Catalytic Enantioselective Conjugate Alkynylation of α,β-Unsaturated 1,1,1-Trifluoromethyl Ketones with Terminal Alkynes

Article abstract of DOI:10.1002/chem.201601303

The first catalytic enantioselective conjugate alkynylation of α,β-unsaturated 1,1,1-trifluoromethyl ketones has been carried out. Terminal alkynes and 1,3-diynes were treated with trifluoromethyl ketones in the presence of a low catalytic load of a Cu

Full text of DOI:10.1002/chem.201601303

DOI: 10.1002/chem.201601303
Full Paper
&
Asymmetric Catalysis
Catalytic Enantioselective Conjugate Alkynylation of a,b-
Unsaturated 1,1,1-Trifluoromethyl Ketones with Terminal Alkynes
Amparo Sanz-Marco,[a] Gonzalo Blay,*[a] M. Carmen MuÇoz,[b] and Josꢀ R. Pedro*[a]
Abstract: The first catalytic enantioselective conjugate alky-
nylation of a,b-unsaturated 1,1,1-trifluoromethyl ketones has
been carried out. Terminal alkynes and 1,3-diynes were treat-
ed with trifluoromethyl ketones in the presence of a low cat-
alytic load of a CuI-MeOBIPHEP complex (2.5 mol%) and trie-
thylamine (10 mol%) to give the corresponding trifluoro-
methyl ketones bearing a propargylic stereogenic center at
the b position with good yields and excellent enantiomeric
excesses in most of the cases. No 1,2-addition products
were formed under the reaction conditions. The procedure
showed broad substrate scope for alkyne, diyne, and enone.
A rationale for the observed stereochemistry has been pro-
vided. Finally, the potential application of the reaction prod-
ucts in the synthesis of chiral tetrahydrofurans bearing a tri-
fluoromethylated quaternary stereocenter has been devised.
ly available a,b-unsaturated trifluoromethyl ketones[6] has
proved to be an efficient procedure for the synthesis of b-sub-
stituted trifluoromethyl ketones. This reaction can be per-
formed in some cases in an enantioselective fashion[7] provid-
ing chiral nonracemic trifluoromethyl ketone building blocks
for the synthesis of fluorinated chiral drugs.[8] However, conju-
gate addition reactions with 1,1,1-trifluoromethyl enones are
challenging because the presence of the strongly electron-
withdrawing trifluoromethyl group renders the ketone func-
tionality highly reactive, making the control over regioselectivi-
ty difficult.
Introduction
Fluorinated organic molecules are playing a growing role in
medicinal, agricultural, and material chemistry because of the
significant changes in the physical, chemical, and biological
properties that the introduction of fluorine atoms causes in
the parent molecules.[1] For instance, trifluoromethyl, a bulky
and highly electron-withdrawing group, is known to enhance
the metabolic stability and membrane permeability of drugs
and to serve as a bioisostere for several functionalities.[2] Fur-
thermore, because of its strongly electron-withdrawing nature,
it can impart considerable changes to the reactivity of vicinal
functional groups. Among CF3-containing compounds, 1,1,1-tri-
fluoromethyl ketones[3] hold a prominent position because of
their own biological activity, especially as enzyme inhibitors,[4]
as well as their role as critical intermediates in the construction
of trifluoromethylated heterocycles, medicinal compounds, and
fluorinated analogues of natural products.[5] Direct transforma-
tion of trifluoromethyl-containing building blocks is a very ap-
pealing strategy for the construction of trifluoromethylated
compounds. Thus, 1,4-addition of carbon nucleophiles to readi-
During the last years the catalytic enantioselective conjugate
alkynylation of enones has been developed as a way to obtain
chiral ketones bearing a propargylic stereocenter at the b posi-
tion.[9] The resulting compounds are very versatile building
blocks because of two functional moieties, that is, ketone car-
bonyl and a triple CꢀC bond. However, the enantioselective
conjugate alkynylation of 1,1,1-trifluoromethyl enones has
been elusive. Thus, only two examples of enantioselective alky-
nylation of this kind of enones have been reported so far, both
taking place regioselectively on the carbonyl group (1,2-addi-
tion).[10] On the other hand, although the conjugate alkynyla-
tion of 1,1,1-trifluoromethyl enones has been achieved by
using alkynylboranes,[11] an enantioselective version of this re-
action has not been developed.
[a] Dr. A. Sanz-Marco, Prof. Dr. G. Blay, Prof. Dr. J. R. Pedro
Department de Quꢀmica Orgꢁnica-Facultat de Quꢀmica
Universitat de Valꢂncia
C/Dr. Moliner 50, 46100 Burjasso (Spain)
Fax: (+34)963544328
E-mail: gonzalo.blay@uv.es
jose.r.pedro@uv.es
Homepage: www.uv.es
In this paper we report a full account of our research on the
development of the catalytic enantioselective conjugate alky-
nylation and diynylation[12] of 1,1,1-trifluoromethyl enones by
using terminal alkynes under copper(I) catalysis.
[b] Prof. Dr. M. C. MuÇoz
Departament de Fꢀsica Aplicada
Universitat Politꢂcnica de Valꢂncia
Camꢀ de Vera s/n, 46022 Valꢂncia (Spain)
Supporting information and the ORCID identification numbers for some of
the authors of this article can be found under
http://dx.doi.org/10.1002/chem.201601303.
Chem. Eur. J. 2016, 22, 1 – 9
1
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
provided the expected product 3aa with low yield and enan-
tiomeric excess (Table 1, entries 2 and 5). Fortunately, MeOBI-
PHEP ligand L7, gave compound 3aa with high enantiomeric
excess (94%) although in moderate yield (66%). Examination
of the reaction mixture showed the formation of compound
3’aa (25%), which is most probably produced after a 1,2-addi-
tion of phenylacetylene to the initially formed compound 3aa.
To minimize the formation of compound 3’aa, several ex-
periments were carried out using L7 as chiral ligand (Table 2).
Results and Discussion
1. Enantioselective conjugate alkynylation of trifluoromethyl
enones
To start our research we tested the reaction between phenyla-
cetylene (2a) and trifluoromethyl enone 1a under reaction
conditions similar to those developed by us for the alkynyla-
tion of 1,1-difluoro-1-(phenylsulfonyl)-3-en-2-ones,[9e] which in-
volved a terminal alkyne (7.5 equiv), Et3N (1 equiv) and CuI-bis-
phopshane complex (20 mol%) as catalyst in toluene. Seven
complexes formed in situ from [Cu(CH3CN)4]BF4 and bis-phos-
phane ligands L1–L7 were tested under these conditions
(Scheme 1, Table 1).
Table 2. Copper-catalyzed enantioselective conjugate alkynylation of
enone 1a with phenylacetylene (2a). Optimization of conditions.[a]
Entry
L7
[mol%]
2a
[equiv]
Et3N
[equiv]
3aa yield
[%]
3aa ee
[%][b]
3’aa yield
[%]
Surprisingly, unlike in our previous work,[9e] only ligands L2,
L5 and L7 formed complexes with [Cu(CH3CN)4]BF4 sufficiently
reactive to promote the conjugate addition. Ligands L2 and L5
1
2
3
4
5
6
7
8
9
20
20
10
10
5
5
5
2.5
2.5
7.5
5
7.5
5
1
1
1
1
1
1
0.1
0.1
–
66
35
45
52
59
63
72
87
–
94
94
94
94
94
94
94
94
–
25
25
25
15
15
5
5
–
–
3
1.3
1.3
1.3
1.3
[a] Compound 1a (1 equiv), 2a, L7, [Cu(CH3CN)4]BF4, Et3N, toluene, RT,
24 h. [b] Determined by HPLC using chiral stationary phases.
Decreasing only one of the variables, either the catalyst load
or the number of alkyne equivalents, did not avoid formation
of compound 3’aa. However, when both the catalyst load and
the equivalents of alkyne were simultaneously reduced, a de-
crease in the formation of byproduct 3’aa was observed, with-
out detriment in the ee value of the desired product 3aa
(Table 2, entries 4–6). Further improvement was brought about
by reducing also the amount of base. Thus it was possible to
completely avoid the formation of 3’aa by using 2.5 mol% of
catalyst, 1.3 equivalents of alkyne and 10 mol% of Et3N. Under
these conditions, compound 3aa was obtained in 87% yield
and 94% ee (Table 2, entry 8). It should be noted that the use
of a small amount of base is required, as the reaction did not
proceed without Et3N (Table 2, entry 9).
Scheme 1. Copper-catalyzed conjugate alkynylation of enone 1a with phe-
nylacetylene (2a) and ligands used in this study.
With the best available conditions we explored the scope of
the reaction with different enones and alkynes (Table 3). First,
the addition of phenylacetylene (2a) to various 1,1,1-trifluoro-
methyl-3-en-2-ones 1a–1i bearing an aromatic ring on the
b carbon of the double bond was studied. The reaction tolerat-
ed either electron-donating or electron-withdrawing substitu-
ents in different positions of the aromatic ring, and the expect-
ed alkynylated products 3aa–3ia were obtained with good
yields and excellent enantiomeric excesses above 90%
(Table 3, entries 2–8), especially with ortho-substituted phenyl
rings (Table 3, entries 2 and 6). Enone 1i bearing a bulky naph-
thyl group also reacted with phenylacetylene to give com-
pound 3ia in moderate yield although with an excellent 94%
ee (Table 3, entry 9). The reaction also worked with enone 1j,
which incorporates a heterocyclic 3-thienyl moiety attached to
the double bond, giving the alkynylated product 3ja with
Table 1. Copper-catalyzed enantioselective conjugate alkynylation of
enone 1a with phenylacetylene (2a). Ligand screening.[a]
Entry
Ligand
t
[h]
Yield
[%]
ee
[%][b]
1
2
3
4
5
6
7[c]
L1
L2
L3
L4
L5
L6
L7
72
48
72
72
48
72
48
–
39
–
–
18
–
–
62
–
–
50
–
66
94
[a] Compound 1a (1 equiv), 2a (7.5 equiv), Ligand (20 mol%),
[Cu(CH3CN)4]BF4 (20 mol%), Et3N (1 equiv), toluene, RT. [b] Determined by
HPLC using chiral stationary phases. [c] Compound 3’aa (25%) was isolat-
ed from the reaction mixture.
&
&
Chem. Eur. J. 2016, 22, 1 – 9
www.chemeurj.org
2
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
2. Enantioselective conjugate diynylation of trifluoromethyl
enones
Table 3. Enantioselective conjugate addition of terminal alkynes 2 to
1,1,1-trifluoromethyl-3-en-2-ones 1.[a]
We also have studied the enantioselective conjugate addition
of 1,3-diynes to trifluoromethyl enones to give chiral diynes
bearing a propargylic stereogenic center.[12] The 1,3-diyne
moiety is present in a large number of natural products and
bioactive compounds,[13] as well as in artificial molecules with
interesting technological properties.[14] Furthermore, conjugate
diynes are intriguing building blocks because of the unique
behavior of alkynes, especially in transition-metal-catalyzed
processes.[15]
Entry
1
R1
2
R2
3
t [h] Yield ee
[%]
[%][b]
1
2
3
4
5
6
7
8
1a Ph
1b 2-MeC6H4
1c 3-MeC6H4
1d 4- MeC6H4 2a Ph
1e 4-MeOC6H4 2a Ph
1 f 2-BrC6H4
1g 3-BrC6H4
1h 4-BrC6H4
1i 2-naphthyl 2a Ph
1j 2-thienyl 2a Ph
1k PhCH2CH2 2a Ph
1a Ph
1a Ph
1a Ph
1a Ph
1a Ph
1a Ph
1b 2-MeC6H4
1 f 2-BrC6H4
1 f 2-BrC6H4
1a Ph
1b 2-MeC6H4
1a Ph
2a Ph
2a Ph
2a Ph
3aa 24
3ba 48
3ca 72
3da 72
3ea 72
3 fa 48
3ga 48
3ha 48
3ia 72
3ja 48
87
96
65
55
56
74
73
68
55
80
–
94
98
96
95
94
98
93
90[c]
94
90
–
The substrate scope of the conjugate diynylation was carried
out under the same optimized conditions used for the addition
of terminal alkynes (for the effect of other ligands see ref. [12]).
The results are gathered in Table 4.
2a Ph
2a Ph
2a Ph
9
10
11
12
13
14
15
16
17
18
19
20
21[d]
22[d]
23
3ka
–
Table 4. Enantioselective conjugate addition of terminal 1,3-diynes 4 to
enones 1. Scope of the reaction.[a]
2b 4-MeOC6H4
3ab 24
3ac 48
3ad 48
3ae 48
96
76
60
78
63
65
99
60
53
31
30
–
94
95
95
92
96
94
98
98
98
78
90[c]
–
2c 3-FC6H4
2d 4-FC6H4
2e 4-ClC6H4
2 f 3,5-(MeO)2C6H3 3af 48
2g 3-thienyl
2c 3-FC6H4
2b 4-MeOC6H4
2c 3-FC6H4
2h PhCH2CH2
2h PhCH2CH2
2i TIPS
3ag 48
3bc 48
3 fb 72
3 fc 72
3ah 72
3bh 72
Entry
1
R1
4
R2
5
Yield ee
[%]
[%][b]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1l
1e
1 f
1h
1i
Ph
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
5aa
5ba
5ca
5da
5la
5ea
5 fa
5ha
5ia
73
94
55
56
69
41
76
55
59
50
93
94
93
92
94
92
94
92
92
84
87
88
92
91
90
92
94
93
95
93
85
3ai
–
2-MeC6H4
3-MeC6H4
4-MeC6H4
2-MeOC6H4
4-MeOC6H4
2-BrC6H4
4-BrC6H4
2-naphthyl
PhCH2CH2
[a] Compound 1 (1 equiv), 2 (1.3 equiv), L7 (2.5 mol%), [Cu(CH3CN)4]BF4
(2.5 mol%), Et3N (0.1 equiv), toluene, RT. [b] Determined by HPLC using
chiral stationary phases. [c] Determined after hydrogenation of the triple
bond. [d] Reaction carried out with 5 mol% catalyst load.
9
10[c]
11[c]
12[c]
13
14
15
16
17
18
19
20
21
1k
5ka
5ma 53
5na
good yield and enantioselectivity (Table 3, entry 10). Unfortu-
nately, enones carrying an aliphatic group at the b carbon
were not suitable substrates for this reaction, and enone 1k
was recovered unaltered (Table 3, entry 11).
1m CH3(CH2)3
1n
1a
1a
1a
1a
1a
1a
1b
1a
1a
(CH3)2CHCH2 4a
Ph
Ph
Ph
Ph
Ph
Ph
2-MeC6H4
Ph
50
89
65
50
68
72
41
50
61
50
4b 2-MeOC6H4 5ab
4c 4-MeOC6H4 5ac
4d 3-FC6H4
4e
4 f
4g PhCH2CH2
4g PhCH2CH2
4h Cl(CH2)4
Next we examined the use of other alkynes. Several phenyla-
cetylene derivatives having a substituted aromatic ring 2a–f as
well as the heterocyclic derivative 2g reacted with different
enones to give the expected products with fair to good yields
and enantiomeric excesses above 90% (Table 3, entries 12–20).
Alkyl-substituted alkynes could be used although they were
less reactive. Thus, 4-phenyl-1-butyne (2h) required 5 mol% of
catalyst load to react with enone 1a providing compound 3ah
with low yield and moderate enantiomeric excess (Table 3,
entry 21). Better enantioselectivity, although still low yield, was
observed in the reaction of alkyne 2h with enone 1b (Table 3,
entry 22). Finally, the silylacetylene 2l, which can be considered
a synthetic equivalent of ethylene did not react under these
conditions (Table 3, entry 23).
5ad
5ae
5af
5ag
5bg
5ah
5ai
4-FC6H4
3-thienyl
Ph
4i
TIPS
[a] Compound 1 (1 equiv), 4 (1.3 equiv), L7 (2.5 mol%), [Cu(CH3CN)4]BF4
(2.5 mol%), Et3N (0.1 equiv), toluene, RT. [b] Determined by HPLC using
chiral stationary phases. [c] Reaction carried out with 10 mol% of catalyst.
Diyne 4a was treated with a number of trifluoromethyl
enones 1 having different substituents at b position of the
double bond. Good enantiomeric excesses were obtained with
enones bearing a substituted aromatic ring at this position
(Table 4, entries 1–9). Phenyl groups substituted at either the
ortho, meta, or para positions with electron-donating or elec-
tron-withdrawing substituents were well tolerated and the ex-
pected products 5 were obtained with enantiomeric excesses
The absolute configuration of the stereogenic center in com-
pound 3aa was determined to be R by comparison with litera-
ture data.[9e] For the rest of compounds 3, the absolute config-
uration of the stereogenic center was assigned on the assump-
tion of a uniform reaction mechanism.
Chem. Eur. J. 2016, 22, 1 – 9
www.chemeurj.org
3
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
above 90% (Table 3, entries 1–8). Enone 1i bearing a bulky 2-
naphthyl group also reacted under the optimized conditions
to give the diynylated product 5ia with good yield and excel-
lent enantioselectivity (Table 4, entry 9). Much more interesting,
diyne 4a reacted with enones 1k, 1m–n, which feature an ali-
phatic group on the b-carbon, providing compounds 5ka, 5a
and 5a in moderate yields but with high enantiomeric excess-
es, although a higher catalytic load (10 mol%) was required in
these cases (Table 4, entries 10–12). This result contrasts with
the complete lack of reactivity observed in the addition of the
monoalkyne phenylacetylene to enone 1k (Table 3, entry 11).
The substituent attached to the diyne permitted more varia-
tion than in the case of simple alkynes (Table 4, entries 13–21).
Substituted 4-aryl-1,3-butadiynes bearing electron-donating
(MeO) or electron-withdrawing (F) groups on the phenyl group
reacted with enone 1a providing the expected internal diynes
with fair to good yields and excellent enantioselectivity
(Table 4, entries 13–16); the reaction also worked well with the
thiophene-derived alkyne 4 f (Table 4, entry 17). Moreover, ali-
phatic alkynes such as hexa-3,5-diyn-1-ylbenzene (4g) and 8-
chloroocta-1,3-diyne (4h) reacted similarly to aromatic diynes
to give the corresponding products with very high enantio-
meric excesses (Table 4, entries 18–20). Finally, unlike alkyne 2i,
the tri-isopropylsilyl-derived diyne 4i, which is an equivalent of
buta-1,3-diyne, could be treated with enone 1a to give the
diynylated product 5ai with 85% ee (Table 3, entry 23 vs.
Table 4, entry 21).
compounds 6 and 7 in 96% and 98% yield, respectively. Simi-
larly, full hydrogenation of diyne 5aa was carried out on 10%
Pd/C to give compound 8. Also, desilylation of compound 5ai
to give the chiral terminal diyne 9 was achieved in 70% yield
upon treatment with TBAF and acetic acid in THF (Scheme 2).
No erosion of the ee value in the resulting products was ob-
served in any of these transformations.
Scheme 2. Modification of the alkyne chain. i) H2, 5% Pd/C, EtOAc, RT, 1 h, 6
(96%), 7 (98%); ii) H2, 10% Pd/C, EtOAc, RT, 0.5 h, 8 (89%); iii) TBAF, AcOH,
THF, 08C, 4 h, 9 (70%).
On the other hand, we envisioned the possibility of using
electrophilic activation of the CꢀC triple bond by metals to
carry out cyclization reactions with compounds 3 or 5 leading
to oxygen-containing heterocycles (Scheme 3). Attempts to
carry out the direct cyclization of compound 3aa or 5aa under
Ag or Au catalysis did not work, both compounds remaining
unaltered. Nevertheless, alcohol 10, readily obtained in a diaste-
reoselective manner by treatment of 3aa with MeMgCl, under-
went cyclization in the presence of AgOTf to give the furan de-
rivative 11, whose structure was unambiguously established by
X-ray analysis (Figure 2).[17]
The absolute stereochemistry of compound 5af (Table 4,
entry 17) could be elucidated by X-ray crystallographic analysis
(Figure 1),[16] which indicated the configuration of the stereo-
genic center in this compound to be R, in a similar way as for
the addition of simple alkynes. For the rest of compounds 5
the absolute stereochemistry was assigned on the assumption
of a uniform reaction mechanism.
Scheme 3. Silver-catalyzed cyclization. i) 3m MeMgCl, THF-Et2O, 08C, 10
(d.r.=3:1, 68%), 12 (d.r.=4.5:1, 78%); ii) a) AgOTf, THF, RT; b) Chromato-
graphic separation, 11 (72%), 13 (60%).
Figure 1. ORTEP plot for the X-ray structure of compound 5af. The thermal
ellipsoids are drawn at the 50% probability level.
3. Synthetic transformations
A similar synthetic sequence permitted the transformation
of diyne 5aa into furan derivative 13. The structure of com-
pound 13 was assigned by comparison of its spectroscopic
data with those of compound 11, and was confirmed by
NOESY experiments. A relevant interaction was observed be-
Compounds 3 and 5 are highly functionalized structures that
can undergo different transformations involving the triple
bond, the carbonyl group or both. For instance, hydrogenation
of compounds 3ha and 3ba on 5% Pd/C in EtOAc furnished
&
&
Chem. Eur. J. 2016, 22, 1 – 9
www.chemeurj.org
4
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
Scheme 4. Possible catalytic cycle for the copper-catalyzed alkynylation of
trifluoromethyl enones.
Figure 2. ORTEP plot for the X-ray structure of compound 11. The thermal
ellipsoids are drawn at the 50% probability level.
copper-acetylide complexes generally have a tendency to ag-
gregate into the corresponding polynuclear complexes II’,[21]
most probably is a monomeric copper-acetylide complex that
works as one species to promote the catalytic reaction as in
the copper-catalyzed conjugate addition of Grignard reagents
to enones.[20d] The copper-acetylide species then forms a p-
complex III with the double bond of the enone bringing both
reaction substrates to proximity. Preference of dialkyl cuprates
to complex the double bond (p-complex) rather than the car-
bonyl group (s-complex) in enones has been demonstrated by
Bertz and Ogle by rapid injection NMR experiments,[22] and it is
more likely to happen in our case due to the low coordinating
ability of the carbonyl group in 1,1,1-trifluoromethylketones
caused by the strong electron-withdrawing CF3 moiety.[23]
Transfer of the alkyne to the b-carbon of the enone, the enan-
tioselectivity-determining step, probably involves a CuIII inter-
mediate IV[22] and leads to a copper enolate V, which after pro-
tonation by triethylammonium liberates the desired product 3
with regeneration of the catalyst.
tween the CH3 group at C2 (d=1.63 ppm) and H4 (d=
4.18 ppm), which indicated the trans disposition between the
Me group at C2 and the phenyl group at C4. NOE was also ob-
served between one of the hydrogen atoms of the phenyl
group at C4 (d=7.30 ppm) and the olefinic hydrogen H1’ (d=
4.30 ppm), which indicated the Z geometry of the exocyclic
double bond. Other interactions detected by NOESY experi-
ments are shown in Figure 3.
The configuration of the stereogenic center in compounds
3aa and 5af indicates the preferred attack of either alkynes 2
or diynes 4 from the Re-face of the double bond of the enone.
This stereochemical outcome can be explained according to
the model outlined in Figure 4. The axial-chirality information
of the biphenyl backbone is transferred through the P-aryl
rings, which define four differentiated quadrants in the space
around the metal center. Quadrants 2 and 4 occupied by the
equatorial aryl rings (pointing forward) are sterically crowded
whereas the other two quadrants 1 and 3 are open for ap-
proach of substrates and reagents.[25] Then, formation of the
stereogenic center takes place through a tetracoordinated CuI
species in which the Re-face of the double bond is exposed to
attack by the alkyne while the Si-face is shielded by one aryl
ring of the (R)-MeO-BIPHEP.
Figure 3. NOEs observed in compound 13.
4. Mechanistic and stereochemical proposal
On the basis of previous mechanistic studies on the formation
of metal alkynylides,[18] organocuprate additions[19] and copper-
catalyzed conjugate addition of organometallic compounds,[20]
it is possible to propose a catalytic cycle for the conjugate al-
kynylation of trifluoromethyl enones (Scheme 4). The reaction
between the cationic complex [Cu(CH3CN)4]BF4 and the MeO-
BIPHEP ligand L7 in a 1:1 ratio forms in situ the catalytic com-
plex I, which upon p-complexation to the CꢀC triple bond can
enhance the acidity of the terminal proton of the alkyne in
such a way that it can be deprotonated by triethylamine, form-
ing the corresponding chiral copper acetylide II.[18] Although
Conclusion
We have developed the first enantioselective conjugate alkyny-
lation of a,b-unsaturated 1,1,1-trifluoromethyl ketones. The re-
Chem. Eur. J. 2016, 22, 1 – 9
www.chemeurj.org
5
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
using residual nondeuterated solvent (CHCl3) as internal standard
(d=7.26 and 77.0 ppm, respectively), and at 282 MHz for 19F NMR
using CFCl3 as internal standard. Chemical shifts are given in ppm.
The carbon type was determined by DEPT experiments. High reso-
lution mass spectra (ESI) were recorded on a Q-TOF spectrometer
equipped with an electrospray source with a capillary voltage of
3.3 kV (ESI). Specific optical rotations were measured using sodium
light (D line 589 nm). Chiral HPLC analyses were performed in
a chromatograph equipped with a UV diode-array detector using
chiral stationary columns from Daicel.
General procedure for the enantioselective conjugate alky-
nylation reaction
Figure 4. Structure of C2-symmetric biaryl phosphane ligands and stereo-
chemical model for the enantioselective conjugate alkynylation.
[Cu(CH3CN)4]BF4 (1.1 mg, 0.0034 mmol) and (R)-L7 (4.1 mg,
0.0034 mmol) were added to a dried round bottom flask that was
purged with nitrogen. Toluene (0.2 mL) was added by a syringe
and the mixture was stirred for 1.5 h at room temperature under
a nitrogen atmosphere. Then, a solution of a,b-unsaturated trifluor-
omethyl ketone 1 (0.144 mmol) in toluene (1.0 mL) was added
through a syringe, followed of triethylamine (2 mL, 0.0144 mmol).
The solution was stirred for 10 min at room temperature. Then,
alkyne 2 or diyne 4 (0.188 mmol) was added by syringe (alkyne 2
was added neat, whereas diyne 4 was added dissolved in 1 mL of
toluene) and the solution was stirred at room temperature until
the reaction was complete (TLC). The reaction mixture was
quenched with 20% aqueous NH4Cl (1.0 mL), extracted with CH2Cl2
(2ꢂ15 mL), washed with brine (15 mL), dried over MgSO4 and con-
centrated under reduced pressure. Purification by flash chromatog-
raphy on silica gel afforded compounds 3 or 5.
action requires the use of only 1.3 equivalents of a terminal
alkyne, and low catalytic amounts of a copper(I)-biphosphane
complex (0.025 equiv) and an amine (0.1 equiv) to provide in-
ternal alkynes bearing a propargylic stereogenic center with
excellent enantioselectivities. The addition of terminal alkynes
could be carried out with 1,1,1-trifluoromethyl enones bearing
substituted aryl and heteroaryl groups at the b carbon of the
double bond, but not aliphatic groups. Regarding the alkyne,
good results were obtained with substituted aryl and heteroar-
yl acetylenes; the reaction also allowed the use of 4-phenyl-1-
butyne although this alkyne showed lower reactivity and enan-
tioselectivity. Furthermore, we have studied the enantioselec-
tive conjugate addition of terminal 1,3-diynes to 1,1,1-trifluoro-
methyl enones. In general, the reaction with diynes showed
broader scope compared with that involving monoalkynes,
permitting in this case also the use of enones having alkyl sub-
stituents at the b position. The substituent on the diyne was
also amenable to variation allowing not only aromatic or heter-
oaromatic groups but also aliphatic and triisopropylsilyl ether
(TIPS) groups. The synthetic potential of the alkynylation and
diynylation products has been show by several transformations
including silver-catalyzed cyclization to chiral tetrahydrofurans
bearing a trifluoromethylated quaternary stereocenter. Finally,
a rationale for the observed stereochemistry has been provid-
ed.
(R)-1,1,1-Trifluoro-4,6-diphenylhex-5-yn-2-one (3aa): Purification
by flash chromatography eluting with hexane-CH2Cl2 (90:10). Enan-
tiomeric excess (94%) was determined by chiral HPLC (Chiralpak
AD-H), hexane/iPrOH 95:05, 1 mLminꢀ1, major enantiomer tr =
4.6 min, minor enantiomer tr =4.3 min. Oil; ½aꢁ2D0 =ꢀ1.0 (c=0.27,
CHCl3, 94% ee); 1H NMR (300 MHz, CDCl3): d=7.49–7.34 (m, 6H),
3
3
7.34–7.27 (m, 4H), 4.49 (dd, J (H,H)=8.2, 6.0 Hz, 1H), 3.39 (ddd, J
(H,H)=18.1, 8.3, 0.5 Hz, 1H), 3.19 ppm (ddd, 3J (H,H)=18.2, 6.0,
0.3 Hz 1H); 13C NMR (75.5 MHz, CDCl3): d=188.5 (q, 2J (C,F)=
35.9 Hz, CF3), 139.5 (C), 131.7 (2CH), 128.9 (2CH), 128.2 (3CH), 127.6
1
(CH), 127.4 (2CH), 122.8 (CH), 115.3 (q, J (C,F)=291.9 Hz, C), 88.6
(C), 84.0 (C), 45.1 (CH2), 32.6 ppm (CH); 19F NMR (282 MHz, CDCl3):
d=ꢀ79.9 ppm (s, 3F); HRMS (ESI) m/z: calcd for C18H14F3: 303.0991
[M+H]+; found: 303.0998.
(R)-1,1,1-Trifluoro-4,8-diphenylocta-5,7-diyn-2-one (5aa): Purifica-
tion by flash chromatography eluting with hexane/ethyl acetate
(99:01). Enantiomeric excess (93%) was determined by chiral HPLC
(Chiralpak AS-H), hexane/iPrOH 95:05, 1 mLminꢀ1, major enantio-
mer tr =4.96 min, minor enantiomer tr =4.61 min. Oil; ½aꢁ2D0 =ꢀ29.3
(c=1.05, CHCl3, 93% ee); 1H NMR (300 MHz, CDCl3) d=7.51–7.48
Experimental Section
3
(m, 2H), 7.42–7.29 (m, 8H), 4.41 (dd, J (H,H)=7.9, 6.2 Hz, 1H), 3.37
3
3
General methods
(ddd, J (H,H)=18.7, 7.9, 0.5 Hz, 1H), 3.19 ppm (ddd, J (H,H)=18.7,
6.2, 0.5 Hz, 1H); 13C NMR (75.5 MHz, CDCl3): d=188.1 (q, J (C,F)=
2
Reactions were carried out under nitrogen atmosphere in round
bottom flasks oven-dried overnight at 1208C. Commercial reagents
were used as purchased. a,b-Unsaturated trifluoromethyl ketones
1[12,26] and diynes 4[12,27] were prepared as described in the litera-
ture. Toluene was distilled from CaH2, THF and Et2O were distilled
from Na-benzophenone. Reactions were monitored by TLC analysis
using Merck Silica Gel 60 F-254 thin layer plates. Flash column
chromatography was performed on Merck silica gel 60, 0.040–
0.063 mm. Melting points were determined in capillary tubes. NMR
spectra were run at 300 MHz for 1H and at 75 MHz for 13C NMR
36.2 Hz, C), 138.3 (C), 132.6 (2CH), 129.2 (CH), 129.1 (2CH), 128.4
(2CH), 127.9 (CH), 127.4 (2CH), 121.5 (C), 115.3 (q, 1J (C,F)=
291.8 Hz, CF3), 82.2 (C), 77.3 (C), 73.5 (C), 68.4 (C), 44.4 (CH2),
32.6 ppm (CH); 19F NMR (282 MHz, CDCl3): d=ꢀ79.7 ppm (s, 3F);
HRMS (ESI) m/z calcd for C20H14F3O: requires 327.0997 [M+H]+;
found: 327.0982.
&
&
Chem. Eur. J. 2016, 22, 1 – 9
www.chemeurj.org
6
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
f) S. Sasaki, T. Yamauchi, K. Higashiyama, Tetrahedron Lett. 2010, 51,
2326–2328; g) P. Li, Z. Chai, S.-L. Zhao, Y.-Q. Yang, H.-F. Wang, C.-W.
Zheng, Y.-P. Cai, G. Zhao, S.-Z. Zhu, Chem. Commun. 2009, 7369–7371;
h) C. Zheng, Y. Li, Y. Yang, H. Wang, H. Cui, J. Zhang, G. Zhao, Adv. Synth.
Catal. 2009, 351, 1685–1691.
Acknowledgements
Financial support (Grant CTQ2013-47494-P) from the Ministerio
de Economꢃa y Competitividad (MINECO-Gobierno de EspaÇa).
A.S.M. thanks the MINECO for a predoctoral grant (FPI pro-
gram). Access to NMR and MS facilities from the Servei Central
de Suport a la Investigaciꢄ Experimental (SCSIE)-UV is also ac-
knowledged.
[8] Chiral Drugs: Chemistry and Biological Action (Eds.: G.-Q Lin, Q.-D. You,
J.-F. Cheng), Wiley, Hoboken, 2011.
[9] Selected examples. Cu catalysis: a) T. F. Knçpfel, P. Zarotti, T. Ichikawa,
E. M. Carreira, J. Am. Chem. Soc. 2005, 127, 9682–9683; b) R. Yazaki, N.
Kumagai, M. Shibasaki, J. Am. Chem. Soc. 2010, 132, 10275–10277; c) A.
Sanz-Marco, A. Garcia-Ortiz, G. Blay, J. R. Pedro, Chem. Commun. 2014,
50, 2275–2278; d) A. Sanz-Marco, A. Garcia-Ortiz, G. Blay, I. Fernandez,
J. R. Pedro, Chem. Eur. J. 2014, 20, 668–672; see also ref. [24]. Rh cataly-
sis: e) T. Nishimura, T. Sawano, T. Hayashi, Angew. Chem. Int. Ed. 2009,
48, 8057–8059; Angew. Chem. 2009, 121, 8201–8203–82013; f) E. Fil-
lion, A. K. Zorzitto, J. Am. Chem. Soc. 2009, 131, 14608–14609; g) X.
Dou, Y. Huang, T. Hayashi, Angew. Chem. Int. Ed. 2016, 55, 1133–1137;
Angew. Chem. 2016, 128, 1145–1149. Zn catalysis: h) G. Blay, L. Cardona,
J. R. Pedro, A. Sanz-Marco, Chem. Eur. J. 2012, 18, 12966–12969; i) G.
Blay, M. C. MuÇoz, J. R. Pedro, A. Sanz-Marco, Adv. Synth. Catal. 2013,
355, 1071–1076.
[10] a) G.-W. Zhang, W. Meng, H. Ma, J. Nie, W.-Q. Zhang, J.-A. Ma, Angew.
Chem. Int. Ed. 2011, 50, 3538–3542; Angew. Chem. 2011, 123, 3600–
3604; Angew. Chem. Angew.Chem. 2011, 123, 3600–3604; b) H. Wang,
K.-F. Yang, L. Li, Y. Bai, Z.-J. Zheng, W. Q. Zhang, Z. W. Gao, L.-W. Xu,
ChemCatChem ChemCatChem. 2014, 6, 580–591.
[11] E. Takada, S. Hara, A. Suzuki, Heteroat. Chem. 1992, 3, 483–486.
[12] A preliminary communication containing part of this research has been
published: A. Sanz-Marco, G. Blay, M. C. MuÇoz, J. R. Pedro, Chem.
Commun. 2015, 51, 8958–8961.
[13] Reviews: a) A. L. K. Shi Shun, R. Rik, R. Tykwinski, Angew. Chem. Int. Ed.
2006, 45, 1034–1057; Angew. Chem. 2006, 118, 1050–1073; b) Modern
Acetylene Chemistry (Eds.: P. J. Stang, F. Diederich), VCH, Weinheim,
1995; c) K. S. Sindhu, G. Anilkumar, RSC Adv. 2014, 4, 27867–27887; H.-
J. Jung, B.-S. Min, J.-Y. Park, Y.-H. Kim, H.-K. Lee, K.-H. Bae, J. Nat. Prod.
2002, 65, 897–901; d) S. F. Mayer, A. Steinreiber, R. V. A. Orru, K. Faber, J.
Org. Chem. 2002, 67, 9115–9121; e) Y. Satoh, M. Satoh, K. Isobe, K.
Mohri, Y. Yoshida, Y. Fujimoto, Chem. Pharm. Bull. 2007, 55, 561–564;
f) N. P. McLaughlin, E. Butler, P. Evans, N. P. Brunton, A. Koidis, D. K. Rai,
Tetrahedron 2010, 66, 9681–9687; g) D. Shin, J.-E. Yang, S. B. Lee, C. W.
Nho, Bioorg. Med. Chem. Lett. 2010, 20, 7549–7552.
Keywords: alkynes
·
asymmetric catalysis
·
conjugate
addition · enones · fluorine
[1] a) T. Hiyama, Organofluorine Compounds: Chemistry and Applications
(Ed.: H. Yamamoto), Springer, Heidelberg, 2000; b) J.-P. Begue, D.
Bonnet-Delpon, Bioorganic and Medicinal Chemistry of Fluorine, Wiley,
Hoboken, New Jersey, 2000; c) S. Purser, P. R. Moore, S. Swallow, V. Gou-
verneur, Chem. Soc. Rev. 2008, 37, 320–330; d) P. Shah, A. D. Westwell,
J. Enzyme Inhib. Med. Chem. 2007, 22, 527–540; e) K. Mꢅller, C. Faeh, F.
Diederich, Science 2007, 317, 1881–1886; f) V. D. Romanenko, V. P.
Kukhar, Tetrahedron 2008, 64, 6153–6190; g) J. Wang, M. Sanchez-
Rosello, J. L. AceÇa, C. del Pozo, A. E. Sorochinsky, S. Fustero, F. A. Solo-
shonok, H. Liu, Chem. Rev. 2014, 114, 2432–2506; h) Y. Zhou, J. Wang, Z.
Gu, S. Wang, W. Zhu, J. L. AceÇa, V. A. Soloshonok, K. Izawa, H. Liu,
Chem. Rev. 2016, 116, 422–518.
[2] a) N. A. Meanwell, J. Med. Chem. 2011, 54, 2529–2591; b) W. K. Hag-
mann, J. Med. Chem. 2008, 51, 4359–4369; c) M. Jagodzinska, F. Huge-
not, G. Candiani, M. Zanda, ChemMedChem 2009, 4, 49–51; d) Y. Zheng,
J.-A. Ma, Adv. Synth. Catal. 2010, 352, 2745–2750.
[3] C. B. Kelly, M. A. Mercadante, N. E. Leadbeater, Chem. Commun. 2013,
49, 11133–11148.
[4] a) D. Yang, Y. Zhou, Q. Chang, Y. Zhao, J. Qu, Huaxue Jinzhan 2014, 26,
976–986; b) J. P. Doucet, A. Doucet-Panaye, SAR QSAR Environ. Res.
2014, 25, 589–616; c) J. P. Doucet, A. Doucet-Panaye, J. Devillers, SAR
QSAR Environ. Res. 2013, 24, 481–499; d) Y. S. Lee, Yong, Biomol.Ther.
2009, 17, 379–387; e) M. Iturralde, J. Pardo, E. Lacasa, G. Barrio, M. A.
Alava, A. Pineiro, J. Naval, A. Anel, Apoptosis 2005, 10, 1369–1381; f) S.
Bhattacharya, R. Patel, S. Rashmi, N. Sen, S. Quadri, K. Parthasarathi, J.
Bhattacharya, Am. J. Physiol. 2001, 280, L1049–L1056; g) T. Akaki, H. To-
mioka, T. Shimizu, S. Dekio, K. Sato, Clin. Exp. Immunol. 2000, 121, 302–
310; h) E. Burgermeister, U. Tibes, H. Stockinger, W. V. Scheuer, Eur. J.
Pharmacol. 1999, 369, 373–386; i) D. L. Flynn, N. A. Aboodl, B. C. Hol-
werdaz, Curr. Opin. Chem. Biol. 1997, 1, 190–196; j) M. G. Cifone, P. Ron-
caioli, L. Cironi, C. Festuccia, A. Meccia, S. D’Alo, D. Botti, A. Santoni, J.
Immunol. 1997, 159, 309–317; k) F. J. Brown, D. W. Andisik, P. R. Bern-
stein, C. B. Bryant, C. Ceccarelli, J. R. Damewood, Jr., P. D. Edwards, R. A.
Earley, S. Feeney, R. C. Green, B. Gomes, B. J. Kosmider, R. D. Krell, A.
Shaw, G. B. Steelman, R. M. Thomas, E. P. Vacek, C. A. Veale, P. A. Tuthill,
P. Warner, J. C. Williams, D. J. Wolanin, S. A. Woolson, J. Med. Chem.
1994, 37, 1259–1261.
[5] a) A. A. Gakh, Y. Shermolovich, Curr. Top. Med. Chem. 2014, 14, 952–
965; b) C. Baskakis, V. Magrioti, N. Cotton, D. Stephens, V. Constantinou-
Kokotou, E. A. Dennis, G. Kokotos, J. Med. Chem. 2008, 51, 8027–8037;
c) L. E. Kiss, H. S. Ferreira, D. A. Learmonth, Org. Lett. 2008, 10, 1835–
1837; d) N. Zanatta, J. M. F. M. Schneider, P. H. Schneider, A. D. Wouters,
H. G. Bonacorso, M. A. P. Martins, L. A. Wessjohann, J. Org. Chem. 2006,
71, 6996–6998; e) D. Riber, M. Venkataramana, S. Sanyal, T. Duvold, J.
Med. Chem. 2006, 49, 1503–1505.
[14] a) Review: M. B. Nielsen, F. Diederich, Chem. Rev. 2005, 105, 1837–1867;
b) W. B. Wan, S. C. Brand, J. J. Pak, M. M. Haley, Chem. Eur. J. 2000, 6,
2044–2052; c) K. West, C. Wang, A. S. Batsanov, M. R. Bryce, Org. Biomol.
Chem. 2008, 6, 1934–1937.
[15] a) D.-G. Yu, F. de Azambuja, T. Gensch, C. G. Daniliuc, F. Glorius, Angew.
Chem. Int. Ed. 2014, 53, 9650–9654; Angew. Chem. 2014, 126, 9804–
9809; b) N.-K. Lee, S. Y. Yun, P. Mamidipalli, R. M. Salzman, D. Lee, T.
Zhou, Y. Xia, J. Am. Chem. Soc. 2014, 136, 4363–4368; c) S. Y. Yun, K.-P.
Wang, N.-K. Lee, P. Mamidipalli, D. Lee, J. Am. Chem. Soc. 2013, 135,
4668–4671; d) G. Huang, K. Xie, D. Lee, Y. Xia, Org. Lett. 2012, 14, 3850–
3853; e) S. Gupta, P. K. Agarwal, M. Saifuddin, B. Kundu, Tetrahedron
Lett. 2011, 52, 5752; f) E. J. Cho, M. Kim, D. Lee, Org. Lett. 2006, 8, 5413.
[16] X-ray data for compound 5af: crystallized from dichloromethane/n-
hexane at ꢀ208C; C18H11F3O1S1; Mr =332.33; monoclinic; space group=
P21; a=5.5930(1), b=8.1070(3); c=17.5700(5) ꢆ.; a=90.00, b=
95.029(2), g=90.008; V=793.60(4) ꢆ3; Z=2; 1calcd =1.391 Mgmꢀ3; m=
0.235 mmꢀ1; F(000)=240. A colorless crystal of 0.04ꢂ0.08ꢂ0.10 mm3
was used; 2709 [R(int)=0.0399] independent reflections were collected
on a Enraf Nonius CCD diffractometer by using graphite-monochromat-
ed MoKa radiation (l=0.71073 ꢆ) operating at 50 kV and 30 mA. The
cell parameters were determined and refined by a least-squares fit of
all reflections. The structure was solved by direct methods and Fourier
synthesis. It was refined by full-matrix least-squares procedures on F2
(SHELXL-97). All non-hydrogen atoms were refined anisotropically. All
hydrogen atoms were included in calculated positions and refined
riding on the respective carbon atoms. Final R(wR) values were R=
0.0689 and wR=0.1968. CCDC 1046444 (5af), contain the supplementa-
ry crystallographic data for this paper. These data are provided free of
charge by The Cambridge Crystallographic Data Centre.
[6] a) S. V. Druzhinin, E. S. Balenkova, V. G. Nenajdenko, Tetrahedron 2007,
63, 7753–7808; b) A. Sanz-Marco, Synlett 2015, 26, 271–272.
[7] Selected examples of enantioselective 1,4-additions to trifluoromethyl
enones: a) B. S. Donslund, A. Monleꢄn, J. Larsen, L. Ibsen, K. A. Jørgen-
sen, Chem. Commun. 2015, 51, 13666–13669; b) L. C. Morrill, S. M.
Smith, A. M. Z. Slawin, A. D. Smith, J. Org. Chem. 2014, 79, 1640–1655;
c) P.-P. Yeh, D. S. B. Daniels, D. B. Cordes, A. M. Z. Slawin, A. D. Smith,
Org. Lett. 2014, 16, 964–967; d) L. C. Morrill, J. Douglas, T. Lebl, A. M. Z.
Slawin, D. J. Fox, A. D. Smith, Chem. Sci. 2013, 4, 4146–4155; e) Z.-K.
Pei, Y. Zheng, J. Nie, J.-A. Ma, Tetrahedron Lett. 2010, 51, 4658–4661;
Chem. Eur. J. 2016, 22, 1 – 9
www.chemeurj.org
7
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
[17] X-ray data for compound 11: crystallized from n-hexane at ꢀ208C;
C19H17F3O1; Mr =318.32; orthorhombic; space group=P212121; a=
9.7760(3), b=11.0750(2); c=14.8050(3) ꢆ.; V=1602.93(7) ꢆ3; Z=4;
1calcd =1.319 Mgmꢀ3; m=0.104 mmꢀ1; F(000)=664. A colorless crystal of
0.03ꢂ0.08ꢂ0.08 mm3 was used; 2598 [R(int)=0.0314] independent re-
flections were collected on a Enraf Nonius CCD diffractometer by using
graphite-monochromated MoKa radiation (l=0.71073 ꢆ) operating at
50 kV and 30 mA. The cell parameters were determined and refined by
a least-squares fit of all reflections. The structure was solved by direct
methods and Fourier synthesis. It was refined by full-matrix least-
squares procedures on F2 (SHELXL-2014). All non-hydrogen atoms were
refined anisotropically. All hydrogen atoms were included in calculated
positions and refined riding on the respective carbon atoms. Final
R(wR) values were R=0.0440 and wR=0.1027. CCDC 1464259 (11) con-
tain the supplementary crystallographic data for this paper. These data
are provided free of charge by The Cambridge Crystallographic Data
Centre.
[18] a) L. Brandsma, Preparative Acetylene Chemistry, Elsevier, Amsterdam,
1988; b) Modern Alkyne Chemistry: Catalytic and Atom-Economic Trans-
formations, Part III (Eds.: B. M. Trost, C.-J. Li), Wiley-VCH, Weinheim,
2015.
[19] a) S. Mori, E. Nakamura in Modern Organocopper Chemistry (Ed.: N.
Krause), Wiley-VCH, Weinheim, 2002, pp. 315–346; b) E. Nakamura, N.
Yoshiaki in The Chemistry of Organocopper Compounds (Eds.: Z. Rappo-
port, I. Marek), Wiley, Hoboken, 2009, pp. 1–22; c) S. Woodward, Chem.
Soc. Rev. 2000, 29, 393–401; d) E. Nakamura, S. Mori, Angew. Chem. Int.
Ed. 2000, 39, 3750–3771; Angew. Chem. 2000, 112, 3902–3924; e) N.
Yoshikai, E. Nakamura, Chem. Rev. 2012, 112, 2339–2372.
[20] a) M. Tissot, H. Li, A. Alexakis in Copper-Catalyzed Asymmetric Synthesis
(Eds.: A. Alexakis, N. Krause, S. Woodward), Wiley-VCH, Weinheim, 2014,
pp. 69–84; b) T. den Hartog, Y. Huang, M. FaÇanꢇs-Mastral, A. Meuwese,
A. Rudolph, M. Pꢀrez, A. J. Minnaard, B. L. Feringa, ACS Catal. ACS Catal-
ysis 2015, 5, 560–574; c) N. Yoshikai, T. Yamashita, E. Nakamura, Angew.
Chem. Int. Ed. 2005, 44, 4721–4723; Angew. Chem. 2005, 117, 4799–
4801; d) S. R. Harutyunyan, F. Lꢄpez, W. R. Browne, A. Correa, D. PeÇa, R.
Badorrey, A. Meetsma, A. J. Minnaard, B. L. Fering, J. Am. Chem. Soc.
2006, 128, 9103–9118.
[21] G. Hattori, K. Sakata, H. Matsuzawa, Y. Tanabe, Y. Miyake, Y. Nishibayashi,
J. Am. Chem. Soc. 2010, 132, 10592–10608.
[22] S. H. Bertz, R. A. Hardin, M. D. Murphy, C. A. Ogle, J. D. Richter, A. A.
Thomas, J. Am. Chem. Soc. 2012, 134, 9557–9560.
[23] N. Asao, T. Asano, Y. Yamamoto, Angew. Chem. Int. Ed. 2001, 40, 3206–
3208; Angew. Chem. 2001, 113, 3306–3308.
[24] R. Yazaki, N. Kumagai, M. Shibasaki, Chem. Asian J. 2011, 6, 1778–1790.
[25] T. Ohkuma, N. Kurono in Privileged Chiral Ligands and Catalysts (Ed.: Q.-
L. Zhou), Wiley-VCH, Weinheim, 2011, chapter 1, pp. 1–53.
[26] R. P. Singh, G. Cao, R. L. Kirchmeier, J. M. Shreeve, J. Org. Chem. 1999,
64, 2873–2876.
[27] M. Turlington, Y. Du, S. G. Ostrum, V. Santosh, K. Wren, T. Lin, M. Sabat,
L. Pu, J. Am. Chem. Soc. 2011, 133, 11780–11794.
Received: March 18, 2016
Published online on && &&, 2016
&
&
Chem. Eur. J. 2016, 22, 1 – 9
www.chemeurj.org
8
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
FULL PAPER
&
Asymmetric Catalysis
A. Sanz-Marco, G. Blay,* M. C. MuÇoz,
J. R. Pedro*
&& – &&
The first catalytic enantioselective
conjugate alkynylation (and diynylation)
of 1,1,1-trifluoromethyl enones has
been carried out using a CuI-MeOBI-
PHEP complex as the catalyst. Internal
alkynes and diynes were formed with
good yields and excellent enantioselec-
tivities. No 1,2-addition products were
formed (see scheme).
Catalytic Enantioselective Conjugate
Alkynylation of a,b-Unsaturated 1,1,1-
Trifluoromethyl Ketones with Terminal
Alkynes
Chem. Eur. J. 2016, 22, 1 – 9
www.chemeurj.org
9
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ