Reactions of β-alkoxyvinyl trifluoromethyl ketones with terminal alkynes - Reagent-controlled regioselectivity addition reactions

Article abstract of DOI:10.1139/v05-247

Reactions of β-alkoxyvinyl trifluoromethyl ketones ROCH=CHCOCF ₃ (1, R = Et, Me₂CHCH₂), and their cyclic analogues 4-trifluoroacetyl-2,3-dihydrofuran (2a) and 5-trifluoroacetyl-3,4- dihydro-2H-pyran (2b), with terminal alk

Full text of DOI:10.1139/v05-247

2127
Reactions of ␤-alkoxyvinyl trifluoromethyl ketones
with terminal alkynes — Reagent-controlled
regioselectivity addition reactions
Shizheng Zhu, Guifang Jin, and Huiling Jiang
Abstract: Reactions of β-alkoxyvinyl trifluoromethyl ketones ROCH=CHCOCF3 (1, R = Et, Me2CHCH2), and their cy-
clic analogues 4-trifluoroacetyl-2,3-dihydrofuran (2a) and 5-trifluoroacetyl-3,4-dihydro-2H-pyran (2b), with terminal al-
kynes R-CϵCH (3, R = Ph, PhCH2, HOCH2, C5H11) mainly gave the 1,2-addition products (carbonyl alkynylation) in
the presence of n-BuLi. However, promoted by ZnCl2–Et3N, the reaction of 1 or 2 with equivalent alkyne predomi-
nately provided 1,4-addition products.
Key words: β-alkoxyvinyl trifluoromethyl ketones, alkynes, 1,2-addition, 1,4-addition, catalysts.
Résumé : En présence de butyl lithium, les réactions des β-alcoxyvinyl trifluorométhyl cétones de formule générale
ROCH=CHCOCF3 (1; R = Et, Me2CHCH2) et de leurs analogues cycliques, tels le 4-trifluoroacétyl-2,3-dihydrofurane
(2a) et le 5-trifluoroacétyl-3,4-dihydro-2H-pyrane (2b) avec des alcynes vrais de formule générale R-CϵCH (3; R = Ph,
PhCH2, HOCH2, C5H11) conduisent principalement à des produits d’additions 1,2 (alcynylation du carbonyle). Toute-
fois, lorsque la réaction est catalysée par du ZnCl2 en présence de Et3N, les réactions des composés 1 et 2 avec un
équivalent d’alcyne conduisent principalement aux produits d’additions 1,4.
Mots clés : β-alcoxyvinyl trifluorométhyl cétones, alcynes, addition 1,2, addition 1,4, catalyseurs.
[Traduit par la Rédaction] Zhu et al. 2131
Introduction
in situ reacted with β-alkoxyvinyl trifluoromethyl ketones
giving only the 1,2-addition products (Scheme 1) (6d, 8).
The factors determining the selectivity between 1,2- and
1,4-additions to a wide range of α,β-unsaturated carbonyl
compounds have received much attention and, in particular,
asymmetric conjugate additions have been developed (9).
The hard acid – soft base concepts have been used to permit
the generalizations that among organometallic reagents,
organolithiums, which are hard nucleophiles, react by 1,2-
addition, and organocopper reagents, which are softer ones,
react by 1,4-addition (10). Grignard reagents were seen to
lie somewhere between them. Since then there have been
major advances in explaining the selectivity of these addi-
tions. In reactions that proceed by kinetic control with
organometallic reagents having a highly localized negative
charge, a charge-controlled 1,2-addition can be expected. In
contrast, in additions of nucleophiles having charge
dislocalization where the reaction is frontier orbital con-
trolled, a 1,4-addition is expected. However, other factors,
notably steric and solvent effects and the nature of the
nucleophile, disturb these simple generalizations.
The present strongly developed interest in organofluorine
chemistry has led to considerable studies of trifluoromethyl
ketones (1) and, in particular, α,β-unsaturated trifluoro-
methyl ketones (2). Such ketones have been used as interme-
diates in heterocyclic synthesis (3) and have also been
viewed as synthetic targets owing to their possible pharma-
cological interest (4). β-Alkoxylvinyl trifluoromethyl ketones
(ROCH=CHCOCF3, 1) are potential fluorinated 1,3-
dicarbonyl compounds. Since they were first prepared in
1967 (5), their preparations and chemical transformations
have been extensively investigated (6). Our group and others
have studied the reactions of acyclic β-alkylvinyl
trifluoromethyl ketones with Grignard reagents derivated
from alkyl and aryl halides. Generally, acyclic β-alkoxyvinyl
trifluoromethyl ketones and the cyclic analogues 2a and 2b
reacted with Grignard reagents gave the corresponding α,β-
unsaturated trifluoromethyl ketone as the sole product,
which arose from 1,4-addition on the β-position of the dou-
ble bond and was followed by β-elimination of alkoxyl
group (7). In contrast, the organic zinc compounds prepared
During our continuous study on the fluorinated push–pull
Received 14 June 2005. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on 21 February 2006.
S. Zhu.1 Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, China.
G. Jin and H. Jiang. Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Lu, Shanghai 200032, China.
1Corresponding author (e-mail: zhusz@mail.sioc.ac.cn).
Can. J. Chem. 83: 2127–2131 (2005)
doi: 10.1139/V05-247
© 2005 NRC Canada

2128
Can. J. Chem. Vol. 83, 2005
Scheme 1.
Table 1. Reactions of β-alkoxyvinyl trifluoromethyl ketone with
alkynes promoted by n-BuLi.
O
O
R1: CH3, Ph
1,4-Addition
R1MgX
R2ZnX
R1
CF3
HO R2
RO
CF3
CF3
Mol.
ratio
Time
(h)
Products and
yields (%)a
Entry
Reactants
O
1
2
3
4
5
6
7
8
9
2
2
2
2
4
1a, 3a
1a, 3a
1b, 3a
1b, 3a
1a, 3b
1b, 3b
1a, 3c
1b, 3c
1b, 3d
2a, 3a
2a, 3a
2b, 3a
1:1
1:2
1:1
1:2
1:1
1:1
1:1
1:1
1:1
1:1
1:2
1:1
4a (41), 5a (20)
4a (18), 5a (52)
4b (39), 5a (28)
4b (23), 5a (59)
4c (68)
4d (65)
4e (64)
4f (61)
4g (67)
R2: PhCH2, CH2=CHCH2
1,2-Addition
( )
n
( )
CF3
n
O
O
Scheme 2.
4
R'
R'
O
24
24
24
4
4
4
RO
CF3
1a-1b
n-BuLi/THF
HO
HO
+
+
CF3
r.t.
RO
CF3
10
11
12
6a (81)
6a (84)
6b (81)
R'
4
5
R'C CH
3a-3d
R: C2H5 (a); CH2CH(CH3)2 (b); R': Ph (a); PhCH2 (b); HOCH2 (c ); C5H11 (d)
aThe yields are calculated on the ketones.
Scheme 3.
ethylene compounds (11), we investigated the alkynylation
of β-substituted unsaturated trifluoromethyl ketones 1 and 2
with terminal alkynes in detail. We found that the reaction
products mainly depend on the promoted reagents. n-Butyl
lithium promoted addition reactions gave 1,2-addition prod-
ucts, a process favored by charge control. ZnCl2–Et3N pro-
moted addition reactions provided 1,4-addition products, a
process favored by orbital control. Herein we report these
results.
R
O
HO
n-BuLi/THF
( )
CF3
n
RC CH
+
( )n
CF3
r.t.
O
O
2a (n = 1)
2b (n = 2)
3
6a-6b
R: Ph (a); PhCH2 (b); HOCH2 (c); C5H11 (d)
products because their ions have highly localized negative
charges without conjugation structures.
Results and discussion
Reaction of β-alkoxyvinyl trifluoromethyl ketone 1a with
PhCϵCH 3a proceeded smoothly at room temperature in the
presence of 1 equiv. of n-BuLi in THF and finished in 2 h
(monitored by TLC). Flash chromatographic purification on
silica gel (n-hexane – ethyl acetate) gave two products, 1-
ethoxy-5-phenyl-3-trifluoromethyl-1penten-4-yne-3-ol (4a,
41%) and 1,7-diphenyl-3-trifluoromethyl-4-heptene-1,6-
diyn-3-ol (5a, 20%), which is an over addition product.
When 2 equiv. of n-BuLi and 3a were used, the yield of 5a
increased to 52% (See Scheme 2, Table 1).
The proton NMR spectra of 4a and 5a showed that both
of them are trans-alkenes. The coupling constants between
the two alkene’s protons were 13 Hz in 4a and 15 Hz in 5a,
and the chemical shifts of the two alkene’s protons in 4a
were 7.12 and 5.00 ppm owing to the presence of the
ethoxyl group on the double bond; while in compound 5a
they were 6.56 and 6.31 ppm. Under the same reaction con-
ditions, the reaction of β-isobutoxyvinyl trifluoromethyl
ketone (1b) with 3a gave the same results as 1a.
Interestingly, terminal alkynes 3b–3d reacted with 1 af-
fording only 1,2-addition products. No further addition prod-
ucts were detected or isolated even when excessive
equivalents of alkynes 3 and n-BuLi were used or by pro-
longing the reaction time to 24 h. When reacted with ke-
tones 1a and 1b, the terminal alkynes 3 have excellent
regioselectivity except for 3a. The selectivity could be ex-
plained by the structures of the nucleophiles. The phenyl-
acetylene ion is charge delocalized owing to its conjugation
structure, therefore, it gave both 1,2-addition and 1,4-
addition products. The alkynes 3b–3d only gave 1,2-addition
In contrast, the cyclic analogues, 4-trifluoroacetyl-2,3-
dihydrofuran (2a) and 5-trifluoro-3,4-dihydro-2H-pyran (2b)
are less reactive. In the presence of n-BuLi, the reactions be-
tween 2 and 3a needed a longer time period (typical 4 h) and
only 1,2-addition products 6a and 6b were obtained in good
yields (Scheme 3). With 2 equiv. of 3a and n-BuLi, no fur-
ther reaction product was observed. These results indicated
the considerable difference between the phenylacetylene
lithium reagent and the Grignard reagents that gave exclu-
sively the 1,4-addition products, carbon–carbon double bond
attacking products (7, 8).
Recently, considerable progress has been developed in the
alkynylation of carbonyl compounds using Lewis acids in
combination with bases (12). For example, Jiang and Si (13)
prepared a series of propargylic alcohols by treatment of the
aromatic aldehydes with terminal alkynes promoted by zinc
chloride and triethyl amine. In the subsequent studies on the
alkynylation of the β-substituted unsaturated trifluoromethyl
ketones 1 and 2, we also used the ZnCl2–Et3N system as the
promotor. Thus, a mixture of 3a (1.5 mmol), anhydr. ZnCl2
(2.25 mmol), and Et3N (2.25 mmol) in toluene was stirred at
room temperature for 1 h, then 1a (1.5 mmol) in 10 mL THF
was added. After it was stirred overnight, TLC analysis
showed that the reaction was finished, and chromatography
purification gave the ketone 7a (14) in 81% yield. When
2 equiv. of 3a was used, this reaction gave two products, 7a
(58%) and the double-alkylated product 5a (25%)
(Scheme 4).
Under the same reaction conditions, the reaction of equiv-
alent 3a to 2a afforded product 8a (53%) (Table 2). How-
© 2005 NRC Canada

Zhu et al.
2129
Scheme 5.
Scheme 4.
Ph
Ph
O
O
HO
O
HO
PhC CH
(
)
n
HO
+
OH
CF3
( )
(
)
CF3
PhC CH
n
CF3
n
Ph
ZnCl2/Et3N
CF3
+
EtO
CF3
O
CF3
Ph
ZnCl2/Et3N
O
Ph
1a
7a
5a
9a-9b
8a-8b
n = 1 (2a); 2 (2b)
PhC C-Zn+Cl
Ph
Hydrolysis
1,4-Addition
Table 2. Reactions of β-alkoxyvinyl trifluoromethyl ketone with
OZnCl
CF3
alkynes promoted by ZnCl2–Et3N.
Hydrolysis
(
)
n
(
)
n
CF3
OZnCl
Ph
Mol.
ratio
Time
(h)
Products and
yields (%)a
O
12
O
10
Entry
Reactants
Ph
Ph
1
2
3
4
5
1a, 3a
1a, 3a
2a, 3a
2a, 3b
2b, 3a
1:1
1:2
1:1
1:1
1:1
24
24
24b
24b
36
7a (81)
1,4-Elimination
Intramolecular
1,2-addition
O
ClZnO
7a (58), 5a (25)
8a (53), 9a (7)
No reaction
8b (44)
CF3
CF3
( )
n
(
)
n
Intermolecular
1,2-addition
ClZnO
13
ClZnO
11
Ph
Ph
aThe yields are calculated on the ketones.
1
bThe reactions were carried out at 80 °C, the other reactions were at
room temperature.
uncorrected. H NMR and 19F NMR spectra were recorded
on Varian-360 or Bruker AM-300 instruments with Me4Si
and CFCl3 (with upfield negative) as internal and external
standards, respectively; NMR spectra were recorded in chlo-
roform-d unless otherwise stated. IR spectra were obtained
with a PerkinElmer 983G spectrophotometer using KBr
disks of the compound. Low- and high-resolution mass spec-
tra were obtained on HP 5989a and Finnigan MAT instru-
ments, respectively. This institute performed the elemental
analyses.
ever, for the reaction of 2b with 3a, the alkynylation only
occurred at the double bond carbon atom giving the product
8b. The final product was obtained from a rearrangement of
1,4-addition intermediate 10, followed by an 1,4-elimination
of the alkoxyl group to produce intermediate 11, then an
intramolecular 1,2-addition occurred and gave the final sta-
ble product (Scheme 5). The driving force for the rearrange-
ment might be the conjugation of the double bond with the
triple bond. Since the intermediate 11 has a ketone func-
tional group, the intermolecular 1,2-addition gave the double
addition intermediate 13, which was hydrolyzed and pro-
duced product 9. It is noteworthy that five-membered 2a
produced two addition products 8a and 9a, while six-
membered ketone 2b only afforded 8b. This difference is
aroused from the intermediate 11. When n = 1 (2a), the
ethoxyl 11a is not as flexible as the propoxyl chain 11b (n =
2, 2b). Therefore, 11b can occur through an intramolecular
1,2-addition reaction exclusively, and 11a can proceed to
both intra- and inter-molecular 1,2-addition reactions. Un-
fortunately, the ketones did not react with 3-phenylpropyne
(3b) under several different reaction conditions, even at high
temperature. The possible reason is that 3-phenylpropyne is
not as active as phenylacetylene and ZnCl2–Et3N could not
promote the addition reaction.
In summary, we have studied the reaction and regioselecti-
vity of terminal alkyne addition to β-alkoxyvinyl trifluoro-
methyl ketone, which is very sensitive to the promoted
reagents and ketone structure. Promoted by n-BuLi, the ad-
dition of terminal alkynes gave 1,2-addition products in high
yields, in marked contrast to the 1,4-additions promoted by
ZnCl2–Et3N. The high regioselectivity and its tenability of
the terminal alkynes to enones and the accessibility of fluo-
rine-contained adducts may be useful in the application of
these reactive compounds for the effective synthesis of
bioactive fluorine-containing substances.
General procedure for the reaction of the alkyne with
ketone in the presence of n-BuLi
A solution of n-butyl lithium – THF (3 mL, 4.8 mmol)
and 10 mL THF was added dropwise to a 50 mL three-
necked flask containing phenylacetylene (0.49 g, 4.8 mmol)
in 15 mL THF, after stirring at room temperature for 15 min,
β-alkoxylvinyl trifluoromethyl ketone (1a) (0.806 g,
4.8 mmol) in 10 mL THF was added. The solution was
stirred for 2 h and TLC analysis showed the reaction was
completed, and then 40 mL of a satd. NH4Cl solution was
added and extracted with ether (3 × 20 mL). The organic
layer was washed with brine (30 mL), dried over Na2SO4,
and concentrated in vacuum. The residue was purified by
flash chromatography by using n-hexane–EtOAc as eluent to
give two products, 4a (26%) and 5a (51%).
1-Ethoxy-5-phenyl-3-trifluoromethyl-1-penten-4-yn-3-ol (4a)
Yield: 41%. FT-IR (KBr, cm–1) ν: 3423 (s), 2984 (w),
1
2239 (s), 1655 (s), 1491 (s), 1189 (vs). H NMR (CDCl3) δ:
7.43 (m, 5H, Ph), 7.12 (d, 1H, J = 12.6 Hz, CH), 5.00 (d,
1H, J = 12.6 Hz, CH), 3.84 (q, J = 7.5 Hz, 2H, OCH2), 2.90
(s, 1H, OH), 1.32 (t, J = 7.5 Hz, 3H, CH3). 19F NMR
(CDCl3): –81.73 (s, CF3). MS (70 eV) m/z (%): 270 (M+,
7.13), 241 (M+ – Et, 14.11), 225 (M+ – OEt, 2.72), 201 (M+ –
CF3, 100.00), 173 (M+ – CF3CO, 37.16), 102 (PhCϵCH,
8.40), 77 (Ph+, 14.85). HR-MS (EI) M+ calcd. for
C14H13F3O2: 270.0893; found: 270.0865.
1-Isobutoxy-5-phenyl-3-trifluoromethyl-1-penten-4-yn-3-ol
(4b)
Experimental
Yield: 39%. FT-IR (KBr, cm–1) ν: 3423 (s), 2961 (s), 2235
1
Solvents were purified and dried before use. Melting
points were determined on a Mel-Temp apparatus and are
(s), 1651 (w), 1491 (m), 1191 (vs). H NMR (CDCl3) δ:
7.51 (m, 5H, Ph), 7.18 (d, 1H, J = 12.6 Hz, CH), 5.01 (d,
© 2005 NRC Canada

2130
Can. J. Chem. Vol. 83, 2005
1H, J = 12.6 Hz, CH), 3.55 (d, J = 6.6 Hz, 2H, OCH2), 2.82
(s, 1H, OH), 2.04 (m, 1H, CH(CH3)2), 0.98 (d, J = 6.9 Hz,
6H, 2CH3). 19F NMR (CDCl3): –81.99 (s, CF3). MS (70 eV)
m/z (%): 299 (M+H, 0.41), 298 (M+, 2.11), 229 (M+ – CF3,
1,7-Diphenyl-3-trifluoromethyl-4-heptene-1,6-diyn-3-ol (5a)
Yield: 20%. FT-IR (KBr, cm–1) ν: 3404 (s), 2976 (m),
1
2236 (s), 1655 (m), 1491 (vs), 1191 (vs). H NMR (CDCl3)
δ: 7.40 (m, 10H, 2Ph), 6.56 (d, 1H, J = 15.6 Hz, CH), 6.31
(d, 1H, J = 15.6 Hz, CH), 3.01 (s, 1H, OH). 13C NMR
(75.3 MHz, CDCl3) δC: 134.7 (C-4), 132.1, 132.0, 129.7,
45.04), 173 (M+ – CF3
–
+CHCH(CH3)2), 100.00), 102
(PhϵCH, 12.11), 77 (Ph+, 7.08). HRMS (EI) M+ calcd. for
C16H17F3O2: 298.1186; found: 298.1181.
1
128.9, 128.8, 128.5 (ArC), 122.7 (q, JC-F = 280 Hz, CF3),
122.7 (ArC-1), 120.7 (ArC-1), 116.3 (C-5), 93.7 (C-7), 89.0
1
(C-2), 86.0 (C-1), 81.8 (C-6), 71.9 (q, J = 48 Hz, C-3). 19F
1-Ethoxy-6-phenyl-3-trifluoromethyl-1-hexen-4-yn-3-ol
(4c)
NMR (CDCl3): –80.48 (s, CF3). MS (70 eV) m/z (%): 326
(M+, 15.73), 257 (M+ – CF3, 100.00), 226 (M+H – PhCϵC+,
20.70), 127 (PhCϵCCH=CH+, 14.24), 101 (PhCϵC+, 10.57),
77 (Ph+, 14.85). HR-MS (EI) M+ calcd. for C20H13F3O:
326.0895; found: 326.0919.
Yield: 68%. FT-IR (KBr, cm–1) ν: 3423 (s), 2983 (s), 2237
1
(m), 1656 (s), 1183 (vs). H NMR (CDCl3) δ: 7.35 (m, 5H,
Ph), 7.03 (d, 1H, J = 12.6 Hz, CH), 4.96 (d, 1H, J =
12.6 Hz, CH), 3.81 (q, J = 6.9 Hz, 2H, OCH2), 3.78 (s, 2H,
PhCH2), 2.81 (s, 1H, OH), 1.31 (t, J = 6.9 Hz, 3H, CH3). 19
F
2-(4,5-Dihydrofuran-3-yl)-1,1,1-trifluoro-4-phenyl-3-
butyn-2-ol (6a)
NMR (CDCl3): –82.21 (s, CF3). MS (70 eV) m/z (%): 284
(M+, 0.97), 267 (M+H – H2O, 22.38), 215 (M+ – CF3,
100.00), 187 (M+ – CF3CO, 10.43), 115 (PhCH2CϵC+,
Yield: 81%. FT-IR (KBr, cm–1) ν: 3407 (s), 2971 (m),
1
+
24.41), 91 (PhCH2 , 16.55), 77 (Ph+, 5.62). Anal. calcd. for
2234 (s), 1656 (s), 1490 (s), 1173 (vs). H NMR (CDCl3) δ:
7.40 (m, 5H, Ph), 6.76 (s, 1H, CH), 4.50 (m, 2H, OCH2),
3.35 (s, 1H, OH), 2.83 (m, 2H, CH2). 19F NMR (CDCl3):
–79.52 (s, CF3). MS (70 eV) m/z (%): 268 (M+, 8.56), 251
(M+ – OH, 10.52), 199 (M+ – CF3, 100.00), 97 (M+ – CF3 –
PhCϵC+, 38.99). Anal. calcd. for C14H11O2F3 (%): C 62.69,
H 4.10; found: C 62.92, H 4.22.
C15H15O2F3 (%): C 63.38, H 5.28; found: C 63.63, H 5.55.
1-Isobutoxy-6-phenyl-3-trifluoromethyl-1-hexen-4-yn-3-ol
(4d)
Yield: 65%. FT-IR (KBr, cm–1) ν: 3427 (s), 2962 (s), 2240
1
(m), 1672 (s), 1655 (vs), 1181 (vs). H NMR (CDCl3) δ:
7.36 (m, 5H, Ph), 7.07 (d, 1H, J = 12.6 Hz, CH), 4.95 (d,
1H, J = 12.6 Hz, CH), 3.73 (s, 2H, PhCH2), 3.51 (d, J =
6.6 Hz, 2H, OCH2), 2.75 (s, 1H, OH), 1.96 (m, 1H,
CH(CH3)2), 0.96 (d, J = 7.2 Hz, 6H, 2CH3). 19F NMR
(CDCl3): –82.20 (s, CF3). MS (70 eV) m/z (%): 312 (M+,
2-(5,6-Dihydro-4H-pyran-3-yl)-1,1,1-trifluoro-4-phenyl-3-
butyn-2-ol (6b)
Yield: 81%. FT-IR (KBr, cm–1) ν: 3412 (s), 2955 (m),
1
2232 (s), 1658 (s), 1491 (s), 1167 (vs). H NMR (CDCl3) δ:
7.41 (m, 5H, Ph), 7.08 (s, 1H, CH), 4.04 (m, 2H, OCH2),
2.97 (s, 1H, OH), 2.27 (m, 2H, CH=C-CH2), 1.90 (m, 2H,
CH2). 19F NMR (CDCl3): –79.24 (s, CF3). MS (70 eV) m/z
(%): 282 (M+, 6.91), 213 (M+ – CF3, 100.00), 111 (M+ –
CF3 – PhCϵCH, 5.67), 83 (OCH2CH2CH2C=CH+, 8.40), 77
(Ph+, 10.85). HR-MS (EI) M+ calcd. for C15H13F3O2:
282.0893; found: 282.0868.
1.84), 243 (M+ – CF3, 100.00), 187 (M+ – CF3
–
+CHCH(CH3)2), 85.68), 115 (PhCH2CϵC+, 24.83), 91
+
(PhCH2 , 19.01), 77 (Ph+, 5.62), 57 (CH2CH(CH3)2, 61.2).
Anal. calcd. for C17H19O2F3 (%): C 65.38, H 6.09; found: C
64.99, H 6.48.
6-Ethoxy-4-trifluoromethyl-5-hexen-2-yn-1,4-diol (4e)
Yield: 64%. FT-IR (KBr, cm–1) ν: 3392 (vs), 2983 (s),
General procedure for the reaction of acetylene with
ketone in the presence of ZnCl2–Et3N
1
2235 (m), 1727 (s), 1186 (vs). H NMR (CDCl3) δ: 7.00 (d,
J = 12.6 Hz, 1H, CH), 4.92 (d, J = 12.6 Hz, 1H, CH), 4.36
(s, 2H, CH2), 3.82 (q, J = 6.9 Hz, 2H, OCH2), 3.10 (m, 1H,
OH), 2.19 (m, 1H, OH), 1.31 (t, J = 6.9 Hz, 3H, CH3). 19F
NMR (CDCl3): –81.82 (s, CF3). MS (70 eV) m/z (%): 225
(M+H, 1.81), 224 (M+, 0.83), 207 (M+H – H2O, 46.76), 179
(M+ – OEt, 6.89), 155 (M+ – CF3, 100.00), 109 (M+ – CF3 –
Phenylacetylene (0.153 g, 1.5 mmol) was added under an
argon atmosphere at room temperature to a solution of
anhydr. ZnCl2 (0.306 g, 2.25 mmol) and triethylamine
(0.32 mL, 2.25 mmol) in dried toluene (10 mL). After stir-
ring for 1 h, β-alkoxylvinyl trifluoromethyl ketone (0.252 g,
1.5 mmol) was added dropwise. The mixture was stirred
overnight and TLC analysis confirmed that the reaction was
finished, then the mixture was washed with 40 mL of a satd.
NH4Cl solution, followed by extraction with ether (3 ×
20 mL). The organic layer was washed with brine (30 mL),
dried over Na2SO4, and concentrated in vacuum to give a
residue, which was purified by flash chromatography by us-
ing n-hexane–EtOAc as eluent to give the product.
+
HOEt, 49.74), 69 (CF3 , 17.44). Anal. calcd. for C9H11O3F3
(%): C 48.21, H 4.91; found: C 48.51, H 5.23.
6-Isobutoxy-4-trifluoromethyl-5-hexen-2-yn-1,4-diol (4f)
Yield: 61%. FT-IR (KBr, cm–1) ν: 3398 (vs), 2963 (s),
2234 (m), 1727 (s), 1653 (s), 1194 (vs). 1H NMR (CDCl3) δ:
7.01 (d, J = 12.6 Hz, 1H, =CH), 4.93 (d, J = 12.6 Hz, 1H,
=CH), 4.51 (d, J = 6.6 Hz, 2H, OCH2), 4.35 (s, 2H, CH2),
2.19 (s, 2H, 2OH), 2.01 (m, 1H, CH(CH3)2), 0.95 (d, J =
6.6 Hz, 6H, CH3). 19F NMR (CDCl3): –82.08 (s, CF3). MS
(70 eV) m/z (%): 252 (M+, 3.17), 234 (M+ – H2O, 1.75), 183
(M+ – CF3, 76.91), 127 (M+ – CF3 – CHϵCCH2OH,
100.00), 109 (M+ – CF3 – H2O – CHϵCCH2OH, 47.73), 69
(CF3, 12.71), 57 (CH2CH(CH3)2, 96.42). HR-MS (EI) M+
calcd. for C11H15F3O3: 252.0979; found: 252.0973.
1,1,1-Trifluoro-6-phenyl-hex-3-en-5-yn-2-one (7a)
Yellow liquid; yield: 58%–81%. FT-IR (KBr, cm–1) ν:
1
2195 (s), 1722 (s), 1602 (s), 1582 (s), 1205 (s), 1148 (s). H
NMR (CDCl3) δ: 7.42 (m, 5H, Ph), 7.25 (d, J = 15.3 Hz,
1H, CF3COCH=), 6.85 (d, J = 15.0 Hz, 1H, CH=C). 19F
NMR (CDCl3): –77.80 (s, CF3). MS (70 eV) m/z (%): 224
(M+, 90.95), 155 (M+ – CF3, 100.00), 127 (M+ – COCF3,
© 2005 NRC Canada

Zhu et al.
2131
66.73), 77 (Ph+, 14.43). Anal. calcd. for C12H7OF3 (%): C
64.29, H 3.15; found: C 64.29, H 3.16.
References
1. (a) R.E. Banks, B.E. Smart, and J.C. Tatlow (Editors).
Organofluorine chemistry, principles and commercial applica-
tion. Plenum, New York. 1994; (b) R. Filler, Y. Kobayashi,
and L.M. Yagupolskii (Editors). Organofluorine compounds in
medicinal chemistry and biomedical applications. Elsevier,
Amsterdam. 1993; (c) J.P. Begue and D. Bonnet-Delpon. Tet-
rahedron, 47, 3207 (1991).
2. (a) W.S. Huang and C.Y. Yuan. J. Chem. Soc. Perkin Trans. 1,
741 (1995); (b) A.V. Sanin, V.G. Nenajdenko, K.I. Smolko,
D.I. Detrisenko, and E.S. Balenkova. Synthesis, 842 (1998);
(c) V.G. Nenajdenko, A.L. Krasovsky, M.V Lebedev, and E.S.
Balenkova. Synlett, 1349 (1997); (d) S.Z. Zhu, C.Y. Qin, G.L.
Xu, Q.L. Chu, and Q.C. Huang. J. Fluorine Chem. 99, 141
(1999).
3-(3-Phenylprop-2-ynylidene)-2-hydroxy-2-(trifluoro-
methyl)tetrahydrofuran (8a)
White solid; mp 72–74 °C; yield: 53%. FT-IR (KBr, cm–1)
1
ν: 3361 (s), 2913 (s), 2200 (m), 1650 (s), 1193 (vs). H
NMR (CDCl3) δ: 7.40 (m, 5H, Ph), 6.18 (s, 1H, CH), 4.19
(m, 2H, OCH2), 3.07 (m, 2H, CH2), 2.95 (m, 1H, OH). 13C
NMR (75.3 MHz, CDCl3) δC: 132.2 (C=CH), 131.6 (ArC-4),
128.9 (ArC-3, ArC-5), 128.2 (ArC-2), 122.3 (ArC-1), 122.6
(q, 1JC-F = 280 Hz, CF3), 109.4 (C=CH), 100.7 (C-CF3), 97.1
(C=CH-CϵC), 88.3(C=CH-CϵC), 68.3 (OCH2), 31.3 (CH2).
19F NMR (CDCl3): –83.53 (s, CF3). MS (70 eV) m/z (%):
268 (M+, 27.41), 251 (M+ – OH, 3.01), 199 (M+ – CF3,
100.00), 181 (M+ – CF3 – H2O, 3.03), 91 (PhCϵC+, 5.45),
77 (Ph+, 19.36). HR-MS (EI) M+ calcd. for C14H11F3O2:
268.0692; found: 268.0711.
3. (a) V.G. Nenjdenko, A.V. Sanin, and E.S. Balenkova. Russ.
Chem. Rev. 68, 437 (1999); (b) M.W. Walter, R.M. Adlington,
J.E. Baldwin, and C.J. Schofield. J. Org. Chem. 63, 5179
(1998).
3-(3-Phenylprop-2-ynylidene)-2-hydroxyl-2-(trifluoro-
methyl)tetrahydropyran (8b)
4. (a) M. Kawase, H. Harada, S. Satio, J.M. Cui, and S. Tani.
Biorg. Med. Chem. Lett. 9, 193 (1999); (b) D.L. Boger, H.
Sato, A.E. Lemet, B.J. Austin, J.E. Patterson, M.P. Patricelli,
and B.F. Cravatt. Biorg. Med. Chem. Lett. 9, 265 (1999).
5. N.P. Gambaryan, L.A. Simonyan, and P.V. Petrovskii. Izv.
Akad. Nauk SSSR Ser. Khim. 918 (1967).
6. (a) M. Hojo, R. Masuda, Y. Kokuryo, H. Shioda, S. Matsuo,
and I.I. Gerus. Chem. Lett. 499 (1976); (b) M.G. Gorbunova,
S.I. Vdovenko, Y.L. Yagupolskii, and V.P. Kukhar. Zh. Org.
Khim. 26, 1877 (1990); (c) S.I. Vdovenko, I.I. Gerus, and
M.G. Gorbunova. J. Chem. Soc. Perkin Trans. 1, 559 (1993);
(d) M.G. Gorbunova, I.I. Gerus, and V.P. Kukhar. J. Fluorine
Chem. 65, 25 (1993); (e) H.G. Bonacorso, I.S. Lopes, A.D.
Wastowski, N. Zanatta, and M.A.P. Martins. J. Fluorine Chem.
120, 29 (2003).
White solid; mp: 56–58 °C; yield: 44%. FT-IR (KBr, cm–1)
ν: 3397 (s), 2999 (m), 2204 (m), 1658 (m), 1443 (s), 1185
1
(vs). H NMR (CDCl3) δ: 7.48 (m, 5H, Ph), 6.24 (s, 1H,
CH), 3.98 (dd, J = 4.8, 7.5 Hz, 2H, OCH2), 3.14 (s, 1H,
OH), 3.04 (m, 1H, CH2), 2.60 (m, 1H, CH2), 2.03 (m, 1H,
CH2), 1.85 (m, 1H, CH2). 19F NMR (CDCl3): –82.43 (s,
CF3). MS (70 eV) m/z (%): 282 (M+, 19.72), 213 (M+ – CF3,
100.00), 195 (M+ – CF3 – OH, 3.10), 185 (M+ – COCF3,
30.70), 77 (Ph+, 10.47). Anal. calcd. for C15H13O2F3 (%): C
63.83, H 4.61; found: C 64.09, H 4.67.
4-(2-Hydroxyethyl)-1,8-diphenyl-3-trifluoromethyl-4-
heptene-1,6-diyn-3-ol (9)
7. R.J. Andrew and J.M. Mellor. Tetrahedron, 56, 7261 (2000).
8. S.Z. Zhu, G.L. Xu, C.Y. Qin, Q.L. Chu, and Y. Xu. Monatsh.
Chem. 130, 671 (1999).
9. I.S. Kruchok, I.I. Gerus, and V.P. Kukhar. Tetrahedron, 56,
6533 (2000).
Yield: 7%. FT-IR (KBr, cm–1) ν: 3317 (s), 2233 (m), 1640
1
(m), 1491 (s), 1444 (m), 1186 (vs). H NMR (CDCl3) δ:
7.52–7.31 (m, 10H, 2Ph), 7.30 (m, 1H, CH), 5.18 (d, J =
6 Hz, 1H, CH), 4.07 (m, 2H, OCH2), 3.32 (s, 1H, OH), 3.09
(d-q, J = 6.3, 8.4 Hz, 1H, OH), 2.25 (m, 2H, CH2). 13C
NMR (75.3 MHz, CDCl3) δC: 132.1 (C-4), 131.9, 129.7,
10. S.J. Coles, J.M. Mellor, A.H. El-Sagheer, E.E.M. Salem, and
R.N. Metwally. Tetrahedron, 56, 10057 (2000).
1
128.5, 128.2, 128.2, 125.7 (ArC), 125.1 (q, JC-F = 280 Hz,
11. (a) Q.L. Chu, L.P. Song, G.F. Jin, and S.Z. Zhu. J. Fluorine
Chem. 108, 51 (2001); (b) S.Z. Zhu, G.F. Jin, W.M. Peng, and
Q.C. Huang. Tetrahedron, 59, 2899 (2003).
12. M. Yamaguchi, A. Hayashi, and M. Hirama. Chem. Lett. 2479
(1992); N.K. Anand and E.M. Carreira. J. Am. Chem. Soc.
123, 9687 (2001).
13. B. Jiang and Y.G. Si. Tetrahedron Lett. 43, 8323 (2002).
14. M.A.R. Martins, D.J. Emmerich, C.M.P. Pereira, W. Cunico,
M. Rossato, N. Zanatta, and H.G. Bonacorso. Tetrahedron
Lett. 45, 4935 (2004).
CF3), 123.2 (C-5), 88.9 (C-7), 88.4 (C-1), 85.5 (C-6), 81.6
(C-2), 73.9 (C-3), 70.3 (CH2OH), 51.6 (CH2). 19F NMR
(CDCl3): –79.34 (s, CF3). MS (70 eV) m/z (%): 370 (M+,
19.72), 301 (M+ – CF3, 100.00), 284 (M+ – CF3 – OH, 3.10),
269 (M+ – PhCϵC+, 30.70), 77 (Ph+, 10.47). Anal. calcd. for
C22H17O2F3 (%): C 71.35, H 4.59; found: C 71.21, H 4.69.
Acknowledgment
This work was supported by the National Natural Science
Foundation of China (NNSFC) (Grant Nos. 20372077 and
20532040).
© 2005 NRC Canada

This article has been cited by:
1. Yoshihiro Nishimoto, Hiroki Ueda, Makoto Yasuda, Akio Baba. 2012. Gallium Tribromide Catalyzed Coupling Reaction of
Alkenyl Ethers with Ketene Silyl Acetals. Angewandte Chemie 124:32, 8197-8200. [CrossRef]
2. Yoshihiro Nishimoto, Hiroki Ueda, Makoto Yasuda, Akio Baba. 2012. Gallium Tribromide Catalyzed Coupling Reaction of
Alkenyl Ethers with Ketene Silyl Acetals. Angewandte Chemie International Edition 51:32, 8073-8076. [CrossRef]
3. Tao Song, Lei Liu, Jingwei Zhao, Huiling Jiang, Shizheng Zhu, Liangzhong Xu. 2012. Reactions of 4-ethoxy-1,1,1-
trifluorobut-3-en-2-one with diethyl malonate anion: synthesis and crystal structures of fluorinated organo alkali–metal
complexes. Tetrahedron . [CrossRef]
4. Shizheng Zhu, Guifang Jin, Huiling Jiang. 2006. Reactions of β-Alkoxyvinyl Trifluoromethyl Ketones with Terminal Alkynes
— Reagent-Controlled Regioselectivity in Addition Reactions. ChemInform 37:39. . [CrossRef]