Palladium(II)-Catalyzed Enantioselective Aminotrifluoromethoxylation of Unactivated Alkenes using CsOCF3 as a Trifluoromethoxide Source

Article abstract of DOI:10.1002/anie.201813591

Asymmetric Pd^II-catalyzed intramolecular aminotrifluoromethoxylation of unactivated alkenes using readily accessible and stable CsOCF₃ as a trifluoromethoxide source has been developed, which affords a wide variety of enantiomerically enriched β-substituted OCF₃-containing piperidines in good yields. Introducing a sterically bulky group into pyridine-oxazoline (Pyox) ligands is crucial to increasing both reactivity and enantioselectivity for the reaction. Additionally, the reaction features good functional group compatibility and mild reaction conditions.

Full text of DOI:10.1002/anie.201813591

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201813591
German Edition: DOI: 10.1002/ange.201813591
Palladium Catalysis
Palladium(II)-Catalyzed Enantioselective
Aminotrifluoromethoxylation of Unactivated Alkenes using CsOCF3
as a Trifluoromethoxide Source
Chaohuang Chen, Philipp Miro Pflꢀger, Pinhong Chen, and Guosheng Liu*
Dedicated to Professor Qingyun Chen on the occasion of his 90th birthday
Abstract: Asymmetric PdII-catalyzed intramolecular amino-
trifluoromethoxylation of unactivated alkenes using readily
accessible and stable CsOCF3 as a trifluoromethoxide source
has been developed, which affords a wide variety of enantio-
merically enriched b-substituted OCF3-containing piperidines
in good yields. Introducing a sterically bulky group into
pyridine-oxazoline (Pyox) ligands is crucial to increasing both
reactivity and enantioselectivity for the reaction. Additionally,
the reaction features good functional group compatibility and
mild reaction conditions.
O
ptically pure organofluorines are frequently found in both
pharmaceuticals and agrochemicals.[1] Therefore, much
efforts have been devoted to the synthesis of chiral organo-
fluorines during the last few decades.[2] Compared to reported
methods for the synthesis of optically active F- and CF3-
containing compounds,[3] the development of methodologies
for the preparation of chiral OCF3-containing molecules lags
far behind,[4] which is possibly attributed to the nature of easy
decomposition of the OCF3 anion[5] and limited OCF3
reagents.[6] Very recently, Tang and co-workers reported the
sole example of the asymmetric trifluoromethoxylation
reaction through an organocatalytic process, employing
stable trifluoromethyl arylsulfonates (TFMS) as a precursor
for AgOCF3 (Scheme 1a).[7]
Scheme 1. Catalytic asymmetric trifluoromethoxylation.
3
À
nation of alkenes or sp C H bonds using strong electrophilic
À
fluorinating reagents, in which the C F bond was enantiose-
In recent years, transition metal catalysis has been
considered as a powerful and prevalent tool to directly
introduce fluorine and fluorine-containing moieties (Rf) into
organic compounds.[8] Among them, transition metal-cata-
lyzed asymmetric fluorination using chiral ligands has been
achieved. For instance, Gagnꢀ,[9] Toste,[10] and Yu[11] inde-
pendently reported Pt and Pd-catalyzed asymmetric fluori-
lectively forged by reductive elimination at a high-valent Pd
or Pt center (Scheme 1b).[12] Although the same mechanism
À
for the formation of C Rf bonds was proposed as well, no
such asymmetric catalytic reaction has been documented to
date.
As our continuous efforts to develop palladium-catalyzed
oxidative difunctionalization of alkenes, recently our group
has demonstrated selective trifluoromethoxylations of
alkenes through a Pd(II/IV) catalytic cycle, using readily
accessible AgOCF3 as a trifluoromethoxide source.[13] For
instance, PdII-catalyzed intramolecular aminotrifluorome-
thoxylation of unactivated alkenes has been developed, in
[*] Dr. C. Chen, Dr. P. Chen, Prof. G. Liu
State Key Laboratory of Organometallic Chemistry, Center for
Excellence in Molecular Synthesis, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032 (China)
E-mail: gliu@sioc.ac.cn
À
which the alkyl C OCF3 bond was generated from CF3O–
PdIVR species by reductive elimination.[13a] However, com-
monly-used nitrogen-containing ligands, such as bipyridines,
phenanthrolines and bioxazolines, have a detrimental effect
on the reactivity of the palladium catalysts. Therefore,
designing novel chiral ligands that can accelerate the reaction
is essential for accomplishing an asymmetric version. Herein,
we communicate a modified Pyox ligand bearing a sterically
bulky ortho-substituted group, which can remarkably enhance
Homepage: http://guoshengliu.sioc.ac.cn
P. M. Pflꢀger
Organisch-Chemisches Institut, Westfꢁlische Wilhelms-Universitꢁt
Mꢀnster
Corrensstraße 40, Mꢀnster 48149 (Germany)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201813591.
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reaction efficiency and enantioselectivity. Additionally, the
use of the more stable and easily prepared CsOCF3 reagent
derived from inexpensive trifluoromethanesulfonic acid
(TfOH),[14] instead of AgOCF3, is crucial to the asymmetric
aminotrifluoromethoxylation reaction (Scheme 1b).
and reasons are as follows: 1) The H NMR studies revealed
that the competitive ligand coordination to PdII and Ag salts
existed (Scheme 2b). Owing to the employment of excessive
amounts of AgOCF3 (Pd:Ag = 1:30), the naked PdII catalyst is
predominant. 2) Similar reaction rates were observed in the
presence or absence of the chiral ligand (Figure 1, red A and
blue B).
Recently, we have demonstrated that introducing a steri-
cally bulky group into a chiral Pyox ligand at the C6-position
could significantly increase the catalytic reactivity of L*PdII
complex toward amination of alkenes and induce excellent
enantioselectivity as well,[15] which prompted us to survey the
possibility of the catalytic asymmetric trifluoromethoxylation
reaction. As an initial investigation, we focused on the
reaction of 1a in the presence of the privileged chiral Pyox
ligand L1 under our PdII/SelectFluorꢁ/AgOCF3 systems.
Although the reaction did occur and gave the desired product
2a in good yield; unfortunately, poor enantioselectivity (9%
ee) was observed (Scheme 2a). Further optimization of the
reaction conditions failed to improve the enantioselectivity,
Then, we turned our attention to screening other nucle-
ophilic trifluoromethoxide reagents, such as CsOCF3 and
R4NOCF3, which are not effective in our previously reported
racemic reaction (less than 20% yield). Surprisingly, these
reagents exhibited much higher reactivity in the presence of
the sterically bulky ligand L1 (Scheme 2a). Notably, CsOCF3
gave the desired product 2a in a slightly lower yield (62%),
but with much better enantioselectivity (79% ee) than
AgOCF3. The reaction using Me4NOCF3 and TASOCF3
yielded the product 2a with slightly lower yields (38% and
53%) and poorer enantioselectivity (69% ee). Further opti-
mization of the reaction conditions revealed that the reaction
in a mixed solvent (CH2Cl2/CH3CN, v/v = 5:1) at À308C gave
the desired product 2a in 77% yield with 88% ee (ligand L1,
Scheme 2c). Further ligand screening demonstrated that the
sterically bulkier Pyox ligand (L1) indeed exhibited much
higher reactivity than less hindered Pyox ligands (L2–L4),
which is consistent with the fact that increasing the sterics in
Py
II
À
the Pyox ligand at the C6 position can weaken the N Pd
bond, thus it is beneficial to enhance the electrophilicity of
palladium catalyst for activation of the double bond.[16]
Additionally, sterically bulky groups in the ligands at the C6
position are also beneficial to the enantioselective induction
of the products (L1 > L4 > L3 @ L2, Scheme 2c).
Based on these studies, the Pyox ligand L5 bearing
a sterically bulkier alkyl group was synthesized, which
exhibited excellent reactivity to give the product 2a in 81%
yield with 90% ee (Scheme 2c). Notably, when the prepared
palladium complex (L5)PdCl2 as a wire-like solid[17] was used
to catalyze the reaction, the product 2a was obtained in
moderate yield (58%); while, the yield of 2a was increased to
82% yield again by adding extra 5 mol% L5. In these two
reactions, the similar enantioselectivities (89–91% ee) were
provided. These results indicated that the ligand L5 would
dissociate from the palladium center owing to the sterically
bulky group in L5, thus extra amounts of L5 was required to
prevent the ligand dissociation of (L5)PdCl2.
With the optimal reaction conditions in hand, the
substrate scope of this asymmetric aminotrifluoromethoxyla-
tion reaction was then examined. As shown in Table 1a,
substrates bearing different arylsulfonyl groups were firstly
surveyed. Electron-rich arylsulfonamides (1a–1d) exhibited
good reactivity to afford the corresponding products 2a–2d in
excellent yields (80–85%); notably, sterically bulkier sulfo-
nylamides, such as 1b with 2,4-dimethylbenzenesulfonyl
(DMPs) and 1c with 2,4,6- trimethylbenzenesulfonyl
(TMPs) gave the desired products with higher enantioselec-
tivity (93% ee in both cases). However, electron-deficient
arylsulfonamides exhibited low reactivities (37% for 2e and
4% for 2 f, respectively), and poorer enantioselectivity
(79% ee for 2e) was obtained. Notably, the substrate bearing
Bz group was not suitable for the reaction (2g).
Scheme 2. Initial studies and ligand screening. [a] Reaction conditions:
1a (0.1 mmol), Pd(PhCN)2Cl2 (10 mol%), Ligand (15 mol%), Select-
Fluorꢂ (0.12 mmol), and CsOCF3 (0.4 mmol) in CH2Cl2/CH3CN
(1.8 mL, v/v=5:1) at À308C for 36 hours. [b] 1H NMR yields with CF3-
DMA as an internal standard, and the ee value in parenthesis was
determined by HPLC on a chiral stationary phase. [c] Addition of extra
5 mol% ligand L5. THF=Tetrahydrofuran. TAS=tris(dimethylamino)-
sulfonium difluorotrimethylsilicate. CF3-DMA=N,N-dimethyltrifluoroa-
cetamide. OTFA=Trifluoroacetate.
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Next, substrates with gem-disubstitutents on carbon
enantiomerically enriched products 9 and 10 in good yields
chains were surveyed (Table 1b). To our delight, substrates
bearing different alkyl groups, such as Et and n-Pr, were
suitable for the reaction to afford the corresponding products
3 and 4 in good yields (76–80%) with excellent enantiose-
lectivities (89–91% ee). Additionally, the reaction of alkenes
with various ring sizes also proceeded smoothly under the
standard conditions to deliver the spiro-piperidine products
5–8 in good yields (79–88%) with excellent ee values (89–
92% ee). Moreover, the reactions of substrates bearing cyclic
ether and cyclic amide also worked nicely to give the
(52–71%) with high enantioselectivities (87–88% ee).
Importantly, substrates bearing three olefinic moieties
proved to be good candidates for the reaction to yield the
olefin-containing products 11–13 in good to excellent yields
(65–91%) with excellent enantioselectivities (86–92% ee).
À
Notably, the reaction exclusively occurred on the C C double
bond of the allylic group to give the six-membered ring
products 12–13, while homoallylic or 1-pentenyl groups were
remained. Additionally, the substrate bearing ester was also
suitable to give the product 14 in 51% yield with 94% ee.
Substrates bearing gem-diaryl groups afforded various OCF3-
substituted piperidines 15–20 with good regioselectivities
(ranged from 5:1 to 16:1) and excellent enantioselectivities
(89–93% ee), although the reaction had to be prolonged
(48 hours) to give satisfied yields. The substrates bearing the
N-Ts group (15a) gave the product in higher yield with similar
enantioselectivity than the substrate bearing the N-DMPs
group (15b). Notably, the linear substrate without gem-
substituents on the carbon chain gave the 6-endo product 21
in 57% yield with good regioselectivity (7:1) and excellent
enantioselectivity (96% ee).
Table 1: Substrate scope.[a,b]
Moreover, racemic substrates bearing a substituent on the
carbon chain were also suitable to deliver the desired
trifluoromethoxylated products (22–23) in good yields with
good to excellent enantioselectivities (83–97% ee); notably,
the formed two enantiomerically enriched diastereomers in
each reaction [(3R,5R)-22 vs. (3R,5S)-22] and [(3R,5R)-23 vs.
(3R,5S)-23] could be easily separated by silica column,
respectively. However, the current reaction was limited to
mono-substituted olefins, 1,1- or 1,2-disubstituted olefinic
substrates were not suitable for this reaction. Furthermore,
the absolute configuration of the products (R)-2c and (R)-15a
were unambiguously confirmed by X-ray analysis.[18]
More importantly, owing to the well compatibility with
olefinic moieties, the products 11 and 12 could be further
transformed into the spiro-fused piperidines bearing cyclo-
pentene (24) and bearing cycloheptene (25) in good to
excellent yields without loss of enantiomeric excess (Sche-
me 3a, left). Additionally, the compound 11 could undergo
Wacker oxidation to provide the carbonyl product 26 in 68%
yield. The regioselective hydrochlorination of 12 using
Cp2ZrHCl/NCS afforded 27 in 93% yield (Scheme 3a,
right). Moreover, arylsulfonyl groups in the chiral products
could be easily removed by using Mg/MeOH under ultrasonic
conditions, leading to piperidine 28 from both 15a and 15b in
good yields without loss of enantiomeric excess (Scheme 3b).
Introducing a fluorine-containing moiety on the piper-
idine ring was found to significantly weaken the basicity of the
amine while reducing cellular efflux and improving metabolic
stability.[19] We thus envisioned that efficient synthesis of
optically pure b-CF3O piperidines with our method provides
an opportunity for the further investigation of its bioactivity.
For instance, Pridinol is an antiparkinsonian and anticholi-
nergic drug,[20] and the enantio-enriched CF3O-modified
Pridinol 29 (96% ee) was efficiently prepared from 21 in
three steps and 62% overall yield (Scheme 3c). To further
clarify the ligand effect, the reaction under different reaction
conditions was monitored at various times (Figure 1). In the
[a] Reaction conditions: alkene (0.2 mmol), Pd(PhCN)2Cl2 (10 mol%),
L5 (15 mol%), SelectFluorꢂ (1.2 equiv), CsOCF3 (4 equiv) in a mixture
solvent of CH2Cl2/CH3CN (5:1, 3.6 mL), À308C for 36 h. [b] Yield of
isolated product, and ee determined by HPLC on chiral stationary phase.
[c] Yield was determined by 1H NMR using CF3-DMA as internal
standard. [d] Reaction was conducted at À358C. [e] 48 h. [f] Regiose-
lectivity (endo-/exo-cyclization) 15a 13:1, 15b 15:1, 16 13:1, 17 9:1, 18
8:1, 19 5:1, 20 16:1, 21 7:1; [g] Diastereoselectivty (d.r. ratio) from the
racemic substrate. ORTEP diagrams were shown with thermal ellipsoids
set at 40% probability.
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In conclusion, we have developed the first enantioselec-
tive PdII-catalyzed aminotrifluoromethoxylation of unacti-
vated alkenes, which provides an easy access to a variety of
enantiomerically enriched 3-OCF3 piperidines in good to
excellent yields with excellent enantioselectivities. Notably,
a sterically bulky Pyox ligand is critical to the success of this
process. Moreover, using the stable CsOCF3 salt makes this
catalytic trifluoromethoxylation reaction of alkenes particu-
larly practical. Further exploration of this methodology is still
in progress in our laboratory.
Acknowledgements
We are grateful for financial support from the National Basic
Research Program of China (973-2015CB856600), the
National Nature Science Foundation of China (Nos.
21532009, 21472217, 21790330, 21821002 and 21761142010),
the Science and Technology Commission of Shanghai Munic-
ipality (Nos. 17QA1405200 and 17JC1401200), and the
strategic Priority Research Program (No. XDB20000000)
and the Key Research Program of Frontier Science
(QYZDJSSW-SLH055) of the Chinese Academy of Sciences.
GL thanks Prof. Arkadi Vigalok at Tel Aviv University for
helpful discussion.
Scheme 3. Synthetic applications.
Conflict of interest
The authors declare no conflict of interest.
Keywords: asymmetric trifluoromethoxylation ·
oxidative amination · palladium · piperidines ·
unactivated alkene
Figure 1. Ligand effect on the catalytic reaction.
absence of ligands, the reaction using CsOCF3 (green C)
exhibited a much slower rate than the reaction using AgOCF3
(red A). The catalytic species became ineffective after 10
hours,[21] and a low yield of the product (16%) was obtained in
the former case. The rate of both two reactions could be
accelerated by adding 15 mol% L5. With comparison to
a slightly increased rate when AgOCF3 was used (blue B), the
remarkably increased rate was observed for the reaction using
CsOCF3 which had a short induction period (black D).
However, when the prepared (L5)PdCl2 and 5 mol% L5 were
used for the reaction, the induction period disappeared and
a slightly higher reaction rate was observed (pink E).
Additionally, these two reactions gave the desired products
in almost the same yields (81% vs. 82%) and enantioselec-
tivities (90% vs. 91% ee). Overall, these outcomes indicated
a significant ligand-accelerating effect on the reaction using
CsOCF3. The observed induction period in the case of
Pd(PhCN)2Cl2/L5 is probably attributed to the slow coordi-
nation of the sterically bulky ligand L5 to a palladium center,
thus higher ligand loading over palladium catalyst loading was
required for the successful asymmetric reaction (see Sche-
me 2c).[22]
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Py
À
[16] For the N Pd bond length (ꢄ): (L2)PdCl2 (2.027(7)) !
(L3)PdCl2 (2.131(2)) < (L4)PdCl2 (2.135(12)) ! (L1)PdCl2
(2.162(8)). For details, see SI.
[17] Unfortunately, we failed to obtain a crystal of the (L5)PdCl2
complex.
[18] CCDC 1884988 (2c) and 1884993 (15a) contain the supplemen-
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charge from The Cambridge Crystallographic Data Centre.
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coordination of 30 produced from SelectFluor. In fact, adding
external 30 (20 mol%) could remarkably inhibit the reaction
under the conditions C (Figure 1); however, the palladium
catalyst poisoning was not observed in the presence of L5
(conditions E) or excess amounts of AgOCF3 (conditions A). For
details, see the Supporting Information.
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[22] The stereochemistry of the reaction is quite similar to our
previous studies (refs. [13a,15]), see the Supporting Information
for the details.
À
a secondaryl C heteroatom bond formation, generally under-
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Manuscript received: November 29, 2018
Version of record online: && &&, &&&&
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Communications
Palladium Catalysis
C. Chen, P. M. Pflꢁger, P. Chen,
G. Liu*
&&& — &&&
Palladium(II)-Catalyzed Enantioselective
Aminotrifluoromethoxylation of
Unactivated Alkenes using CsOCF3 as
a Trifluoromethoxide Source
PdII-catalyzed enantioselective intramo-
lecular aminotrifluoromethoxylation of
unactivated alkenes using readily acces-
sible and stable CsOCF3 as a trifluoro-
methoxide source has been developed,
which affords a wide variety of enantio-
merically enriched b-substituted OCF3-
containing piperidines in good yields.
Introducing a sterically bulky group into
pyridine-oxazoline (Pyox) ligands is cru-
cial to increasing both reactivity and
enantioselectivity.
6
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