
25/75
7/93
35/65
35/65
37/63
n-C6H13
TMS
Ph
n-C6H13
TMS
TMS
TIPS
TMS
6g
6h
6i
TMS
TIPS
a Isolated yield.
b E/Z ratio was determined by 19F NMR spectrum.

H. H. Jeon et al. / Tetrahedron Letters 48 (2007) 627–631
629
R1
C
R1
_
C
CF3
Ph
C
C
60o rotation
C
top attack
SO2Ph
CF3
R C
C
R1-C
CLi
C
CF3
SO2Ph
R C
C
Ph
R
Ph
(Z)-3
SO2Ph
[C]
_
[A]
R1-C
CLi
bottom attack
-SO2Ph
_
R1
SO2Ph
CF3
CF3
Ph
SO2Ph
CF3
C
60o rotation
C
-SO2Ph
R C
C
R C
C
Ph
C
C
_
C
C
R
Ph
C
R1
C
R1
[B]
(Z)-6
[D]
Table 2. Preparation of trifluoromethylated enediynes 6 from trifluoromethylated vinyl sulfones 5
R1
CF3
CF3
C
R1C
CLi (4 equiv)
Solvent, 0 oC, t h
C
SO2Ph
C
F
C
R1
R
R
5
6
Compound
R
R1
Solvent
t
Yielda (%)
E/Zb
6a
6e
6g
6j
Ph
Ph
Ph
Ph
Me
Me
Me
Ph
Toluene
Toluene
Ether
2
1
2
2
4
4
4
72
66
90
69
64
41
84
37/63
42/58
42/58
37/63
64/36
66/34
64/36
n-C6H13
TMS
TIPS
Ph
n-C6H13
TMS
Ether
6k
6l
Toluene
Toluene
Ether
6m
a Isolated yield.
b E/Z ratio was determined by 19F NMR spectrum.
CF3
Ph
CF3
CF3
CF3
Ph
C
C
PhC
toluene, 0 oC, 2 h
CLi (2.5 equiv)
SO2Ph
+
+
C
SO2Ph
C
C
F
F
C
C
C
Ph
3a (13%)
Ph
Ph
Ph
5a
Ph
3e (15%)
Ph
6a (58%)
When 6c (E/Z = 9/91) was treated with phenyl iodide in
the presence of Pd(PPh3)2Cl2 (10 mol %), Ag2CO3
(0.5 equiv) and n-Bu4NBr (1.0 equiv) in toluene at room
temperature for 12 h, the cross-coupled product 6a (E/
Z = 9/91) was formed in 55% yield along with a large
amount of self-coupled product (36%). The use of other
Pd catalysts such as Pd(PPh3)4 and Pd(OAc)2 and other
bases such as K2CO3, Ce2CO3, and KF did not improve
the yield of 6a. Toluene is the best solvent in this reac-
tion among THF, DMF, CHCl3, CH2Cl2, CH3CN,
and benzene. The cross-coupling reaction of 6c with var-
ious phenyl iodides bearing methoxy, methyl, fluoro,
chloro, bromo, trifluoromethyl, and nitro on para posi-
tion under the same reaction condition afforded the
cross-coupled products 6n–t in 20–71% yields. Similar
experiments were performed with (Z)-6f and the cross-
coupled products (Z)-6d and (Z)-6u–v were obtained
in 40–46% yields. The results of the cross-coupling reac-
tion are summarized in Table 3. Double cross-coupling
reaction of (Z)-6g under the same reaction condition
also yielded the corresponding enediynes (Z)-6a and
(Z)-6w–x in low yields.
R1
CF3
TMS
CF3
C
C
R1I/Pd(PPh3)2Cl2(10 mol%)/Ag2CO3(0.5 equiv)
n-Bu4NBr(1.0 equiv), toluene, rt, 12 h
C
C
C
C
C
C
R1
TMS
Ph
Ph
(Z)-6g
(Z)-6a (R1 = Ph, 30%)
(Z)-6w (R1 = p-MePh, 27%)
(Z)-6x (R1 = p-CF3Ph, 32%)

630
H. H. Jeon et al. / Tetrahedron Letters 48 (2007) 627–631
Table 3. The cross-coupling reaction of 6c and 6f with aryl iodides in the presence of the Pd catalyst
R1
CF3
TMS
CF3
C
C
R1I/Pd(PPh3)2Cl2(10 mol%)/Ag2CO3(0.5 equiv)
n-Bu4NBr(1.0 equiv), toluene, rt, 12 h
C
C
C
C
C
C
R
R
Ph
Ph
6c, 6f
6
Compound
R
R1
Yielda (%)
E/Zb
6a
6n
6o
6p
6q
6r
6s
6t
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
55
20
44
41
51
50
71
45
55
40
46
9/91
9/91
10/90
10/90
9/91
10/90
8/92
10/90
0/100c
0/100c
0/100c
p-MeOPh
p-MePh
p-FPh
p-ClPh
p-BrPh
p-CF3Ph
p-NO2Ph
Ph
6d
6u
6v
n-C6H13
n-C6H13
n-C6H13
p-MePh
p-CF3Ph
a Isolated yield.
b E/Z ratio was determined by 19F NMR spectrum.
c (Z)-Isomer of 6f was used.
Dimerization reaction of (Z)-6f and (Z)-6i was
performed in the presence of CuBr2 and K2CO3 in a
1:1 ratio of pyridine and methanol, and thus
oligoenediyne dimers 7a and 7b22 were obtained in
78% and 77% isolated yields, respectively.
73 (14); IR (neat) 3060, 2945, 2894, 2867, 2139,
1557, 1492, 1463, 1446, 1385, 1367, 1329, 1251,
1194, 1075, 1041, 1020, 998, 894, 770, 760,
697 cmÀ1. Anal. Calcd for C25H35F3Si2: C, 66.92; H,
7.86. Found: C, 66.79; H, 7.77.
CF3
TMS
CF3
C
R C
C
Ph
CuBr2 (0.6 equiv)/K2CO3 (excess)
pyridine:MeOH = 1:1, rt, 5 h
C
C
C
C
C
C
C
Ph
C
C R
R
Ph
F3C
(
Z
)-6f (R =
n
-C6H13
)
7a (R =
n-C6H13, 78%)
7b (R = TIPS, 77%)
(
Z
)-6i (R = TIPS)
A typical reaction procedure for the preparation of 6i
is as follows. A 25 mL two-neck round bottomed flask
equipped with a magnetic stirrer bar, a septum and
nitrogen tee connected to an argon source was
charged with (trimethylsilyl) acetylene (0.304 g,
3.1 mmol) and 4 mL ether. Methyllithium (1.6 M solu-
tion, 1.9 mL, 3.0 mmol) was added into the mixture at
0 °C. After stirring the reaction mixture at 0 °C for
30 min, ether solution of enynyl sulfone 3d (0.492 g,
1.0 mmol) was added to the mixture at 0 °C and then
the mixture was stirred at 0 °C for 2 h. The reaction
mixture was extracted with diethyl ether twice and
then the diethyl ether solution was dried over anhy-
drous MgSO4. After evaporation of the solvent, the
residue was chromatographed on SiO2 column. Elu-
tion with n-hexane provided 0.327 g of 6i (E/Z = 37/
Acknowledgment
This work was supported by the Academic Research
Fund (2006-7-5014) of Yonsei University.
References and notes
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63) in 73% yield. 6i: yellow oil: H NMR (CDCl3) d
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19F NMR (CDCl3, internal standard CFCl3) d À61.67 (s,
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531 (37), 362 (6), 157 (14), 127 (41), 77 (53); IR (KBr)
3060, 2945, 2892, 2867, 2124, 1733, 1548, 1493, 1463, 1364,
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Anal. Calcd for C44H52F6Si2: C, 70.37; H, 6.98. Found: C,
70.18; H, 6.88.