Enantioselective Alkynylation of Trifluoromethyl Ketones Catalyzed by Cation-Binding Salen Nickel Complexes

Article abstract of DOI:10.1002/anie.201913057

Cation-binding salen nickel catalysts were developed for the enantioselective alkynylation of trifluoromethyl ketones in high yield (up to 99 %) and high enantioselectivity (up to 97 % ee). The reaction proceeds with substoichiometric quantities of base (

Full text of DOI:10.1002/anie.201913057

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Accepted Article
Title: Enantioselective Alkynylation of Trifluoromethyl Ketones
Catalyzed by Cation-Binding Salen Nickel Complexes.
Authors: Dongseong Park, Carina I. Jette, Jiyun Kim, Woo-ok Jung,
Yongmin Lee, Jongwoo Park, Seungyoon Kang, Min Su Han,
Brian Stoltz, and Sukwon Hong
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10.1002/anie.201913057
Angewandte Chemie International Edition
COMMUNICATION
Enantioselective Alkynylation of Trifluoromethyl Ketones
Catalyzed by Cation-Binding Salen Nickel Complexes.
Dongseong Park, 1,# Carina I. Jette, 2,# Jiyun Kim, 1,# Woo-Ok Jung, 1 Yongmin Lee, 3 Jongwoo Park, 4
Seungyoon Kang, 1 Min Su Han, 1 Brian M. Stoltz, 2,* and Sukwon Hong1,3,*
A. Examples of bioactive compounds containing a chiral trifluorocarbinol
Abstract: Cation-binding salen nickel catalysts were developed for
MeO
the enantioselective alkynylation of trifluoromethyl ketones in high
HO CF3
CONH2
H
N
O
F3
C
yield (up to 99%) and high enantioselectivity (up to 97% ee). The
reaction proceeds with substoichiometric quantities of base (10-20
mol% KOt-Bu) and open to air. In the case of trifluoromethyl vinyl
ketones, excellent chemo-selectivity was observed, generating 1,2-
addition products exclusively over 1,4-addition products. UV-vis
analysis revealed the pendant oligo-ether group of the catalyst
strongly binds to the potassium cation (K+) with 1:1 binding
stoichiometry (Ka = 6.6 × 105 M-1).
*
Cl
CF3
O
N
Ph
H
N
H
O
Efavirenz
HIV reverse transcriptase inhibitor
CJ-17493
NK-1 receptor agonist
Anticonvulsant
B. Previous reports of asymmetric alkynylation of trifluoromethyl ketones:
H
CF3
HO
O
Catalyst, Base
+
Ph
Ph
CF3
Ph
Ph
Shibasaki, 2007
Ma, 2011
Mashima, 2016
Meggers, 2017
Ar
OMe
Me
Me
N
N
Ru
N
O
O
O
C
C
Fluorinated organic compounds have proven to be
exceptionally useful in many areas of organic chemistry,
including materials, agrochemicals, and pharmaceuticals.1 In
particular, chiral trifluoromethyl substituted tertiary alcohols and
related derivatives are important structural motifs present in a
number of bioactive compounds.2 Of particular importance is
Efavirenz, a frequently prescribed HIV reverse transcriptase
inhibitor (Figure 1a).3 One attractive strategy for the synthesis of
such stereocenters is the asymmetric alkynylation of
trifluoromethyl ketones, as this type of reaction may be catalytic
in base, resulting in exceptionally mild reaction conditions.
Furthermore, the newly installed alkyne functional handle may
be easily converted to a diverse array of functional groups.
OH
N
N
N
N
Ph
Ph
AcO
Mes N
Mes N
N
N
N
N
Cu
Rh
N
N
OTf
H2
O
OAc
Ph
Ph
Bn
N
iPr
N
20 mol %
20 mol %
Ar
Ti(Oi-Pr)4 (2 equiv)
BaF2 (20 mol %)
Me2Zn (3 equiv)
KOt-Bu (20 mol %)
5 mol %
0.5 mol %
Et3N (20 mol %)
66% yield, 52% ee
89% yield, 91% ee
75% yield, 88% ee
97% yield, 99% ee
C. This research: Ni-catalyzed enantioselective alkynylation via bifunctional catalysis:
H
O
L7-Ni (5 mol %)
CF3
HO
R1
Br
Br
N
O
N
O
KOt-Bu (10-20 mol %)
Ni
K
R1
CF3
+
R2
4Å MS, THF
R2
25-40 °C, 24 h
O
O
R1= aryl vinyl
R2= aryl, cyclopropyl
up to 98% yield
and 97% ee
> 30 examples
O
O
Me Me
L7-Ni + KOt-Bu
Figure 1. Enantioselective addition of terminal alkynes to trifluoromethyl ketones.
1.
2.
Dongseong Park, Jiyun Kim, Woo-ok Jung, Seungyong Kang, Min
Su Han, Sukwon Hong
Department of Chemistry, Gwangju Institute of Science and
Technology (GIST), 123 Cheomdan-gwagiro, Buk-gu, Gwangju
61005, Republic of Korea
E-mail: shong@gist.ac.kr
Carina I. Jette, Brian M. Stoltz
Warren And Katharine Schlinger Laboratory for Chemistry and
Chemical Engineering, California Institute of Technology,
Pasadena CA 91125 (USA)
E-mail: stoltz@caltech.edu
Yongmin Lee, Sukwon Hong
School of Materials Science and Engineering, Gwangju Institute of
Science and Technology (GIST), 123 Cheomdang-gwagiro Buk-gu,
Gwangju 61005, Republic of Korea
Since Carreira’s pioneering report,4a several catalysts have
been developed for the enantioselective
alkynylation of
aldehydes,4 imines,5 and alkyl ketones.6 In contrast, there are
fewer reports on the enantioselective alkynylation of
trifluoromethyl ketones,7,8 as the high reactivity of these electron-
deficient electrophiles has led to significant challenges
associated with facial selectivity. Although there have been
some reports on the enantioselective variant of this
transformation, they all suffer from significant drawbacks, such
as high temperatures,7a large excesses of expensive
reagents,7b,d or the use of precious, second-row transition metals
as catalysts (Figure 1b).7c,h-k
3.
4.
Jongwoo Park
Department of Chemistry, University of Florida, P.O.Box 117200,
Gainesville, FL 32611–7200 (USA)
Current Address: Process R&D Center, SK biotek, 325 Exporo,
Yuseong-gu, Daejeon, 34124, Republic of Korea
In an effort to develop a more sustainable method for the
enantioselective alkynylation of trifluoromethyl ketones, we
turned our attention to the development of a cooperative catalyst
involving a Lewis acid and Brønsted base (Figure 1c).9 The use
of a single catalytic species to activate and bring together both
the nucleophile and electrophile could lead to a well-defined
environment for the reactive intermediates, which could enable
# D.P., C.I.J., and J.K. all contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201913057
Angewandte Chemie International Edition
COMMUNICATION
Table 1. Optimization of Reaction Conditionsa
butyl substituent at this position completely shut down the
reaction (entry 4, L4). We found Ni(II) to be the optimal Lewis
Acid; switching to Co or Zn led to a significant drop in ee, and Pd
led to complete loss of reactivity (entries 5-7).
H
Catalyst (5 mol %)
Base (20 mol %)
O
F3C OH
CF3
Ph
4Å MS, THF (0.48 M)
Temp, 24 h
Ph
Next, we assessed the importance of the counter-ion on the
tert-butoxide base. The highest enantioselectivity and yield was
observed with KOt-Bu; both LiOt-Bu and NaOt-Bu led to a slight
reduction in yield and ee (entry 1 vs entries 8 and 9). When the
reaction temperature was lowered from 50 °C to 25 °C, the ee
was increased to 89% ee (entry 10). Lowering the temperature
even further to –10 °C, however, led to the complete loss of
reactivity (entry 11).
1a
1 equiv
2a
4 equiv
3aa
Yield (%)b
% eec
Entry
Ligand
Temp (°C)
Metal
Base
1
2
3
4
Ni
Ni
Ni
Ni
L1
L2
L3
L4
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
50
50
50
50
97
48
86
–
84
82
86
–
5
6
7
Co
Zn
Pd
L1
L1
L1
KOt-Bu
KOt-Bu
KOt-Bu
50
50
50
91
64
–
49
77
–
Having investigated all other parameters, we returned
to our ligand, focusing on examining the effect of different steric
and electronic modifications on the backbone. We found that the
binapthyl backbone was crucial for reactivity: when a ligand
possessing a cyclohexyl backbone was used instead, no product
was observed (entry 12). In agreement with the work of Wang
and co-workers13 we found that the introduction of bromide
substituents on the salicyl arenes led to a slight improvement in
the ee (entries 13 and 14). Using the 6-Bromo-Salen ligand (L7),
the product was obtained in 93% yield and 93% ee at 25 °C
under air (entry 15).
8
9
Ni
Ni
Ni
Ni
L1
L1
L1
L1
LiOt-Bu
NaOt-Bu
KOt-Bu
KOt-Bu
50
50
86
83
93
–
78
85
89
–
10
11
25
–10
–
–
12
13
14
15
Ni
Ni
Ni
Ni
L5
L6
L7
L7
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
50
50
50
25
97
95
93
88
91
93
N
O
N
O
Table 2: Substrate Scope with Aryl Trifluoromethyl Ketonesa
L7-Ni (5 mol %)
R3
N
O
N
R3
M
H
M
O
N
O
N
O
HO CF3
R2
KOt-Bu (20 mol %)
O
R2
+
M
R1
CF3
R1
O
O
R2
4Å MS, THF (0.48M)
25 °C, 24 h
R2
O
O
1a-h
1 equiv
2a-h
3
O
O
R1
R1
O
O
4 equiv
Me Me
Me Me
L1: R1 = O-CH2CH2O-CH3
L2: R1 = O-CH3
L3: R1 = O-[CH2CH2O]2-CH3
L4: R1 = t-Bu
HO CF3
HO CF3
HO CF3
HO CF3
L6: R2 = Br, R3 = H
L7: R2 = H, R3 = Br
L5
Ph
Ph
Ph
Ph
F
Cl
Br
3aa
3ba
3ca
3da
93% yield
93% ee
93% yield
91% ee
94% yield
89% ee
97% yield
89% ee
aReactions were performed on a 0.242 mmol scale. See Supporting Information for
catalyst synthesis.
analysis.
bIsolated yields. cThe ee values were determined by HPLC
HO CF3
HO CF3
HO CF3
F
HO CF3
Br
Ph
Ph
Ph
Ph
MeO
Me
efficient control over the facial selectivity.10 We envisioned that
the use of the salen ligand framework with a pendant crown
ether11,12 which can interact with an alkali metal cation would
facilitate this form of cooperative catalysis, as the Lewis acid and
Brønsted base could be held in close proximity by a very rigid
and specific structure.
3ga
3ea
86% yieldb
96% ee
3fa
86% yieldb
97% ee
3ha
70% yieldb
87% ee
93% yield
89% ee
HO CF3
HO CF3
HO CF3
F
Br
OMe
3ab
3ac
3ad
To assess the efficacy of this type of cooperative
98% yield
91% ee
86% yield
94% ee
99% yield
93% ee
catalyst we first synthesized and tested a number of ligand
frameworks possessing oligo-ethers of varying length. We were
pleased to find that ligand L1, with a binapthyl backbone and
methoxyethane side chains, in combination with a Ni Lewis Acid
and KOt-Bu Brønsted Base, furnished the desired product in
excellent yields and ee (Table 1, entry 1). Interestingly, we found
that although oligo-ether chain length did not have a significant
effect on the ee, it did have an effect on the yield. Switching to a
ligand possessing methoxy substituents (L2), or extending the
chain length (L3) resulted in less efficient catalysts (entries 2
and 3). It is also important to note that the presence of a
coordinating ether moiety was critical for reactivity, as a tert-
HO CF3
HO CF3
HO CF3
Cl
Me
F
3ae
94% yield
90% ee
3af
89% yield
89% ee
3cb
88% yield
89% ee
HO CF3
HO CF3
HO CF3
Cl
MeO
MeO
3eg
93% yieldb
92% ee
3ee
71% yieldb
96% ee
3eh
95% yieldb
80% ee
Me
(a) Isolated yields on 0.242 mmol scale. Enantiomeric excess was determined by
HPLC analysis. (b) Isolated yield after 48 h.
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10.1002/anie.201913057
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COMMUNICATION
With the optimized reaction conditions in hand, we
explored the substrate scope of the asymmetric alkynylation
(Table 2). We found that electrophiles possessing both electron-
donating substituents (3aa, 3ea, 3fa) and electron-withdrawing
substituents (3ba, 3ca, 3da) at the para-position of the arene
were well-tolerated, resulting in the desired products in up to a
97% ee and 97% yield. Although substitution at the meta-
position of the aryl ring was also tolerated (3ga), ortho-
substitution did lead to a drop in reactivity (3ha). We noted that
generally, the yields for electron-deficient trifluoromethylketones
were slightly higher than with electron-rich substrates, with the
latter requiring extended reaction times. However, we did note
that the ee’s for electron-rich substrates were consistently higher
than their electron-deficient counter-parts.
Gratifyingly, we found that vinyl trifluoromethyl ketones were
also tolerated under slightly modified reaction conditions (See
Supporting Information for more details). Substrates possessing
aryl rings with substituents at the para (5ba, 5ca, 5da, 5ea),
meta (5ga), and even ortho (5ha and 5ia) positions were all
well-tolerated. We were also pleased to see that a tert-butyl
ester-containing substrate (5fa) and a diene (5na) fared well
under these mild reaction conditions. Even substrates
possessing heteroaromatic substituents such as a furan (5aj),
thiophene (5ak), and indole (5al) led to product formation in
excellent ee.
To investigate the binding behavior between L7-Ni and
K+, we carried out metal ion titration studies by UV-vis
absorption spectroscopy.14 Upon addition of KOt-Bu to a solution
of L7-Ni, the UV-vis absorption spectra exhibited characteristic
peaks at 350, 403, and 350 nm with two clear isosbestic points
at 376 and 460 nm, as shown in Figure 4a. The absorbance at
403 nm for L7-Ni/K+ tended to proportionally increase with KOt-
Bu concentration up to 20 µM, and then reached saturation
region. Job plot analysis (Figure 4b) was in good agreement
with the titration study, clearly confirming that L7-Ni binds to K+
through 1:1 binding stoichiometry. From the titration data based
on the 1:1 binding model, the association constant (Ka) for
binding of L7-Ni and K+ ions was calculated to be 6.6 × 105 M-1
using non-linear regression analysis by DynaFit (see Supporting
Information).
We found that the nature of the alkyne had
a less
pronounced effect on the overall outcome of the reaction, and
alkynes possessing both electron-withdrawing (3ab, 3ac, 3cb)
and electron-donating substituents (3ad, 3ae, 3ee) at the para-
position of the aryl substituent were well-tolerated. Furthermore,
we were pleased to see that a bulky napthyl substituent (3af)
and a cyclopropyl substituent (3eg and 3eh) also led to product
formation in good yields and ee.
Table 3. Substrate scope with Trifluoromethyl Vinyl
Ketonesa
H
L7-Ni (5 mol %)
HO CF3
O
KOt-Bu (10 mol %)
R
R
CF3
4Å MS, THF (0.1 M)
40 °C, 24 h
Ph
Ph
4a-n
1 equiv
2a
4 equiv
5
HO CF3
HO CF3
HO CF3
Ph
Ph
Ph
Ph
Ph
Me
MeO
5aa
86% yield
90% ee
5ba
86% yield
90% ee
5ca
98% yield
92% ee
HO CF3
HO CF3
HO CF3
Ph
Ph t-BuO
F
Br
5da
92% yield
92% ee
5ea
93% yield
90% ee
5fa
82% yield
90% ee
O
HO CF3
HO CF3
HO CF3
Ph
Ph
Me
OMe
5ha
92% yield
84% ee
5ia
92% yield
86% ee
5ga
97% yield
90% ee
Me
HO CF3
HO CF3
HO CF3
O
Ph
S
Ph
Ph
N
5ja
5ka
5la
Me
89% yield
90% ee
84% yield
90% ee
63% yield
96% ee
HO CF3
HO CF3
Ph
Ph
5ma
96% yield
92% ee
5na
42% yield
91% ee
Figure 4. (a) UV-Vis spectra of L7-Ni (20 µM) in the presence of varying amounts of
(a) Isolated yields on 0.2 mmol scale. enantiomeric excess was determined by SFC
analysis.
KOt-Bu (0
~ 70 µM) in THF. Inset: Plot of absorbance at 403 nm versus
concentration of KOt-Bu. (b) Job plot for binding mode between L7-Ni and K+ ions in
THF. Aobs: Absorbance of L7-Ni at 403 nm with varying amounts of KOt-Bu; [L7-Ni] +
[KOt-Bu] = 40 µM, Acon.: Absorbance of L7-Ni (40 to 0 µM) at 403 nm without KOt-
Bu.
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10.1002/anie.201913057
Angewandte Chemie International Edition
COMMUNICATION
8420. (b) de Armas, P.; Tejedor, D.; García–Tellado, F. Angew.
Chem. Int. Ed. 2010, 49, 1013–1016 and Angew. Chem. 2010,
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J.–R.; Lan, Y.; Jia, Y.–X. Chem. Commun. 2017, 53, 5890–5893.
For examples of enantioselective alkynylation of ketones see: (a)
Cozzi, P.G. Angew. Chem. Int. Ed. 2003, 42, 2895–2898 and
Angew. Chem. 2003, 115, 3001–3004. (b) Zhou, Y.; Wang, R.; Xu,
Z.; Yan, W.; Liu, L.; Kang, Y.; Han, Z. Org. Lett. 2004, 23, 4147–
4149. (b) Lu, G.; Li, X.; Li, Y.-M.; Kwong, F. Y.; Chan, A. S. C. Adv.
Synth. Catal. 2006, 348, 1926–1933. (c) Lu, G.; Li, X.; Jia, X.;
Chan, W. L.; Chan, A. S. C. Angew. Chem. Int. Ed. 2003, 42,
5057–5058 and Angew. Chem. 2003, 115, 5211–5212. (d) Lu, G.;
Li, Y.–M.; Li, X.–S.; Chan, A. S. C. Coord. Chem. Rev. 2005, 249,
1736–1744. (e) Liu, L.; Wang, R.; Kang, Y.–F.; Chen, C.; Xu, Z.–
Q.; Zhou, Y.–F.; Ni, M.; Cai, H.–Q.; Gong, M.–Z. J. Org. Chem.
2005, 70, 1084–1086. (f) Chen, C.; Hong, L.; Xu, Z. Q.; Liu, L.;
Wang, R. Org. Lett. 2006, 8, 2277–2280.
In summary, we have developed cation-binding salen
Ni catalysts for enantioselective alkynylation of trifluoromethyl
ketones. The cation-binding NiII/K+ heterobimetallic catalyst
plays
a
key role in promoting the alkynylation with
substoichiometric base and open to air, resulting in high
enantioselectivity (up to 97% ee) and yield (up to 99%).
Additionally, we confirmed a 1:1 binding stoichiometry of the
designed catalyst with K+ by UV-vis absorption spectroscopy.
Further study of plausible mechanism and extension of reaction
scope are ongoing.
6.
Acknowledgement
This work was supported by the “GIST-Caltech Research
Collaboration” grant funded by the GIST in 2017, and by the
National Research Foundation of Korea grant funded by the
Korean Government (NRF-2012R1A1A2044550). The NIH-
NIGMS (R01GM080269) and Caltech are also thanked for
support of our research program. C. I. Jette thanks the National
Science Foundation for a predoctoral fellowship.
7.
For alkynylation of trifluoromethylketones: (a) Motoki, R.; Kanai,
M.; Shibasaki, M. Org. Lett. 2007, 9, 2997–3000. (b) Zhang, G.-W.;
Meng, W.; Ma, H.; Nie, J.; Zhang, W.–Q.; Ma, J.–A. Angew. Chem.
Int. Ed. 2011, 50, 3538–3542 and Angew. Chem. 2011, 123,
3600–3604.
(c) Ohshima, T.; Kawabata, T.; Takeuchi, Y.;
Kakinuma, T.; Iwasaki, T.; Yonezawa, T.; Murakami, H.;
Nishiyama, H.; Mashima, K. Angew. Chem., Int. Ed. 2011, 50,
6296–6300. (d) Dhayalan, V.; Murakami, R.; Hayashi, M. Asian J.
Chem. 2013, 25, 7505–7508. (e) Cook, A. M.; Wolf, C. Angew.
Chem. Int. Ed. 2016, 55, 2929–2933 and Angew. Chem. 2016,
128, 2982–2986. (f) Ito, J.–I.; Ubukata, S.; Muraoka, S.;
Nishiyama, H. Chem. Eur. J. 2016, 22, 16801–16804. (g) Zheng,
Y.; Harms, K.; Zhang, L.; Meggers, E. Chem. Eur. J. 2016, 22,
11977–11981. (h) Zheng, Y.; Zhang, L.; Meggers, E. Org. Process
Res. Dev. 2018, 22, 103–107. (i) Chen, S.; Zheng, Y.; Cui, T.;
Meggers, E.; Houk, K. N. J. Am. Chem. Soc. 2018, 140, 5146–
5152. (j) Cui, T.; Qin, J.; Harms, K.; Meggers, E. Eur. J. Inorg.
Chem. 2019, 195–198. For alkenylation and phenylation of
trifluoromethyl ketones: (k) Motoki, R.; Tomita, D.; Kanai, M.;
Shibasaki, M. Tetrahedron Lett. 2006, 47, 8083–8086.
Keywords: Nickel • Bifunctional Catalysis • Alkynylation •
Trifluoromethylketones
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Ni-catalyzed Enantioselective Alkynylation via Bifunctional Catalysis:
H
O
L7-Ni (5 mol %)
CF3
HO
R1
Br
Br
N
O
N
O
KOt-Bu (10-20 mol %)
Ni
K
R1
CF3
+
R2
4Å MS, THF
R2
25-40 °C, 24 h
O
O
R1= aryl vinyl
R2= aryl, cyclopropyl
up to 98% yield
and 97% ee
> 30 examples
O
O
Me Me
L7-Ni + KOt-Bu
Cation-binding salen nickel catalysts were developed for the enantioselective alkynylation of trifluoromethyl
ketones in high yield (up to 99%) and high enantioselectivity (up to 97% ee). The reaction proceeds with
substoichiometric quantities of base (10-20 mol% KOt-Bu) and open to air. UV-vis analysis revealed the pendant
oligo-ether group of the catalyst strongly binds to the potassium cation (K+) with 1:1 binding stoichiometry (Ka =
6.6 × 105 M-1).
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