Catalytic enantioselective alkynylation of trifluoromethyl ketones: Pronounced metal fluoride effects and implications of zinc-to-titanium transmetallation

Article abstract of DOI:10.1002/anie.201007341

Lost in transmetalation: The titanium(IV)-catalyzed title reaction, utilizing chiral cinchona alkaloids as ligands (L1 and L2), was developed for the synthesis of both enantiomers of trifluoromethylated propargylic tertiary alcohols in high yield and enan

Full text of DOI:10.1002/anie.201007341

Communications
DOI: 10.1002/anie.201007341
Asymmetric Catalysis
Catalytic Enantioselective Alkynylation of Trifluoromethyl Ketones:
Pronounced Metal Fluoride Effects and Implications of Zinc-to-
Titanium Transmetallation**
Guang-Wu Zhang, Wei Meng, Hai Ma, Jing Nie, Wen-Qin Zhang, and Jun-An Ma*
Propargylic alcohols are valuable intermediates in organic
synthesis and pharmaceutical science.[1] Metal-catalyzed
direct asymmetric addition of alkyne nucleophiles to alde-
hydes and prochiral ketones represents the most convergent
and efficient approach to the synthesis of optically active
propargylic alcohols.[2] The asymmetric titanium-catalyzed
zinc alkynylide addition to carbonyl substrates has been
extensively studied in the past decade, and numerous chiral
ligands have been developed to give the desired propargylic
alcohols in excellent enantioselectivity.[3] In spite of the
importance of this practical transformation, some challenging
problems remain unsolved. These problems include the
stereochemical control for reactions involving challenging
substrates as well as the mechanism of the putative zinc-to-
titanium transmetallation, a key process in this type of
asymmetric addition that has been reasonably implicated but
remains largely unproven.
Trifluoromethyl ketones are a class of particularly chal-
lenging substrates for this asymmetric transformation because
of the presence of the strongly electron-withdrawing fluorine
atoms. The activating trifluoromethyl group renders the
ketone functionality highly reactive and has a detrimental
effect on the control of facial selectivity.[4] Although the
asymmetric additions of alkyne nucleophiles to trifluoro-
methyl ketones have been well studied using stoichiometric
chiral-auxiliary-based methods to control the absolute con-
figuration,[5] to the best of our knowledge, there are no
effective methods for catalyzing the asymmetric addition of
alkynes to trifluoromethyl ketones.[6,7] We report herein a
catalytic enantioselective addition of zinc alkynylides to
various trifluoromethyl ketones with selectivities that surpass
94% ee. We demonstrate that with the application of
pseudoenantiomeric cinchona alkaloids as chiral ligands, the
synthesis of both enantiomers of the trifluoromethylated
products is possible. Additionally, we provide the first
experimental and computational evidence that the alkynyl
group is bound to the titanium catalyst through transmetalla-
tion, and the organotitanium complex is responsible for the
addition to trifluoromethyl ketones.
In an initial investigation, we conducted the reaction of
the alkynylzinc, which was generated in situ from alkyne 4a
(see Table 1 for structure) and Et2Zn, with 2,2,2-trifluoro-
acetophenone 3a by employing (S)-3,3’-disubstituted binol
(binol = 1,1ꢀ-bi-2-naphthol)
ligands
and
(S,S)-taddol
(taddol = tetraaryl-1,3-dioxolane-4,5-dimethanol) ligands to
afford the desired adduct 5a in quantitative yields and poor
enantioselectivities (< 20% ee). Next, a large number of
chiral amino alcohol ligands, which included DAIB [(2S)-(À)-
3-exo-(dimethylamino)isoborneol], salen (N,Nꢀ-bis(salicyli-
dene)ethylenediamine), cinchona alkaloids, ephedrine, proli-
nol, and some of their derivatives, were screened for the
Ti(OR)4-catalyzed alkynylation of 3a. It was found that the
pseudoenantiomeric cinchona alkaloids 1b and 2b were the
most promising ligands for the test reaction (Table 1,
entries 1–6), whereas all the other chiral ligands tested
resulted in poor yields or enantioselectivities (not listed in
Table 1). Interestingly, the introduction of CaH2 as a base was
found to significantly increase the conversion and selectivity
for the reaction catalyzed by quinine 1b (entry 7). The
replacement of diethylzinc with dimethylzinc further
improved the result (81% yield and 80% ee; entry 8). By
using the same reaction conditions as used in entry 8, chiral
alkaloid ligands such as DHQD (1c), CPN (1d), and BnOPN
(1e) showed lower conversion and diminished enantioselec-
tivity (entries 9–11). The superior level of asymmetric induc-
tion and reaction efficiency exhibited by the Ti(OiPr)4/
cinchona alkaloid catalyst upon addition of CaH2 prompted
us to examine the effect of various other additives. In view of
the similarity in the nature of the hydride and the fluoride
anions,[8] we expected that the use of a fluoride salt could have
a comparable effect on the selectivity. Therefore a number of
metal fluorides were subsequently examined (entries 12–17).
Pleasingly, the use of BaF2 led to a 90% yield of the isolated
adduct (R)-5a with 87% ee. This beneficial effect was found
to be sensitive to the metal center because metal ions of
different sizes and Lewis acidity relative to barium imparted a
deleterious impact on the enantioselectivity. Other barium
salts including BaCl2 and BaBr2 were found to exhibit low
levels of conversion and selectivity (entries 18 and 19). The
pronounced rate and selectivity enhancement obtained when
using BaF2 probably stems from the good p-donating proper-
ties of fluoride, which could coordinate to titanium(IV) to
[*] G.-W. Zhang, W. Meng, H. Ma, J. Nie, W.-Q. Zhang, Prof. J.-A. Ma
Department of Chemistry, Tianjin University
Tianjin 300072 (China)
Fax: (+86)22-2740-3475
E-mail: majun_an68@tju.edu.cn
Prof. J.-A. Ma
State Key Laboratory of Elemento-Organic Chemistry
Nankai University
Tianjin 300071 (China)
[**] This work was supported financially by NSFC (No. 20772091 and
20972110). We thank the NSCC-TJ for help with the computational
studies.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201007341.
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Angew. Chem. Int. Ed. 2011, 50, 3538 –3542

Table 1: The reaction conditions for the catalytic enantioselective
Table 2: Catalytic enantioselective alkynylation of trifluoromethyl ke-
alkynylation of trifluoromethyl ketones.[a]
tones.[a]
Entry Ligand R1, R2 (Product 5)
Yield [%][b] ee [%][c]
1
2
3
4
5
6
1b
2b
1b
2b
1b
2b
1b
2b
1b
2b
1b
2b
1b
2b
1b
2b
1b
2b
1b
2b
1b
2b
1b
2b
1b
2b
1b
2b
1b
1b
1b
1b
1b
Ph, Ph (5a)
Ph, Ph (5a’)
4-FC6H4, Ph (5b)
4-FC6H4, Ph (5b’)
89
86
95
92
98
98
69
68
82
82
89
86
81
81
93
94
76
80
98
98
93
95
98
98
98
98
86
91 (R)
84 (S)
90 (R)
86 (S)
88 (R)
84 (S)
86 (R)
85 (S)
85 (R)
85 (S)
88 (R)
80 (S)
86 (R)
82 (S)
83 (R)
86 (S)
89 (R)
83 (S)
80 (R)
76 (S)
83 (R)
84 (S)
84 (R)
84 (S)
85 (R)
80 (S)
87 (R)
84 (S)
65 (R)
94 (R)
66 (R)
67 (R)
88 (R)
4-ClC6H4, Ph (5c)
4-ClC6H4, Ph (5c’)
4-BrC6H4, Ph (5d)
4-BrC6H4, Ph (5d’)
4-MeC6H4, Ph (5e)
4-MeC6H4, Ph (5e’)
3,5-Me2C6H4, Ph (5 f)
3,5-Me2C6H4, Ph (5 f’)
4-MeOC6H4, Ph (5g)
4-MeOC6H4, Ph (5g’)
4-PhC6H4, Ph (5h)
4-PhC6H4, Ph (5h’)
2-naphthyl, Ph (5i)
2-naphthyl, Ph (5i’)
Ph, 4-FC6H4 (5j)
7[d]
8[d]
9[d]
10[d]
11[d]
12[d]
13[d]
14[d]
15
16
17[e]
18[e]
19
20
21
22
23
24
25
26
27
28
29
30
31
32[f]
33[g]
Entry
Ligand
Additive (equiv) T [8C]
Yield [%][b]
ee [%][c]
1[d]
1a
1b
2a
2b
1b
1b
1b
1b
1c
1d
1e
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b (QN)
2b (QD)
–
–
–
–
–
–
25
25
25
25
0
41
70
30
72
70
68
76
81
75
69
41
95
73
85
90
57
90
29
30
70
96
89
86
27 (R)
49 (R)
39 (S)
53 (S)
50 (R)
53 (R)
78 (R)
80 (R)
73 (R)
68 (R)
40 (R)
3
12 (R)
86 (R)
84 (R)
53 (R)
87 (R)
39 (R)
23 (R)
84 (R)
84 (R)
91 (R)
84 (S)
2[d]
3[d]
4[d]
5[d]
6[d]
À20
À20
À20
À20
À20
À20
À20
À20
À20
À20
À20
À20
À20
À20
À40
À20
À20
À20
7[d]
CaH2 (0.6)
CaH2 (0.6)
CaH2 (0.6)
CaH2 (0.6)
CaH2 (0.6)
CsF (0.6)
TiF4 (0.6)
CaF2 (0.6)
MgF2 (0.6)
SrF2 (0.6)
BaF2 (0.6)
BaCl2 (0.6)
BaBr2 (0.6)
BaF2 (0.6)
BaF2 (0.3)
BaF2 (0.2)
BaF2 (0.2)
8[e]
9[e]
10[e]
11[e]
12[e]
13[e]
14[e]
15[e]
16[e]
17[e]
18[e]
19[e]
20[e]
21[e]
22[e]
23[e]
Ph, 4-FC6H4 (5j’)
4-MeC6H4, 4-FC6H4 (5k)
4-MeC6H4, 4-FC6H4 (5k’)
Ph, 4-MeC6H4 (5l)
Ph, 4-MeC6H4 (5l’)
4-ClC6H4, 4-MeC6H4 (5m)
4-ClC6H4, 4-MeC6H4 (5m’)
4-MeOC6H4,4-MeC6H4 (5n)
4-MeOC6H4,4-MeC6H4 (5n’) 88
Ph, cyclopropyl (5o)
Ph, n-Hex (5p)
96
75
67
98
55
=
trans-PhCH CH, Ph (5q)
Ph, Ph (5r)
Ph, Ph (5s)
[a] General reaction conditions: 3a/4a/Et2Zn/Ti(OiPr)4/ligand=
1.0:2.5:3.0:2.0:0.2 in toluene (0.1m), for 2 days. [b] Yield of isolated
product. [c] The ee values were determined by HPLC analysis on a chiral
stationary phase. The absolute configuration is based on the comparison
of the optical rotation with the literature.[6] [d] Et2Zn was used. [e] Me2Zn
was used.
[a] General reaction conditions: 3/4/Me2Zn/Ti(OiPr)4/1b or 2b/BaF2 =
1.0:2.5:3.0:2.0:0.2:0.2, in toluene (0.10m) at À208C for 2 days. [b] Yield
of the isolated products. [c] The ee values were determined by HPLC
analysis. The absolute configuration of 5a and 5a’ is based on the
comparison of the optical rotation with the literature values.[6] The
absolute configuration of other adducts were assigned on the basis of
analogy with 5a and 5a’. [d] 3 days. [e] 5 days. [f] a,a-Difluoroacetophe-
none was used as the substrate. [g] Pentafluoroethyl phenyl ketone was
used as substrate.
cause the deoligomerization of the catalyst structure, thus
forming a more favorable catalytic precursor.[9] A decrease in
the loading of BaF2 led to the best result [(R)-5a in 89% yield
and 91% ee; entry 22]. Under similar reaction conditions, the
use of QD (2b) as the chiral ligand gave the S-configured
adduct 5a’ with 84% ee (entry 23). Additional solvent screen-
ing demonstrated that toluene was the optimal solvent under
the reaction conditions used.
On the basis of these results, QN (1b) and QD (2b) were
ultimately selected as the ligands and BaF2 as the additive for
the reaction of trifluoromethyl ketones 3 with terminal
alkynes 4 in the presence of Ti(OiPr)4 to give either
enantiomer of 5. Results in Table 2 indicate that both
enantiomers of the desired adducts can be synthesized by
using 1b and 2b to give (R)-5 and (S)-5, respectively, with
good to high yield and enantioselectivity. The reaction can
tolerate a wide range of functional groups on ketones 3 and
alkynes 4, including electron-neutral, electron-withdrawing,
and electron-donating groups (entries 1–28). For ketones 3
that have electron-donating groups and a bromide substituent
on the aromatic ring, a somewhat prolonged reaction time
was required to get satisfactory yields (entries 7–14, 17, and
18). It is noteworthy that aliphatic alkynes also gave the
adducts in good to high yield and enantioselectivity
(entries 29 and 30). Additionally, the reaction worked well
with (E)-1,1,1-trifluoro-4-phenylbut-3-en-2-one to afford the
1,2-adduct in good yield and enantioselectivity (entry 31). To
further define the scope of our methodology, the reactions of
difluoromethyl- and perfluoroethyl ketones were also tested.
The reaction of a,a-difluoroacetophenone proceeded in
Angew. Chem. Int. Ed. 2011, 50, 3538 –3542
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3539

Communications
quantitative yield and good enantioselectivity (entry 32).
Perfluoroethyl phenyl ketone gave a moderate yield whilst
maintaining a high ee value (entry 33). We also investigated
the reaction with 2-fluoroacetophenone and acetophenone.
These less reactive substrates were found to be unsuitable for
this asymmetric transformation and only a racemic mixture of
products were obtained in poor yields (< 15%). Additionally,
a sterically hindered ketone was found to give a good yield
but a low ee value.[10]
To cast some light on the mechanism and to identify the
role of the fluoride additive, electrospray ionization mass
spectrometry (ESI-MS) methods were used to study this 1,2-
addition reaction. An ESI-MS measurement of a mixture of
Ti(OiPr)4, QN (1b), phenylacetylene (4a), BaF2, and Me2Zn
(2.0:0.2:2.5:0.2:3) in toluene displayed a base peak at
m/z 765.4, pertaining to the existence of the zinc-to-titanium
transmetallation intermediate [Ti(OiPr)2(phenyl ethynyl)-
(quininyl)BaF2] (I, Figure 1). When the amount of Me2Zn in
the mixture was increased to six equivalents, the ESI-MS
experiment gave a new base peak at m/z 721.4, thus pointing
to
the
bis(transmetallated)
product
[MeTi-
(OiPr)(phenylethynyl) (quininyl)BaF2] (II, Figure 1).
To gain a better understanding of this reaction, DFT
calculations using the B3LYP/6-31G(d) method[11] were
performed with a view of delineating the details of the
putative zinc-to-titanium transmetallation. The computed
route of the model reaction between the simplified titani-
um(IV)/amino-alcohol complex III and methyl(phenylethy-
Figure 1. ESI-MS experiment of the intermediates (I) and (II).
nyl)zinc is shown in Figure 2.[12] Given the pronounced effect (toluene). Complexation of methyl(phenylethynyl)zinc with
of BaF2 in improving both the yield and the enantioselectivity the isopropoxy ligand on IN1 to give IN2 is also exothermic
of the reaction, and the ESI-MS results, which indicate the and helps bring the reaction to its energy minima. Formation
participation of BaF2 in the formation of the transmetallation of the first transmetallation intermediate IN3 from the
products I and II (Figure 1), the calculation was based on the ligand-bound organozinc IN2 proceeds through a concerted
heterobinuclear metal center IN1 as the platform for the process featuring a zinc-to-titanium migration of the alkynyl
subsequent transmetallation. The formation of IN1 was found group crossing an oxygen bridge (TS), with an energy barrier
to be strongly exothermic, both in gas phase and in solution of 25.5 kcalmolÀ1 in solution. Although significant, this
Figure 2. The DFT computed energy surfaces considered for zinc-to-titanium transmetallation. The values listed for each structure represent
-1
~
G298
~
~
,
Gsol, and E0, respectively, in kcalmol . Calculated bond lengths [ꢀ]: Ti–N 2.532, Ti–O(1) 1.992, Ti–O(2) 2.146, Ti–O(3) 1.940, Ti–F 1.920,
Ti–C 2.785, Ba–O(1) 2.744, Ba–F 2.553, Zn–O(2) 2.270, Zn–O(3) 2.076.
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Angew. Chem. Int. Ed. 2011, 50, 3538 –3542

titanium(IV)-catalyzed enantioselective
alkynylation reaction. The use of fluoride
additives in other transition-metal-cata-
lyzed processes as well as additional
mechanistic studies are underway in our
laboratory.[14]
Received: November 22, 2010
Revised: January 17, 2011
Published online: March 10, 2011
Keywords: alkynylation ·
.
asymmetric catalysis · enantioselectivity ·
fluorides · titanium
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Scheme 1. Proposed mechanism and transition-state models for the alkynylation of 3a into
5a.
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energy requirement is more than compensated for by the
energy released in the preceding steps (from III to IN2).
Furthermore, formation of IN3 from IN2 is nearly thermo-
dynamically neutral and its subsequent conversion into the
final transmetallation product IV through the intermediacy of
IN4 is only slightly endothermic. Therefore, the overall
process for the formation of complex IV is exothermic and
thermodynamically favorable.
The combination of the structure I observed by the ESI-
MS experiments (Figure 1) and the DFT optimized structure
IV (Figure 2) allows proposal of the hitherto putative trans-
metallation intermediate A for the reaction of phenylacety-
lene and 2,2,2-trifluoroacetophenone using 1b as the chiral
ligand (Scheme 1). The mechanistic pathway for the forma-
tion of (R)-5a includes the following steps: a) barium(II)-
assisted addition of the chiral organotitanium species to the
Re face of the trifluoromethyl ketone substrate via the cyclic
transition-state B to give the barium(II) alkoxide intermedi-
ate C; b) barium-to-titanium shift of the alkoxy group to
generate the titanium(IV) alkoxide intermediate D; and
c) transmetallation of methyl(phenylethynyl)zinc with D to
regenerate the organotitanium intermediate A.
[3] For recent examples of titanium complexes as catalysts in
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In summary, we have successfully developed an efficient
titanium(IV)-catalyzed enantioselective alkynylation of tri-
fluoromethyl ketones by utilizing chiral cinchona alkaloids as
ligands.[13] The major advantage of this process is that both
enantiomers of trifluoromethylated propargylic tertiary alco-
hols can be accessed in good to high yields (up to 98%) and
enantioselectivities (up to 94% ee) from cheap and commer-
cially available chiral ligands. Most significant of all is the
remarkable effect of the metal fluoride additive, which has
proven to be essential for effective asymmetric induction.
Moreover, we present the first piece of evidence for the
mechanism of the zinc-to-titanium transmetallation in a
[6] We are aware of one catalytic but only moderately enantiose-
lective alkynylation of trifluoromethyl ketones using copper
complexes. In this case, a very limited range of substrates were
tested and only moderate enantioselectivity was observed, see:
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Communications
R. Motoki, M. Kanai, M. Shibasaki, Org. Lett. 2007, 9, 2997 –
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[10] The enantioselective alkynylation of 2’-chloro-2,2,2-trifluoroa-
ceto-phenone with phenylacetylene; adduct 85% yield, 40% ee.
(by using QN).
[11] The B3LYP calculations were carried out according to Ahlrichsꢀs
SVP all electron basis set model using pseudo-potential basis
sets (LAN2MB) for Ba, Zn, Ti, and 6-31G(d) basis set for C, H,
O, N, F. Computational details and references are given in the
Supporting Information.
[12] For several examples of a titanium(IV)/complex that contains
the alkoxides and one tertiary amine donor, see: a) K.-H. Wu,
H.-M. Gau, Organometallics 2004, 23, 580 – 588; b) L. Lavanant,
L. Toupet, C. W. Lehmann, J.-F. Carpentier, Organometallics
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18, 569 – 1574; d) J. K. Day, R. E. Baghurst, R. R. Strevens, M. E.
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New J. Chem. 2007, 31, 135 – 143.
[13] During the revision of this manuscript, a palladium-catalyzed
enantioselective alkynylation of trifluoropyruvate was de-
scribed: K. Aikawa, Y. Hioki, K. Mikami, Org. Lett. 2010, 12,
5716 – 5719.
[7] For biocatalytic kinetic resolution of racemic substrates for the
preparation of chiral trifluoromethylated propargylic tertiary
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[8] Hydride and fluoride are classified as hard ligands in coordina-
tion chemistry. In addition, the Van der Waals radius of fluorine
of 1.35 ꢄ renders this element only slightly larger (12.5%) than
hydrogen (1.20 ꢄ).
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[14] The enantioselective alkynylation of benzaldehyde with the
complex I under unoptimized reaction conditions gave the
adduct in quantitative yield with 70% ee. We thank one of the
reviewers for suggesting that we examine the reactivity of
complex I towards the aldehyde substrate.
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