Enantioselective alkynylation of trifluoromethyl ketones catalyzed by chiral Schiff bases

Article abstract of DOI:10.14233/ajchem.2013.14943

Enantioselective alkynylation of trifluoromethyl ketones catalyzed by chiral Schiff bases in the presence of Me2Zn afforded the corresponding trifluoroalkynyl alcohols in up to 66 % ee.

Full text of DOI:10.14233/ajchem.2013.14943

Asian Journal of Chemistry; Vol. 25, No. 13 (2013), 7505-7508
http://dx.doi.org/10.14233/ajchem.2013.14943
Enantioselective Alkynylation of Trifluoromethyl Ketones Catalyzed by Chiral Schiff Bases
*
VASUDEVAN DHAYALAN, RYO MURAKAMI and MASAHIKO HAYASHI
Department of Chemistry, Graduate School of Science, Kobe University. 1-1 Rokkodai-cho, Nada-ku, Hyogo 657-8501, Japan
*Corresponding author: Fax: +81 78 803-5688; E-mail: mhayashi@kobe-u.ac.jp
(Received: 8 December 2012;
Accepted: 1 July 2013)
AJC-13738
Enantioselective alkynylation of trifluoromethyl ketones catalyzed by chiral Schiff bases in the presence of Me2Zn afforded the corre-
sponding trifluoroalkynyl alcohols in up to 66 % ee.
Key Words: Alkynylation, Asymmetric catalysis, Schiff base, Enantioselectivity.
from commercial sources and used without further purification
unless otherwise stated. Melting points were measured by
INTRODUCTION
1
Yanaco MP-500D and were not corrected. H and 13C NMR
Optically active propargylic alcohols are important inter-
mediates in organic synthesis1. To the best of our knowledge,
there have been two reports on the enantioselective alkynylation
of trifluoromethyl ketones, so far. In 2007, Shibasaki et al.2
reported alkynylation of trifluoromethyl ketones using CuO-
t-Bu (prepared from CuOTf and KO-t-Bu or Cu(OTf)2 and 2
KO-t-Bu)-xantphos or phenanthroline system. Furthermore,
they also demonstrated the first example of copper(I) alkoxide-
catalyzed asymmetric alkynylation of 2,2,2-trifluoroacetophenone
with phenylacetylene using 20 mol % of a CuOTf·1/2toluene-
KO-t-Bu-chiral pybox complex to afford the alkynylated
product in moderate optical yield (52 % ee). They reported
only one example of asymmetric version. In 2011, Ma and
co-workers3 used stoichiometric amount of Ti(O-i-Pr)4 (2 equiv)
and R2Zn (3.0 equiv) in the presence of cinchona alkaloids
and BaF2 for enantioselective alkynylation of trifluoromethyl
ketones, which resulted in the formation of the corresponding
alkynylation products in up to 94 % ee3,4. Our first report using
the chiral Schiff base-Ti(O-i-Pr)4 complex in asymmetric
silylcyanation of aldehydes5, we have disclosed the utility of
chiral Schiff bases in various types of asymmetric reactions6,7.
Here, we report a simple system for asymmetric alkynylation
of trifluoromethyl ketones, that is, without titanium alkoxide
or additives such as BaF2.
spectra (400 and 100.6 MHz respectively) were recorded on a
JEOL JNM-LA 400 instrument using Me4Si as an internal
standard (0 ppm). Mass spectra were measured using Thermo
Quest LCQ DECA plus. IR spectra were measured with a
Thermo SCIENTIFIC NICOLET iS 5. Elemental analyses
were carried out usingYanako CHN recorder MT-5. Prepara-
tive column chromatography was carried out using Fuji Silysia
BW-820MH silica gel orYMC-GEL Silica (6 nm I-40-63 um).
Thin layer chromatography (TLC) was carried out on Merk
25 TLC aluminium sheets silica gel 60 F254. HPLC analyses
were carried out in a HITACHI L-2000 series instrument
equipped with diode array detector using chiral columns
CHIRALCEL OJ-H or CHIRALCEL OD-H (250 mm × 4.6
mm × 5 µm).
General procedure for the synthesis of ketoimine-type
chiral Schiff base (4c-4j):A mixture of toluene (10 mL), (S)-
(+)-valinol or (S)-(+)-tert-leucinol (1.20 mmol), salicylketone
(1.0 mmol) and anhydrous Na2SO4 (1.0 g) was refluxed at
115 ºC for 48 h. The mixture was filtered through a glass filter
and the filtrate was evaporated. The residue was subjected to
column chromatography on silica gel using hexane/ethyl
acetate as eluent to afford the corresponding ONO-tridentate
chiral Schiff base ligand.
(S,E)-2-((3,5-bis(trifluoromethyl)phenyl)((1-hydroxy-
3-methylbutan-2-ylimino)methyl)-6-tert-butylphenol (4f):
Yellow liquid; Yield: 57 %; IR (neat, νmax, cm–1): 3419, 2961,
1593, 1275, 1131; H NMR (400 MHz, CDCl3): δ 7.98 (s,
1H), 7.91 (s, 1H), 7.64 (s, 1H), 7.35 (dd, J = 8.0, 1.6 Hz, 1H),
6.63 (t, J = 7.6 Hz, 1H), 6.44 (dd, J = 7.6, 1.6 Hz, 1H), 3.84-
EXPERIMENTAL
All reactions were carried out in well cleaned and oven-
dried glassware with magnetic stirring. Operations were
performed under an atmosphere of dry argon using Schlenk
and vacuum techniques. All starting materials were obtained
1

7506 Dhayalan et al.
Asian J. Chem.
3.76 (m, 2H), 3.10-3.06 (m, 1H), 1.94-1.84 (m, 1H), 1.47 (s,
9H), 0.96 (d, J = 6.8 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H); 13
1,1,1-Trifluoro-2-(4-fluorophenyl)-4-phenylbut-3-yn-
2-ol (3b)3: 95 % yield, 60 % ee (R), [α]D = + 18.4 (c 1.0,
31
C
NMR (100.6 MHz, CDCl3): δ 171.9, 162.4, 138.3, 136.7, 131.8
(q, JC-F = 16.6 Hz), 130.0, 129.6, 129.4, 128.1, 127.4, 124.4,
122.6 (m), 121.6, 118.8, 117.0, 68.6, 65.0, 35.6, 30.6, 29.4,
19.7, 18.7; MS (ESI) m/z: 476 (M+H+); Anal. calcd. for
C24H27NO2F6: C, 60.63; H, 5.72; N, 2.95. Found: C, 60.39; H,
5.76; N, 3.03.
CH2Cl2) (lit.3 [α]D = +17.6 (c 1.0, CH2Cl2, 90 % ee (R)).
20
[Daicel Chiralcel OJ-H, n-hexane/i-PrOH = 95/5, 0.8 mL/min,
λ = 250 nm, tR = 17.20 min (R isomer), tR = 22.95 min (S
isomer)].
2-(4-Chlorophenyl)-1,1,1-trifluoro-4-phenylbut-3-yn-
29
2-ol (3c)3: 95 % yield, 64 % ee (R), [α]D = + 13.5 (c 1.0,
20
(S,E)-2-((3,5-bis(trifluoromethyl)phenyl)((1-hydroxy-
3-methylbutan-2-ylimino)methyl)-4,6-di-tert-butylphenol
(4h): Yellow solid;Yield: 48 %; m.p.: 131.8-132.8 ºC; IR (neat,
CH2Cl2) (lit.3 [α]D = + 14.9 (c 1.0, CH2Cl2, 88% ee (R)).
[Daicel Chiralcel OJ-H, n-hexane/i-PrOH = 95/5, 0.8 mL/min,
λ = 250 nm, tR = 15.76 min (R isomer), tR = 18.18 min (S
isomer)].
ν
max, cm–1): 3585, 2960, 1583, 1277, 1129; 1H NMR (400 MHz,
CDCl3): δ 8.00 (s, 1H), 7.95 (s, 1H), 7.68 (s, 1H), 7.42 (d, J =
2.4 Hz, 1H), 6.39 (d, J = 2.4 Hz, 1H), 3.84-3.79 (m, 2H),
3.16-3.11 (m, 1H), 1.93-1.85 (m, 1H), 1.48 (s, 9H), 1.09 (s,
2-(4-Bromophenyl)-1,1,1-trifluoro-4-phenylbut-3-yn-
29
2-ol (3d)3: 94 % yield, 66 % ee (R), [α]D = + 10.8 (c 1.0,
CH2Cl2) (lit.3 [α]D20 = + 6.8 (c 1.0, CH2Cl2, 86 % ee (R)). [Daicel
Chiralcel OJ-H, n-hexane/i-PrOH = 90/10, 0.8 mL/min, λ =
250 nm, tR = 10.74 min (R isomer), tR = 12.46 min (S isomer)].
1,1,1-Trifluoro-4-phenyl-2-p-tolylbut-3-yn-2-ol (3e)3:
90 % yield, 52 % ee (R), [α]D32 = + 12.0 (c 1.0, CH2Cl2) (lit.3
[α]D20 = + 11.3 (c 1.0, CH2Cl2, 85 % ee (R)). [Daicel Chiralcel
OJ-H, n-hexane/i-PrOH = 90/10, 0.8 mL/min, λ = 250 nm, tR
= 13.55 min (R isomer), tR = 24.56 min (S isomer)].
9H), 0.95 (d, J = 6.8 Hz, 3H), 0.85 (d, J = 6.8 Hz, 3H); 13
C
NMR (100.6 MHz, CDCl3): δ 172.1, 160.2, 139.0, 137.7,
136.9, 131.7 (q, JC-F = 18.2 Hz), 129.8, 128.4, 127.7, 125.5,
124.4, 122.4 (m), 121.7, 117.9, 68.7, 65.0, 35.3, 34.0, 31.1,
30.7, 29.5, 19.7, 18.7; MS (ESI) m/z: 532 (M+H+);Anal. calcd.
for C28H35NO2F6: C, 63.26; H, 6.64; N, 2.63. Found: C, 63.43;
H, 6.74; N, 2.74.
(S,E)-2,4-di-tert-butyl-6-((1-hydroxy-3-methylbutan-2-
ylimino)(3,4,5-trifluorophenyl) methyl)phenol (4j):Yellow
solid;Yield: 43 %; m.p.: 165.8-166.3 ºC; IR (neat, νmax, cm–1):
3592, 2955, 1585, 1366, 1039; 1H NMR (400 MHz, CDCl3):
δ 7.41 (d, J = 2.4 Hz, 1H), 7.10 (s, 1H), 6.84 (s, 1H), 6.57 (d,
J = 2.8 Hz, 1H), 3.78 (t, J = 5.2 Hz, 2H), 3.24-3.20 (m, 1H),
1.90-1.84 (m, 1H), 1.47 (s, 9H), 1.14 (s, 9H), 0.93 (d, J = 6.8
Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H); 13C NMR (100.6 MHz,
CDCl3): δ 171.9, 160.1, 152.3, 149.8, 141.0 (t, JC-F = 14.9
Hz), 138.8, 138.5 (t, JC-F = 14.9 Hz), 137.5, 130.5 (q, JC-F = 6.6
Hz), 127.6, 125.5, 117.8, 113.8 (d, JC-F = 16.5 Hz), 112.5 (d,
JC-F = 19.9 Hz), 68.4, 64.9, 35.2, 34.0, 31.2, 30.6, 29.4, 19.6,
18.8; MS (ESI) m/z: 450 (M+H+); Anal. calcd. for
C26H34NO2F3: C, 69.46; H, 7.62; N, 3.12. Found: C, 69.39; H,
7.72; N, 3.11.
1,1,1-Trifluoro-2-phenyl-4-p-tolylbut-3-yn-2-ol (3f)3:
98 % yield, 52 % ee (R), [α]D27 = + 15.5 (c 1.0, CH2Cl2) (lit.3
[α]D20 = + 13.8 (c 1.0, CH2Cl2, 84 % ee (R)). [Daicel Chiralcel
OJ-H, n-hexane/i-PrOH = 90/10, 0.8 mL/min, λ = 250 nm, tR
= 15.58 min (R isomer), tR = 21.22 min (S isomer)].
2-(4-Chlorophenyl)-1,1,1-trifluoro-4-p-tolylbut-3-yn-
28
2-ol (3g)3: 98 % yield, 50 % ee (R), [α]D = + 11.8 (c 1.0,
20
CHCl3) (lit.3 [α]D = + 10.5 (c 1.0, CH2Cl2 CH2Cl2 85 % ee
(R)). [Daicel Chiralcel OD-H, n-hexane/i-PrOH = 95/5, 0.6
mL/min, λ = 250 nm, tR = 10.13 min (R isomer), tR = 11.16
min (S isomer)].
1,1,1-Trifluoro-2-phenyloct-3-yn-2-ol (3h)3: 43 % yield,
58 % ee (R), [α]D29 = + 5.7 (c 1.0, CH2Cl2) (lit.3 [α]D20 = + 1.6
(c 1.0, CH2Cl2, 94 % ee (R)). [Daicel Chiralcel OJ-H, n-hex-
ane/i-PrOH = 92/8, 0.5 mL/min, λ = 250 nm, tR = 15.95 min
(R isomer), tR = 19.00 min (S isomer)].
General procedure for chiral Schiff base catalyzed
alkynylation of trifluoromethyl ketones: Ethynylbenzene
(2 mmol) and dichloromethane (2.5 mL) were added to a
Schlenk tube equipped with a stirring bar and the tube was
dried under vacuum and filled with argon, followed by Me2Zn
(2.3 mmol) was added slowly under Ar atmosphere and then
mixture was stirred at room temperature for 2.5 h. Schiff base
ligand (5 mol %) in dichloromethane (2.5 mL) was added.
Then the solution was stirred at room temperature for 3 h,
trifluoromethyl ketones (1.0 mmol) was added slowly. The
resulting mixture was stirred at room temperature for 24 h
and quenched with a sat. NH4Cl solution (10 mL), extracted
with dichloromethane (20 mL × 3) the combined organic layer
was washed with brine solution (20 mL × 2) and dried
(Na2SO4). Removal of solvent followed by Kugelrohr distillation
afforded the desired trifluoroalkynyl alcohols. The ee values
were determined by HPLC analysis (Chiralcel OJ-H and OD-H).
1,1,1-Trifluoro-2,4-diphenylbut-3-yn-2-ol (3a)3: 96 %
1,1,1-Trifluoro-2.6-diphenylhex-3-yn-2-ol (3i)2: 59 %
yield, 58 % ee, [α]D30 = + 4.9 (c 1.0, CH2Cl2). [Daicel Chiralcel
OJ-H, n-hexane/i-PrOH = 90/10, 0.8 mL/min, λ = 250 nm, tR
= 25.02 min (R isomer), tR = 34.28 min (S isomer)].
4-Cyclopropyl-1,1,1-trifluoro-2-phenylbut-3-yn-2-
ol (3j)3: 80 % yield, 54 % ee (R), [α]D31 = + 3.9 (c 1.0, CH2Cl2)
20
(lit.3 [α]D = + 2.2 (c 1.0, CH2Cl2, 65 % ee (R)). [Daicel
Chiralcel OJ-H, n-hexane/i-PrOH = 90/10, 0.8 mL/min,
λ = 250 nm, tR = 17.40 min (R isomer), tR = 20.24 min (S
isomer)].
RESULTS AND DISCUSSION
We first examined the effect of Ti(O-i-Pr)4 and found only
5 mol % of a chiral Schiff base and Me2Zn (2.3 equiv) were
necessary for the reaction to proceed, obtaining up to 66 % ee
without Ti(O-i-Pr)4. In the case of aldimine-type Schiff bases
(4a and 4b) the obtained enantioselectivities were significantly
low, whereas, in the case of ketoimine-type Schiff bases (4c
and 4d) enantioselectivities were increased to 28 and 38 % ee,
respectively (Scheme-I).
20
yield, 64 % ee (R), [α]D29 = + 19.2 (c 1.0, CH2Cl2) (lit.3 [α]D
= + 20.6 (c 1.0, CH2Cl2, 91 % ee (R)). [Daicel Chiralcel OD-
H, n-hexane/i-PrOH = 99/1, 1.0 mL/min, λ = 250 nm, tR =
19.84 min (R isomer), tR = 25.78 min (S isomer)].

Vol. 25, No. 13 (2013)
Enantioselective Alkynylation of Trifluoromethyl Ketones Catalyzed by Chiral Schiff Bases 7507
O
4g prepared from salicyl ketone derivatives having two
5 mol%
Schiff base
Ph
CF3
trifluoromethyl groups on the phenyl group and (S)-(+)-tert-
leucinol gave the highest ee (64 % ee) in excellent yield (97 %
yield). After optimizing the enantioselectivity, we examined
the effect of Et2Zn and Ph2Zn as additives on asymmetric
alkynylation of 2,2,2-trifluoroacetophenone. Chiral Schiff base
ligand 4g (5 mol %) in the presence of additives such as Et2Zn
and Ph2Zn resulted in corresponding CF3-substituted tertiary
propargyl alcohols in poor enantioselectivities of 8 and 14 %
ee (R) with yields of 12 and 96 %, respectively.
HO CF3
2
H
Ph
+
Me2Zn
26 oC, 3 h
CH2Cl2
26 oC, 2.5 h
26 oC, 48 h
Ph
R
Ph
1
3a
R1
R2
N
OH
OH
; R1 = H, R2 = i-Pr; 69% yield (0% ee)
; R1 = H, R2 = t-Bu; 94% yield (4% ee)
4a
4b
4c; R1 = Ph, R2 = i-Pr; 87% yield (28% ee)
4d; R1 = Ph, R2 = t-Bu; 96% yield (38% ee)
O
5 mol%
Schiff base
Ph
CF3
Scheme-I:Enantioselective alkynylation of 2,2,2-trifluoroacetophenone
catalyzed by chiral Schiff bases
HO CF3
26 oC, 48 h
Ph
2
H
Ph
+
Me2Zn
26 oC, 3 h
CH2Cl2
26 oC, 2.5 h
R
Ph
1
Accordingly, we prepared a variety of ketoimine-type
Schiff bases (4e-4j) according to the following two routes
(Scheme-II). Route A is our previous method involving
oxidation of benzylic alcohols (6) to the corresponding ketones
(7) followed by condensation with chiral β-amino alcohols.
Route B involves a novel step starting from salicyl acid
derivatives7. The reaction of substituted salicylic acids (8) with
benzotriazole in the presence of 1 equiv of SOCl2 in dichloro-
methane at room temperature led to the corresponding diaryl
ketones (9), which further undergo the Grignard reaction with
R2MgX followed by condensation of ketones (7) with chiral
amino alcohols. Thus, ketoimine-type chiral Schiff bases were
prepared easily from commercially available starting materials
in short steps with good yields8.
3a
OMe
CF3
CF3
MeO
F3C
F3C
t-Bu
N
OH
i-Pr
N
OH
t-Bu
N
OH
OH
; 91% yield
42% ee
OH
OH
; 97% yield
64% ee
4e
4f
4g
; 95% yield
48% ee
CF3
t-Bu
CF3
t-Bu
F
t-Bu
F
F3C
F3C
F
i-Pr
N
OH
t-Bu
N
OH
i-Pr
N
OH
OH
OH
OH
4h
4i
4j
; 95% yield
60% ee
; 93% yield
40% ee
; 88% yield
42% ee
Scheme-III: Enantioselective alkynylation of 2,2,2-trifluoroacetophenone
Route A
Pd/C
CH2=CH2
or
activated carbon
O2
Next, we established the best reaction system and then
examined enantioselective alkynylation of trifluoromethyl
ketones. The obtained results are summarized in Table-1. In
all cases, the reactions proceeded smoothly in the presence of
5 mol % of chiral Schiff bases affording the product in high
chemical yield with moderate to good ee (50-66 % ee (R)).
We attempted the enantioselective alkynylation of 2,2,2-
trifluoroacetophenone/halogenated trifluoromethyl ketones
with 2.3 equiv of Me2Zn in the presence 5 mol % of chiral
ligand 4g in dichloromethane at room temperature for 24 h,
which afforded the corresponding trifluoroalkynyl alcohols
in excellent yields (94-96 %) and good enantioselectivities
(60-66 % ee (R)) (entries 1-4, Table-1). Under the optimized
condition, the reaction of the methyl substituted trifluoromethyl
ketone with phenylacetylene furnished the corresponding
propargyl alcohol with enantioselectivity of 52 % ee in 90 %
yield (entry 5, Table-1), whereas the reaction of trifluoromethyl
ketones with methyl substituted phenylacetylene (entries 6 and
7, Table-1) resulted in trifluoromethylated propargylic tertiary
alcohols in a comparatively enhanced yield of 98 % with
enantioselectivities of 50-52 % ee. The reactions of alkyl sub-
stituted acetylenes (entries 8-10, Table-1) with trifluoromethyl
ketones afforded the products in moderate to good yields of
43-80 % and reasonable enantioselectivities of 54-58 % ee.
Using our developed O,N,O tridentate Schiff base prepared
from salicyl ketone derivatives having two trifluoromethyl
groups on the phenyl group and (S)-(+)-tert-leucinol,
enantioselective alkynylation of 2,2,2-trifluoroacetophenone
R1
R1
1) R2MgX, THF
2) H3O+
R2
OHC
t-Bu
t-Bu
OH
OH OH
5
6
R1
R3
NH2
OH
R1
R2
t-Bu
R2
t-Bu
R3
N
OH
Na2SO4
toluene
O
OH
OH
7
4c—4j
Route B
R1
R1
1H-benzo[d][1,2,3]triazole
SOCl2
N
HO
N
N
t-Bu
t-Bu
CH2Cl2, rt
O
OH
O
OH
8
9
R1
R1
R3
NH2
OH
R2
1) R2MgX, THF
2) H3O+
t-Bu
R2
t-Bu
R3
N
OH
Na2SO4
toluene
O
OH
OH
7
4c 4j
—
Scheme-II: Synthesis of ketoimine-type (O,N,O) chiral Schiff bases
Then, we examined the reaction of 2,2,2-trifluoroaceto-
phenone with phenylacetylene. The results are summarized in
Scheme-III.Among the Schiff bases we examined, Schiff base

7508 Dhayalan et al.
Asian J. Chem.
proceeded smoothly to give the alkynylated product in high
yield (up to 98 % yield) and good ee (up to 66 % ee). This is
the third report on enantioselective alkynylation of trifluoro-
methyl ketones. The current method gives higher ee than
Shibasaki's method2 and is much simpler than Ma's method3.
lecularActivation Directed toward Straightforward Synthesis’,
Ministry of Education, Culture, Sports, Science and Technology
(MEXT), Japan and by Special Coordination Funds for
Promoting Science and Technology, Creation of Innovation
Centers for Advanced Interdisciplinary Research Areas
(Innovative Bioproduction Kobe), MEXT, Japan.
TABLE-1
ENANTIOSELECTIVE ALKYNYLATION OF
REFERENCES
TRIFULUOROMETHYL KETONES[a]
5 mol%
CF3
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N. Zimmermann, Eur. J. Org. Chem., 4095 (2004); (c) D.J. Ramón and
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Quintard, Angew. Chem. Int. Ed., 51, 6704 (2012).
F3C
t-Bu
t-Bu
N
OH
OH
4g
O
CF3
HO
R1
H
R2
1a—1e
+
2. R. Motoki, M. Kanai and M. Shibasaki, Org. Lett., 9, 2997 (2007).
3. G.-W. Zhang, W. Meng, H. Ma, J. Nie, W.-Q. Zhang and J.-A. Ma,
Angew. Chem. Int. Ed., 50, 3538 (2011).
R1 CF3
Me2Zn, CH2Cl2
rt, 24 h
*
R2
2a—2e
3a—3j
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Entry
R1
R2
Yield (%)[b]
ee (%)[c]
1
2
Ph
4-FC6H4
Ph
96
95
95
94
90
98
98
43
59
80
64 (R)
60 (R)
64 (R)
66 (R)
52 (R)
52 (R)
50 (R)
58 (R)
58 (+)[d]
54 (R)
Ph
Ph
Ph
Ph
5. M. Hayashi,Y. Miyamoto, T. Inoue and N. Oguni, J. Chem. Soc., Chem.
Commun., 1752 (1991).
3
4-ClC6H4
4-BrC6H4
4-MeC6H4
Ph
4
6. (a) M. Hayashi, M. Tamura and N. Oguni, Synlett, 663 (1992); (b) M.
Hayashi,Y. Miyamoto, T. Inoue and N. Oguni, J. Org. Chem., 58, 1515
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5
6
4-MeC6H4
4-MeC6H4
n-C4H9
7
4-ClC6H4
Ph
Ph
8
9
10
Ph(CH2)2
Cyclopropyl
Ph
[a]General reaction condition: 2/1/Me2Zn/ligand: 1.0:2.0:2.3:0.05 in
CH2Cl2 at room temperature (27-29 ºC) for 24 h. [b]Isolated yield after
Kugelrohr distillation. [c]ee values were determined by HPLC analysis.
Absolute configuration is based on the comparison of the optical
rotation with the literature3. [d]Absolute configuration was not
determined.
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Conclusion
In summary, we have successfully developed a simple
and practical method for enantioselective alkynylation of
trifluoromethyl ketones catalyzed by chiral Schiff base.
Trifluoroalkynyl alcohols were obtained using 5 mol % of a
chiral Schiff base and Me2Zn, which significantly simplified
the enantioselective synthetic procedure by avoiding the use
of titanium alkoxide and other additives. Moderate to good
yields of trifluoroalkynyl alcohols with enantioselectivities up
to 66 % ee were achieved. The methodology reported in this
article can be useful for synthesizing trifluoromethylated
propargylic tertiary alcohols enantioselectively. Further studies
for improving the enantioselectivity are ongoing.
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ACKNOWLEDGEMENTS
This work was supported by a Grant-in-Aid (No.
B23350043) for Scientific Research on InnovativeAreas ‘Mo-