Ligand-Dependent Regiodivergent Enantioselective Allylic Alkylations of α-Trifluoromethylated Ketones

Article abstract of DOI:10.1021/acs.orglett.1c00329

The asymmetric introduction of the CF3 unit is a powerful tool for modifying pharmacokinetic properties and slowing metabolic degradation in medicinal chemistry. A catalytic and enantioselective addition of α-CF3 enolates allows for expeditious access to

Full text of DOI:10.1021/acs.orglett.1c00329

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Letter
Ligand-Dependent Regiodivergent Enantioselective Allylic
Alkylations of α‑Trifluoromethylated Ketones
Yi Zhu,# Yifan Ni,# Chenxi Lu, Xiaochen Wang, Yi Wang,* Xiao-Song Xue,* and Yi Pan
Cite This: Org. Lett. 2021, 23, 2443−2448
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ABSTRACT: The asymmetric introduction of the CF3 unit is a powerful tool for modifying pharmacokinetic properties and slowing
metabolic degradation in medicinal chemistry. A catalytic and enantioselective addition of α-CF3 enolates allows for expeditious
access to functionalized chiral building blocks with CF3-containing stereogenicity. The computational studies reveal that the choice
of ligand in a designed palladium-complex system regulates the regioselectivity and stereoselectivity of the asymmetric allylic
alkyation of α-CF3 ketones and Morita−Baylis−Hillman adducts.
he wide application of fluorinated compounds in
Tagrochemicals, pharmaceuticals, and materials science
has triggered every endeavor to develop efficient methods for
selective incorporation of a trifluoromethyl group into organic
molecules.1 The reliable methodology to access CF3-
containing stereogenicity is still underdeveloped in the context
of matured asymmetric synthesis.2 The electrophilic trifluor-
omethylation of ketones has shown low reactivity and
enantioselectivity, even with the aid of a chiral auxiliary
(Figure 1a).3 Meanwhile, the exploitation of α-CF3 enolate as
an active nucleophile for enantioselective C−C bond-forming
reactions is a viable strategy for pursuing this end, allowing
rapid access to densely functionalized chiral building blocks.4
Despite the significant advances in enolate-based chemistry
over the past decades,5 α-CF3 enolates have only been scarcely
explored because of the M−F elimination of their metal
enolates.6 Electrophilic alkylation of prefunctionalized α-CF3
ketones provided remarkable outcomes by the use of chiral
auxiliaries or directing groups (Figure 1b).7 In contrast, the
direct asymmetric alkylation of naked α-CF3 ketones
represents unmet challenges in terms of reactivity and
selectivity that has not been addressed.8
Despite the broad application of Morita−Baylis−Hillman
(MBH) adducts as functionalized allylic synthons, good regio-
Figure 1. Overview of α-CF3 enolate chemistry.
and enantiocontrol of metal-catalyzed C1-selective adducts has
not yet been realized.9,10 The comprehensive studies on
Received: January 28, 2021
palladium-catalyzed AAA reactions by Trost and co-workers
Published: March 11, 2021
revealed that the regioselectivity can be modulated by both
sterics and electronics of the ligand.10 The nucleophilic attack
of α-CF3 enolate from the Re/Si faces to either terminal of the
π-allylmetal complexes would result in a number of stereo-
https://dx.doi.org/10.1021/acs.orglett.1c00329
© 2021 American Chemical Society
Org. Lett. 2021, 23, 2443−2448
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isomers. To overcome the above issues, we have designed a
regiodivergent enantioselective allylic allylation of auxiliary-free
α-CF3 ketones with MBH adducts. By only switching the chiral
ligands of the palladium complexes, excellent regio- and
stereocontrol can be achieved on both C1 and C3 adducts for
the construction of CF3-bearing quaternary centers (Figure
1c).
To determine the suitable conditions for C1-selective allylic
alkylation of α-CF3 ketone 1, we first studied the reaction of
dihydroindenone 1a and MBH ester 2a (1.2 equiv) in the
presence of Pd2dba3 (5 mol %) with a survey of chiral ligand
(12 mol %) in THF at room temperature (Table 1). Spiro-type
electron density on Pd center can lead to the higher
contribution of the cationic allyl intermediate, which would
lead to the preferred C3-attack.
Further optimization with L8 showed that using dichloro-
methane as the solvent did not improve the reaction yield
(entry 9). With toluene, the yield increased to 92% (entry 10).
By adding 2 equiv of Et3N, both reaction yields and
selectivities were simultaneously improved (entry 11). The
best results were obtained with DIPEA (entry 12, 96%, 95:5
for 3a, > 20:1 dr, 99% ee). Thus, the optimized conditions
were selected for further investigation of the C1-selective AAA
reaction.
The reaction scope of C1-alkylation was explored using CF3-
ketones 1a and different MBH esters 2 (Scheme 1). Phenyls
bearing both electron-withdrawing and electron-donating
Table 1. Optimization of the C1-Selective Reaction
Conditions
a
Scheme 1. C1-Selective Asymmetric Allylic Alkylation
b
d
yield
ee
c
entry
base
ligand solvent
(%)
3a/4a
dr
(%)
1
2
3
4
5
6
7
8
none
none
none
none
none
none
none
none
none
none
NEt3
DIPEA
L1
L2
L3
L4
L5
L6
L7
L8
L8
L8
L8
L8
THF
THF
THF
THF
THF
THF
THF
THF
DCM
toluene
toluene
toluene
85
82
75
84
93
84
87
89
67
92
93
96
7:93
6:94
12:88
9:91
4:96
6:94
35:65
85:15
48:52
87:13
93:7
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
50
25
44
51
60
−90
−60
97
85
98
9
10
11
12
99
>99
95:5
a
Unless otherwise noted, all reactions were performed in solvent (1
mL) at room temperature for 12 h in the presence of 1a (0.05 mmol),
2a (0.06 mmol), [Pd] (0.005 mmol), ligand (0.006 mmol), and base
b
c
(0.10 mmol). Yield of isolated 3a and 4a. The values of 3a/4a and
diastereomeric ratios of 3a were determined by 19F NMR analysis of
d
the crude products. The ee values of 3a were determined by chiral
HPLC analysis.
ligand (L1) afforded the products in a total of 85% yield in
which the C1-adduct 3a was only 7% with 50% ee (entry 1).
When using BINAP (L2) and Phoxphos (L3−L5), low regio-
and enantioselectivities for 3a were obtained (entries 2−5).
The reverse of the absolute configuration was obtained with L6
(entry 6). When switching to monodentate binaphthol-derived
phosphoramidite L7,11 an increased ratio of the C1 adduct 3a
was observed (entry 7, 35:65). SIPHOS L8 resulted in good
regioselectivity (85:15) and 97% ee (entry 8). This could due
to the electron-withdrawing feature of L8. Hence, the reduced
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a
Table 2. Optimization of the C1-Selective Reactions
b
c
d
entry
ligand
base
none
none
none
none
none
none
none
none
Na3PO4
K2CO3
NaOAc
KOH
LG
T (°C)
yield (%)
4/3
E/Z
ee (%)
1
2
3
4
5
6
7
8
L1
L3
L4
L5
L7
L5
L5
L5
L5
L5
L5
L5
OBoc
OBoc
OBoc
OBoc
OBoc
OAc
OAc
OAc
OAc
OAc
OAc
25
25
25
25
25
85
75
84
93
87
52
40
27
50
56
37
25
93:7
88:12
91:9
96:4
65:35
95:5
92:8
95:5
95:5
90:10
92:8
90:10
8:1
10:1
8:1
13:1
1:6
10
44
0
60
−40
80
85
95
93
85
94
80
25
8:1
−10
−30
−30
−30
−30
−30
15:1
13:1
18:1
16:1
16:1
15:1
9
10
11
12
OAc
a
Unless otherwise noted, all reactions were performed in solvent (1 mL) at a certain temperature for 48 h, in the presence of 1 (0.05 mmol), 2
b
c
(0.06 mmol), Pd2(dba)3 (0.005 mmol), L5 (0.012 mmol), and base (0.15 mmol). Yield of isolated 3 and 4. The ratios of 4/3 and E/Z ratio of 4
d
were determined by 19F NMR analysis of the crude products. The ee values of 4a were determined by chiral HPLC analysis.
groups could be readily added to 1a to furnish the CF3-ketones
in high yields with excellent diastereoselectivities and
enantioselectivities (3b−3l). Furan-, thiophene-, and naph-
thyl-derived MBH esters were tolerated (3n and 3o). Various
substituted indenones on benzene ring could also afford the
corresponding the C1-adducts (3p−3x).
Scheme 2. C3-Selective Asymmetric Allylic Alkylation
For the optimization of C3-selective adduct (Table 2), we
slightly modified the reaction conditions for substrate 1a and
MBH ester 2b (LG = OBoc). With L1 and L4, low ee’s were
obtained. For L3 and L7, moderate regioselectivity and
diastereoselectivity were achieved. L5 gave high regioselectivity
(96:4) and 60% ee (entry 6). Switching the temperature to
−10 and −30 °C further improved the diastereoselectivity,
affording the C3-selective adduct in 85% and 95% ee,
respectively. However, the reaction yields decreased signifi-
cantly (entries 8 and 9). By adding bases such as Na3PO4,
K2CO3, and NaOAc, the reaction yields were improved and
the enantioselectivities remained high. KOH was found to be
detrimental both to the reaction efficiency and diastereose-
lectivity.
The reaction scope of asymmetric allylic alkylation is further
extended to a range of MBH esters with L5 to generate C3-
selective adducts (Scheme 2). MBH esters 2 with an −OAc
leaving group and phenyls bearing both electron-withdrawing
groups could readily furnish the CF3-ketones in good yields
with high dr and ee’s (4a−4j). Naphthalene-derived MBH
esters were also tolerated (4k). Using CF3-substituted
tetralones, the corresponding adducts were also formed with
equally high diastereoselectivity (4l−4o).
To gain insight into the regioselectivity, DFT calculations
were carried out with M06L/6-311++G(2d,p)-SDD-SMD-
(THF)//B3LYP/6-31G(d)-LANL2DZ-SMD (THF). For the
Pd/L5 system,12 calculations suggest an outer-sphere SN2-type
attack is 3.6 kcal/mol lower than that for C1 attack, consistent
with the experimental regioselectivity (Figure 2a). Interest-
ingly, the calculated ΔΔG⧧ value of the nucleophilic addition
TS parallels the calculated ΔΔG⧧ of their corresponding π-
allyl-Pd precursor (Figure 2b) with 2.4 kcal/mol energy
difference. Thus, the relative stability of the π-allyl-Pd
complexes preserved in the subsequent nucleophilic addition
TSs and thus dictates the regioselectivity of the Pd/L5 system.
A closer look at Pd−allyl complexes reveals longer C−Pd
distances in C1-attack precursor, indicating a looser Pd−allyl
binding. This is likely the result of the trans influence of
phosphine on the PHOX ligand as well as the delocalization of
positive charges on C1 by the conjugated phenyl group. As
shown in Figure 2c, the back-donation interaction involving
the d orbital of the Pd center and n−π orbital of the allyl
moiety favors C3-attack precursor (−5.90 vs −5.79 eV on
HOMOs). For more details, see the Supporting Information.
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Scheme 3. Proposed Mechanism
B is stable enough and ligand exchange between the leaving
group and substrate 1 in Pd/L5 system is not likely to occur.
Hence, nucleophilic addition of CF3enolate to B from outer-
sphere affords C3-selective intermediate D. For the mono-
dentate SIPHOS ligand L8, only one phosphoramidite ligand
can coordinate to the metal center of the allylpalladium
complexes.14 Thus, a similar oxidative addition process occurs
first. The following decarboxylation of the Boc group releases
tBuO, and the Pd−tBuO complex F is obtained.15 Here, an
equilibrium of ligand exchange between the CF3 enolate and
tBuO controls the regioselectivity of the product. Config-
uration G with less steric hindrance against the Ar group of
MBH ester is more favorable than H, which explains the C1
selectivity for SIPHOS L8.
In summary, we have developed a highly tunable ligand-
regulated regiodivergent asymmetric allylic alkylation of
fluorinated ketones with MBH adducts. The choices of ligand
in the palladium catalytic systems turn out to be critical for
both reactivity and selectivity for the construction of the CF3-
containing quaternary stereocenters. This protocol could
Figure 2. (a) Transition states and their relative free energy of C1/C3
attack of the Pd/L5 system. (b) π-allyl-Pd precursors and their
relative free energy. NBO charges on terminal carbons are marked in
red. (c) HOMO of π-allyl-Pd precursors.
The plausible reaction pathways based on previous reports13
and computational studies are illustrated in Scheme 3. The
AAA process was initiated by the coordination of Pd−L*
complex to the MBH ester followed by oxidative addition to
generate Pd−π allyl species. Subsequent nucleophilic addition
of α-CF3 enolate to the Pd−π allyl species at the C1- or C3-
position afforded trifluoromethylated ketones depending on
the ligand-regulated process. The final decomplexation releases
the corresponding product 3/4 and regenerate palladium
catalysts. The key selectivity deviation is originated from each
catalytic pathway using bidentate or monodentate ligand. For
the bidentate Phoxphos L5, complextion of A with MBH ester
and oxidative addition generated Pd−π allyl species B because
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Letter
access to a variety of fluorine-bearing motifs with high
efficiency and selectivity.
The preprint manuscript was deposited with Research Square.
DOI: 10.21203/rs.3.rs-110638/v1.
ASSOCIATED CONTENT
ACKNOWLEDGMENTS
■
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00329.
This work was funded by the National Natural Science
Foundation of China (Nos. 21772085, 21971107, 22071101),
the Fundamental Research Funds for the Central Universities
(Nos. 020514380220, 020514380131, 020514913412,
020514913214), Natural Science Foundation of Jiangsu
Province (BK20200610) and Postdoctoral Science Foundation
of China (2019M661720). We also thank Jiangsu Provincial
Key Laboratory of Photonic and Electronic Materials at
Nanjing University for support. Professor Hon Wai Lam at
University of Nottingham is gratefully acknowledged for
helpful discussion.
Experimental procedures, compound characterization
data, and NMR spectra (PDF)
Accession Codes
CCDC 1911158 and 2009810 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
■
Corresponding Authors
Yi Wang − Jiangsu Key Laboratory of Advanced Organic
Materials, State Key Laboratory of Coordination Chemistry,
School of Chemistry and Chemical Engineering, Nanjing
University, 210023 Nanjing, China; orcid.org/0000-
0002-8700-7621; Email: yiwang@nju.edu.cn
Xiao-Song Xue − State Key Laboratory of Elemento-organic
Chemistry, College of Chemistry, Nankai University, 300071
Tianjin, China; orcid.org/0000-0003-4541-8702;
Email: xuexs@nankai.edu.cn
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Authors
Yi Zhu − Jiangsu Key Laboratory of Advanced Organic
Materials, State Key Laboratory of Coordination Chemistry,
School of Chemistry and Chemical Engineering, Nanjing
University, 210023 Nanjing, China; Key Laboratory of
Synthetic and Biological Colloids, Ministry of Education,
School of Chemical and Material Engineering, Jiangnan
University, 214122 Wuxi, Jiangsu, China
Yifan Ni − Jiangsu Key Laboratory of Advanced Organic
Materials, State Key Laboratory of Coordination Chemistry,
School of Chemistry and Chemical Engineering, Nanjing
University, 210023 Nanjing, China
Chenxi Lu − State Key Laboratory of Elemento-organic
Chemistry, College of Chemistry, Nankai University, 300071
Tianjin, China
Xiaochen Wang − Jiangsu Key Laboratory of Advanced
Organic Materials, State Key Laboratory of Coordination
Chemistry, School of Chemistry and Chemical Engineering,
Nanjing University, 210023 Nanjing, China
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