Palladium-Catalyzed Asymmetric Allylic Fluoroalkylation/Trifluoromethylation

Article abstract of DOI:10.1021/jacs.9b06231

The first palladium-catalyzed asymmetric allylic trifluoromethylation is disclosed. The methodology evokes a fundamental principle by which the synergistic interplay of a leaving group and its subsequent activation of the nucleophilic trifluoromethyl grou

Full text of DOI:10.1021/jacs.9b06231

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Communication
Palladium–Catalyzed Asymmetric Allylic Fluoroalkylation/Trifluoromethylation
Barry M. Trost, Hadi Gholami, and Daniel Zell
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b06231 • Publication Date (Web): 07 Jul 2019
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Palladium–Catalyzed Asymmetric Allylic Fluoroalkylation/Trifluorometh-
ylation
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Barry M. Trost*, Hadi Gholami, and Daniel Zell
Department of Chemistry, Stanford University, Stanford, California 94305-5580, United States
Supporting Information Placeholder
iphatic trifluoromethylations. One of the early discover-
ies in this line is the addition of a nucleophilic trifluoro-
methyl group to carbonyl compounds (Scheme 1-b).5 The
requisite effect of a catalytic fluoride source to initiate
the reaction has led to the development of chiral quater-
nary ammonium salts to induce asymmetry in the addi-
tion reaction.6, 1f The latter approach has been utilized as
one of the synthetic routes to access efavirenz (dashed
box, Scheme 1), a HIV drug molecule containing a CF3
group, in moderate enantioselectivity.7 In a different ap-
proach, the MacMillan group has developed an asym-
metric radical based a-trifluoromethylation of aldehydes
using organo-catalysis merged with photoredox cataly-
sis.8 Apart from these seminal reports, the asymmetric in-
troduction of nucleophilic trifluoromethyl group into
ABSTRACT: The first palladium-catalyzed asymmetric
allylic trifluoromethylation is disclosed. The methodol-
ogy evokes a fundamental principle by which the syner-
gistic interplay of a leaving group and its subsequent ac-
tivation of the nucleophilic trifluoromethyl group ena-
bled the reaction. Allyl fluorides have been shown to be
superior precursors for generation of p–allyl complexes,
which lead to trifluoromethylated products with high se-
lectivities and functional group tolerance. This study
highlights the unique role of a bidentate diamidophos-
phite ligand class in palladium-catalyzed reactions that
allow a challenging transformation to proceed.
ntroduction of fluorine into organic molecules is of
Iparamount interest, due to the unique properties that
fluorine offers and its broad application in pharmaceuti-
cal products and in agrochemical ingredients.1 Fluoroal-
kyl groups in general and the trifluoromethyl group in
particular are among the privileged fluorinated groups
that appear frequently in numerous pharmaceutically rel-
evant chemicals.1e The effect of fluorinated alkyl groups
is surmised to adjust the acidity or basicity, to increase
metabolite stability, and to modulate lipophilicity of a
compound.1f, 2 With the underlined importance of this
strategic motif, there have been an increasing number of
methods that are developed in the past decades to access
molecules bearing the trifluoromethyl group.3a-d, 1d, 3e, 1f, 2,
3f However, a vast majority of reports are focused on ap-
proaches for trifluoromethylation of aromatic frame-
works utilizing various transition-metal catalytic sys-
tems.4a-f, 3e, 4g, 4h As an example, a very elegant palladium-
catalyzed trifluoromethylation of aryl chlorides was dis-
closed by the Buchwald group (Scheme 1-a).4b
Scheme 1. Trifluoromethylation reactions; The
asymmetic allylic trifluoromethylation.
Pd–catalyzed trifluoromethylation of aryl chlorides
a.
Cl
CF3
Pd°/L
(Buchwald 2010)
Et3SiCF3
CsF
H
N
R
R
O
asymmetric trifluoromethylation
b.
O
Cl
O
Me3SiCF3
OH
F3C
CF3
R4N+F-
R1 R2
R1 R2
O
efavirenz
(HIV antiviral)
O
amine catalyst
CF3
(MacMillan 2009)
H
H
photoredox catalyst
CF3I
R
R
enantioenriched
α-CF3 aldehydes
LG
R2
CF3
Morita−
Baylis−Hillman
type reaction
Me3SiCF3
R1O2C
R1O2C
R2
(DHQD)2PHAL
LG = OAc, OBoc, F
applications of π-allyl complexes
c.
undeveloped
well–established
Nu
CF3
ML*n
nucleophiles
“CF3 ”
Nu = C, O,
N, S, F, etc.
In stark contrast, direct aliphatic trifluoromethylation
has received less attention. More importantly, performing
the latter transformation in an asymmetric fashion with
high enantioselectivity is utterly undeveloped.1f, 2 Pre-
sumably, the challenges in carrying out such a task has
hampered the availability of methods for asymmetric al-
M = Pd, Ir, Mo, etc.
π-allyl complexes
this work
π-allyl complexes for asymmetric trifluoromethylation
d.
Rf :
TMS–Rf (5 equiv)
[CpPd(η3-C3H5)] (6 mol%)
CF3
C2F5
F
Rf
C3F7
X
R
Ligand (7 mol%)
X = CH2, NR
X
R
F5
1
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Page 2 of 8
electrophilic carbon centers is extremely rare. To the best
Herein, we report the first palladium-catalyzed asymmet-
ric allylic trifluoromethylation and more importantly,
fluoroalkylation reactions.
1
2
3
of our knowledge, a Baylis-Hillman type reaction stands
as the only example in this regard (Scheme 1b).9
We began our endeavor by looking into the typical
leaving groups to generate the p-allyl complex and inter-
cept this electrophilic species with the nucleophilic tri-
fluoromethyl anion. Our initial foray of experiments in-
dicated that the proposed allylic trifluoromethylation us-
ing trimethyl(trifluoromethyl)silane (TMSCF3) could not
be accomplished efficiently using prototypical leaving
groups (carbonates, acetate, chloride, etc.). This observa-
tion was presumably due to the incompetency of
TMSCF3 to engage as a pronucleophile in the proposed
reaction under the tested conditions. A possible rationale
was that, the oxygen-based leaving groups in this reac-
tion are insufficiently silylophilic to liberate a nucleo-
philic trifluoromethyl anion. In light of this notion, fluo-
ride was chosen as a leaving group because its high si-
lylophilicity should enhance the polarization of the C–Si
bond presumably via a hypervalent silicon species. Since
a naked trifluoromethyl group can undergo a-elimination
and carbene formation,11, 4b by using allyl fluorides as
substrate, this nucleophile would be generated alongside
the catalytic process and would be consumed by the in
situ generated electrophilic p-allyl complexes. Further-
more, the ionization of the allyl fluoride would be facili-
tated by its interaction with TMSCF3 and a synergistic
interplay can be invoked in this reaction paradigm.12, 9c
In line with our conceptual view, utilization of substrate’s
fluoride in reactions involve acyl fluorides, has been
demonstrated to offer a unique reactivity pattern in vari-
ous transition-metal catalyzed reactions.13
Given the tremendous success of electrophilic p-allyl
complexes with different metals to incorporate various
carbon or heteroatom nucleophiles into organic mole-
cules, we aimed to use this platform to implement an elu-
sive asymmetric allylic trifluoromethylation (Scheme 1-
c).10 Due to the abundance of cyclic frameworks, espe-
cially six-membered ring motifs, in the skeletons of phar-
maceutically relevant compounds, we chose to utilize
this scaffold as the model substrate (Scheme 1-d).
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Table 1. Selected optimization conditions for the
asymmetric allylic trilfuormethylation.
TMS–CF3
[CpPd(η3-C3H5)]
F
CF3
Ligand
solvent, temp
1-a
2-a
entrya
ligand
temp (°C)
yieldb
solvent
erc
n.d.d
<5%d
20%
35%
-
1
2
3
4
L-1 to L-5
L-6
MTBE
MTBE
MTBE
PhCH3
50
50
50
50
-
-
L-7
L-8
91:9
5
6
PhCH3
DME
L-9
L-9
75
75
40%
92:8
-
<5%d
7
8
L-9
L-9
L-9
L-9
L-9
DCE
1,4-dioxane
MTBE
75
75
75
r.t.
50
<5%d
60%
80%
30%
67%
-
90:10
90:10
96:4
95:5
9
10
11
MTBE
MTBE
12e
13e
14e
15h
L-9
L-9
L-9
L-9
MTBE
MTBE
MTBE
MTBE
50
50
50
50
>95%
n.d.d,f
22%g
>90%i
95.5:4.5
Optimization studies revealed that no reaction could
be detected when using ligands typically developed for
allylic alkylation (Table 1, entries 1 and 2).10a-c, 10f-h When
S-Phos (L-7) was utilized as a ligand, the trifluorometh-
ylated product could be detected in low yield (Table 1,
entry 3). This result is significant since L-7 is structurally
similar to the ligands that are utilized by the Buchwald
group for the palladium-catalyzed trifluoromethylation
of aryl chlorides (Scheme 1-a).4b To our delight, di-
amidophosphite ligands L-8 and L-9 delivered the de-
sired product with moderate yield and high enantioselec-
tivity (entries 4 and 5).14 Ligand L-9 that showed slightly
better results was chosen as the optimized ligand, and
further optimization showed that methyl tert-butyl ether
as solvent could deliver the product 2 in 80% yield at el-
evated temperature with good e.r. (Table 1, entry 9). Per-
forming the reaction at lower temperature led to the im-
provement of e.r., albeit with decreasing the yield of 2
due to lower conversion of the allyl fluoride (Table 1, en-
tries 10 and 11). Increasing the catalyst and ligand load-
ings led to complete consumption of the allyl fluoride
and the 2 was formed in >95% NMR yield (Table 1, entry
12). Of note, under these optimized conditions, allyl
chloride and allyl–OBoc (O–tert-butyloxycarbonyl) did
-
-
96:4
aReactions on 0.05 mmol scale (~0.2 M) using [CpPd(η3-C3H5)] (5 mol%), ligand
(5 –15 mol%), and TMSCF3 (5.0 equiv) after 14 h. bDetermined by 1H-NMR
using 1,3,5-trimethoxy benzene as an internal standard. ce.r. are determined
using chiral GC analysis. d>90% of the starting material was recovered.e10
mol% [CpPd(η3-C3H5)], 15 mol% L-9 was employed. fAllyl chloride.
g
Allyl–OBoc
mol%), L-9 (7 mol%) was used. 79% isolated yield. MTBE: methyl tert-butyl
.
h0.25 mmol of the allyl fluoride (0.4 M), [CpPd(η3-C3H5)] (6
i
ether; DME: 1,2-dimethoxyethane; DCE: 1,2-dichloroethane.
selected ligand calsses that were tested for this reaction
O
Ph
Ph
O
O
O
O
P
N
NH
HN
Ar2P
N
tBu
PPh2Ph2P
Ar = o-tolyl
L-3
L-2
L-1
PtBu2
O
P
Cy2P
MeO
PPh2
PPh2
Cy2P
Fe
OMe
Me
O
O
L-6
L-5
Ph
L-4
L-7
Ph
Ph
Ph
O
O
O
O
N
N
N
N
P
N
P
N
P
N
P
N
Ph
Ph
Ph Ph
L-8
Ph Ph
L-9
Ph
Ph
2
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Scheme 2. Scope of the palladium-catalyzed asymmetric allylic fluoroalkylation.a
TMS–Rf (2 – 5 equiv)
1
2
3
F
Rf
Ph
Ph
[CpPd(η3-C3H5)] (6 mol%)
O
O
N
N
P
N
P
N
4
5
6
X
R
X
R
Pd
L-9 (7 mol%)
MTBE (0.4 M), 50 °C, 14h
Ph Ph
L-9
1-a – 1-aa
2-a – 2-aa
[CpPd(η3-C3H5)]
7
F
CF3
CF3
CF3
CF3
CF3
CF3
8
9
F
Cl
Br
OMe
CF3
10
11
12
13
14
15
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2-a
79% yield
96:4 e.r.
2-b
91% yield
96:4 e.r.
2-c
73% yield
96:4 e.r.
2-d
92% yield
96.5:3.5 e.r.
2-e
93% yield
95:5 e.r.
2-f
51% yield (84% brsm)
>96:4 e.r.
CF3
CF3
crystal structure
of 2-i
CF3
CF3
Me
NO2
CN
O
2-h
2-i
88% yield
96:4 e.r.
2-g
65% yield
93:7 e.r.
2-j
86% yield
97:3 e.r.
92% yield
95.5:4.5 e.r.
CF3
CF3
CF3
CF3
CF3
CF3
O
N
S
N
Me
N
N
2-p
88% yield
94:6 e.r.
2-n
86% yield
96:4 e.r.
2-k
64% yield
96:4 e.r.
CF3
2-m
75% yield
>97:3 e.r.
2-l
43% yield
97:3 e.r.
2-o
79% yield
93:7 e.r.
CF3
CF3
CF3
CF3
OTBS
N
N
N
N
Boc
SiEt3
OMe
N
2-r
59% yield
93:7 e.r.
2-s
61% yield
93:7 e.r.
2-t
64% yield
92:8 e.r.
2-u
69% yield
91:9 e.r.
2-q
95% yield
95:5 e.r.
F
F
CF3
O
F
F
F3C
EtO2C
CF3
F
F
F
F
P
F
EtO
EtO
F
F
F
F
F
Ts
N
F
OMe
2-aad
45% yield
95:5 e.r.
2-vb
94% yield
95:5 e.r.
2-yc
72% yield
89:11 e.r.
2-wb
67% yield
97:3 e.r.
2-zc
77% yield
80:20 e.r.
2-xb
69% yield
90:10 e.r.
aReactions were carried out using 0.25 mmol of allyl fluorides. e.r. of the products were determined using GC or HPLC analysis. b2.5 equivalents of TMS–Rf was
utilized. c1.5 equivalents of TMS–Rf was utilized. dThe reaction was carried out on 0.1 mmol of allyl fluoride 1-aa.
not deliver the product 2 with satisfactory results (Table
1, entries 13 and 14). Ultimately, increase in the concen-
tration by carrying out the reaction on 0.25 mmol scale
allowed to lowering the catalyst and ligand loadings to 6
mol% and 7 mol% respectively, to give product 2 in 79%
isolated yield and 96:4 e.r. (Table 1, entry 15).
group showed lower reactivity and complete consump-
tion of allyl fluoride could not be achieved (2-f), which
is presumably due to the competing oxidative addition of
palladium into C–Br bond. The tolerance of the ketone
group in 2-h is noteworthy, as the reaction showed com-
plete chemoselectivity for the allylic trifluoromethyla-
tion. We have demonstrated the reaction with cyclic six
membered ring systems as the main substrates; however,
the reaction could be carried out on a seven-membered
ring system with comparable results (2-m). On the other
hand, p–allyl complexes from five-membered rings did
not give satisfactory results under these conditions. Het-
eroaromatic moieties on the allyl group were also well
tolerated and the desired products were obtained in good
yields and selectivities (2-n to 2-r). In this line, 2-q is of
particular interest since it contains an aminopyridine core
that is a key structural feature in many drug molecules.
Of particular note, alkyne and alkene groups attached to
With this optimized set of conditions in hand, we ex-
plored the generality of the reaction (Scheme 2). The re-
action showed good tolerance with respect to the substit-
uents directly attached to the p–allyl moiety. Electron-
rich as well as electron-deficient aromatic rings were
well tolerated and resulted in the trifluoromethylated
products 2 in good yields and high enantioselectivities.
Different substitution patterns on the aromatic ring were
also tolerated and delivered the functionalized product in
good yield and selectivity. Aromatic rings bearing differ-
ent halogen atoms could be used under these palladium-
catalyzed conditions. Nonetheless, para-bromo phenyl
3
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the allyl fluoride core could also be engaged in this reac-
Page 4 of 8
double bond in 2-j could readily undergo dihydroxyla-
tion to deliver 3 in excellent yield and high diastereose-
lectivity. In addition, hydrogenation of this motif deliv-
ered the disubstituted cyclohexane 4 in quantitative yield
and high d.r.. Additionally, the pentafluoro group in 2-x
could provide a path for aromatic substitution to access
5.15 This transformation is noteworthy since the per-
fluoroaryl rings have been utilized in various bioconju-
gate strategies, thus pentafluorophenyl motif in 2-x could
be exploited in a distinctive interaction with biologically
important targets.
1
2
3
4
5
6
7
8
tion (2-s to 2-u). Nevertheless, the enantioselectivity in
these cases was slightly lower than the aryl-substituted
substrates. We realized that the reaction is not limited to
the trifluoromethyl group. Indeed, perfluoroalkyl groups
such as pentafluoro ethyl, heptafluoro propyl and pen-
tafluorophenyl were excellent reaction partners in this al-
lylic functionalization, leading to 2-v, 2-w, and 2x, re-
spectively in good yields and with excellent enantiose-
lectivity. Nevertheless, the enantioselectivity of the reac-
tion with pentafluorophenyl as a nucleophile is slightly
lower than the sp3–hybridized fluoroalkyl nucleophiles.
We further explored the feasibility of the reaction with
a,a–difluoroester and a,a–difluorophosphate as nucleo-
philes. Thus, products 2-y and 2-z were obtained in good
yield although with diminished enantioselectivity as
compared with the perfluoroalkyl nucleophiles. Addi-
tionally, nitrogen containing cyclic allyl fluorides could
be used in the reaction to access trifluoromethylated het-
erocycle 2-aa in moderate yield and high enantioselec-
tivity. By obtaining a crystal structure of 2-j, the absolute
configuration was readily determined, and all other prod-
ucts were assigned by analogy (Scheme 2).
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46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
With these results in hand, we turned our attention to
the mechanism of the reaction. We first sought to estab-
lish the overall stereochemical outcome of the reaction.
For this purpose, the known allyl fluoride 6,10d, 16 which
possesses a trans disubstituted core can be used to probe
the retention or inversion mechanism of the trifluoro-
methylation process. To this end, 6 was subjected to the
optimized reaction conditions and the trifluoromethyl-
ated product 7 was obtained in high yield, high diastere-
oselectivity and moderate e.r.. The nOe studies were then
employed to determine the relative stereochemistry of
the stereocenters in the product. No nOe was observed
between the hydrogen atoms on the stereocenters in 7.
The latter could potentially suggest a trans configuration
of these two hydrogens. We further reduced the ester
group to the primary alcohol. A positive nOe between the
carbinol hydrogens and the hydrogen atom on the carbon
bearing the trifluoromethyl group places these hydrogens
cis to each other which confirmed the trans configuration
of the substituents. This analysis indicates an overall re-
tention of the stereochemistry during the trifluorometh-
ylation process. The latter could point to a double inver-
sion (ionization and nucleophilic addition) or a double
retention mechanism. The clear scenario of this reaction
is not known; however, the results from Gouverneur,
Brown, and coworkers that have elucidated the stereo-
chemical outcome of allyl fluorides with a series of nu-
cleophiles, suggests an inversion mechanism during the
The reaction could be carried out on gram scale with
some benefits (Scheme 3). Performing the reaction on a
larger scale allowed us to lower the palladium loading to
2 mol% and the ligand loading to 2.5 mol%. The concen-
tration of the reaction for the large scale reaction was in-
creased to compensate for lower catalyst loading, result-
ing in the formation of 2-j in 88% yield and 97:3 e.r., a
slight improvement compared to the smaller scale reac-
tion. Our method gives access to variable chiral cyclic
compounds with a trifluoromethyl group vicinal to a dou-
ble bound. The double bond in these products can be uti-
lized to further access molecular diversity using known
transformations of olefins. As illustrated in Scheme 3, the
Scheme 3. Gram scale reaction and utilization of the
fluoroalkylated products.
TMS–CF3 (5 equiv)
[CpPd(η3-C3H5)] (2 mol%)
F
Scheme 4. Elucidation of the stereochemical outcome of
L-9 (2.5 mol%)
the trifluoromethylation reaction.
MTBE, 50 °C
1-j
CF3
O
OMe
O
OMe
(1.1 g, 5.0 mmol)
88% yield, 97:3 e.r.
(1.2 g, 4.4 mmol)
TMS–CF3 (5 equiv)
[CpPd(η3-C3H5)] (6 mol%)
2-j
L-9 (7 mol%)
MTBE (0.25 M), 50 °C, 14h
F3C
F
6
7
CF3
CF3
>10:1 d.r.
89% yield
OsO4, NMO
H2, Pd/C
25:1 d.r.
79:21 e.r.
acetone
96% yield
>20:1 d.r.
EtOH
>99% yield
>20:1 d.r.
OH
OH
nOe studies
4
O
H1
OMe
3
H
OH
Ha
H
aromatic substitution reaction
F
S
H
nOe
1.7%
F
F
F3C
nOe
1.3%
F
F
H5
NaSEt
F3C
H
F
F
H5
DMSO, rt
47%
H
F
F
nOe
3.6%
No nOe between H1 and H5
2-x
5
4
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ionization event of allyl fluorides.12, 16 Thus, a double in-
version mechanism should be involved in our methodol-
ogy to deliver an overall retention.
Drugs Introduced to the Market in the Last Decade (2001–2011).
Chem. Rev. 2014, 114, 2432; (f) Yang, X.; Wu, T.; Phipps, R. J.;
Toste, F. D., Advances in Catalytic Enantioselective Fluorination,
Mono-, Di-, and Trifluoromethylation, and Trifluoromethylthiolation
Reactions. Chem. Rev. 2015, 115, 826.
1
2
3
4
5
6
7
8
9
In summary, we report the first palladium-catalyzed
asymmetric allylic trifluoromethylation reaction empow-
ered by a unique ligand class. The role of allyl fluorides
as a superior precursor for generation of p-allyl com-
plexes suggests a synergistic interplay of the fluoride
leaving group and TMS–CF3 in ionization and nucleo-
philic activation. This methodology gives access to vari-
ous fluoroalkylated carbo- and heterocycles with high
functional group tolerance and excellent enantioselectiv-
ities. Our mechanistic studies indicate an overall reten-
tion of the stereochemistry during this unprecedented tri-
fluoromethylation reaction.
2.
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ASSOCIATED CONTENT
The Supporting Information is available free of charge on
the ACS Publications website.
Experimental procedures, analytical data (1H-NMR, 13C-
NMR, MS, IR, and [α]D) for all new compounds, crystal
structure data (PDF )
4.
AUTHOR INFORMATION
Corresponding Author
*E-mail:
bmtrost@stanford.edu
ORCID
Barry M. Trost: 0000-0001-7369-9121
Hadi Gholami: 0000-0001-6520-0845
Daniel Zell: 0000-0002-2241-6301
ACKNOWLEDGEMENTS
We would like to thank the Tamaki Foundation, and
Chugai Pharmaceuticals, for their generous, partial fund-
ing support for our program. We thank the DFG Research
Fellowship (D. Z.). We would link to thank Dr. Stephen
R. Lynch (Stanford University) for assistance with nu-
clear magnetic resonance analysis. The crystal structure
analysis of this work was performed at the Stanford Nano
Shared Facilities (SNSF)/Stanford Nanofabrication Fa-
cility (SNF), supported by the National Science Founda-
tion under award ECCS-1542152.
5.
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and reactions. 141. Fluoride-induced trifluoromethylation of carbonyl
compounds with trifluoromethyltrimethylsilane (TMS-CF3).
trifluoromethide equivalent. J. Am. Chem. Soc. 1989, 111, 393.
A
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Addition of a Trifluoromethyl Anion to Aryl Ketones and Aldehydes.
Synthesis 2003, 2003, 1693; (d) Kawai, H.; Kusuda, A.; Nakamura,
S.; Shiro, M.; Shibata, N., Catalytic Enantioselective
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TMS–Rf
[CpPd(η3-C3H5)]
(6 mol%)
F
Rf
X
R
X
R
7
8
Ligand (7 mol%)
X = CH2, NR
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CF3
C2F5
C3F7
F5
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