Regio- And Enantioselective Palladium-Catalyzed Asymmetric Allylation of N-Fluorenyl Trifluoromethyl Imine

Article abstract of DOI:10.1021/acs.orglett.0c01836

A palladium-catalyzed asymmetric allylation of N-fluorenyl trifluoromethyl imine with allylic acetates is disclosed. This method provides scalable and efficient access to polysubstituted chiral α-trifluoromethyl amines bearing two adjacent stereocenters and one allyl group in high yields with excellent regio-, diastereo-, and enantioselectivity. Importantly, this method also provides a powerful strategy for the synthesis of both regioisomeric products and the regioselectivity is controlled by the chiral catalysts and optically active substrates.

Full text of DOI:10.1021/acs.orglett.0c01836

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Letter
Regio- and Enantioselective Palladium-Catalyzed Asymmetric
Allylation of N‑Fluorenyl Trifluoromethyl Imine
Wei Wang,⊥ Qin Xiong,⊥ Liang Gong, Yingwei Wang, Jie Liu,* Yu Lan,* and Xia Zhang*
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ABSTRACT: A palladium-catalyzed asymmetric allylation of N-
fluorenyl trifluoromethyl imine with allylic acetates is disclosed.
This method provides scalable and efficient access to polysub-
stituted chiral α-trifluoromethyl amines bearing two adjacent
stereocenters and one allyl group in high yields with excellent
regio-, diastereo-, and enantioselectivity. Importantly, this method
also provides a powerful strategy for the synthesis of both
regioisomeric products and the regioselectivity is controlled by the
chiral catalysts and optically active substrates.
Scheme 1. Asymmetric Synthesis α-Trifluoromethylated
Amines
mines are important functional groups and commonly used
Iprecursors for the construction of amines in organic
synthesis.1 They usually serve as electrophiles to react with
carbon nucleophiles in the formation of carbon−carbon
bonds.2 Recently, the use of imines as nucleophiles via the
intermediacy of 2-azaallyl anions attracted widespread
attention as a new strategy for amine synthesis.3−5 Such a
reversal in the imine functionality provides an alternative
approach to structures which may not be accessible by
traditional methods. Additionally, this strategy does not
depend on the use of activated imine species and/or sensitive
organometallic reagents and generates products that could
deliver primary amines under mild conditions. Nevertheless,
methods that employ 2-azaallyl anions, particularly in
asymmetric synthesis, remain underdeveloped.6−11
Recently, Deng12 reported highly efficient asymmetric
reactions of 2-azaallyl anions with Michael acceptors by
using a chiral phase-transfer catalyst (Scheme 1a). Zhang13
developed asymmetric synthetic approaches of generating
enantioenriched trifluoromethyl amines by the addition of 2-
azaallyl anions to Morita−Baylis−Hillman carbonates or
allenoates (Scheme 1a). Our group achieved the iridium-
catalyzed asymmetric allylation of imines by employing a
cascade involving an regioselective allylation of 2-azaallyl
anions and a facile 2-aza-Cope rearrangement (Scheme
1b).4s,t,y,z,14 The Wang group also reported the use of this
cascade in the preparation of chiral amines and chiral amino
acid derivatives.15 However, the generation of adjacent
stereocenters by asymmetric reactions of 2-azaallyl anions
remains scarce.7,8,11,12 We then envisaged that palladium
catalysts might promote the asymmetric reaction of trifluor-
omethyl imines with 1,3-diarylallyl acetates, leading to the
formation of two adjacent stereocenters. We are aware,
however, that the success of this reaction requires the enantio-,
diastereo-, and regioselective allylation of the in situ generated
2-azaallyl anions. Despite these challenges, we establish in this
Received: June 1, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01836
© XXXX American Chemical Society
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a
Table 1. Optimization of the Asymmetric Allylic Alkylation of Trifluoromethyl Imine
entry
[Pd]
ligand
base
solvent
yield of 3aa (%)
dr
ee of 4aa (%) major
1
2
3
4
5
6
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(dppf)Cl2
Pd(dba)2
Pd(dba)2
−
L1
L2
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
DBU
DBU
DBU
DBU
DBU
TMG
K3PO4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
THF
THF
THF
toulene
EtOAc
THF
THF
THF
THF
THF
THF
THF
88
24
36
54
21
56
66
96
90
95
88
0
18:1
13.8:1
4:1
−48
−99
83
61
72
87
80
82
52
3.2:1
3.8:1
4.1:1
7.8:1
7.4:1
12.7:1
8.3:1
7.4:1
NA
10
11
12
94
92
NA
b
a
Conditions: 1a (0.05 mmol), 2a (0.065 mmol), [Pd] (4 mol %), ligand (8 mol %), base (0.05 mmol), solvent (0.3 mL). Yields and diastereomeric
ratios (dr) were determined by H NMR and 19F NMR spectroscopy of the crude reaction mixture with 1,3,5-trimethylbenzene as internal
standard; enantiomeric excess values of major diastereomers were determined by HPLC analysis. Pd(dba)2 (2 mol %) and L3 (4 mol %) were
1
b
used.
work the feasibility of such a transformation as shown in
Scheme 1c. Unexpectedly, this transformation does not
proceed via a 2-aza-Cope rearrangement as in the Ir-catalyzed
variant we reported previously. This reaction, which employs
readily available reagents and catalysts, occurs under mild
conditions, proceeds with high enantio-, diastereo-, and
regioselectivity, and is compatible with a broad range of
substrates. Importantly, this method is amenable to generate α-
trifluoromethyl amines16 that contain two adjacent stereo-
centers and one allyl group.
We commenced our study by investigating the model
reaction between N-fluorenyl trifluoromethyl imine 1a and a
racemic (E)-1,3-diphenylallyl acetate 2a (Table 1 and Table
S2). Palladium-based catalysts were used in this study because
of their outstanding performance in conducting selective
allylation of various types of nucleophiles.17 We then identified
the conditions yielding the desired product 3aa in excellent
yield and diastereoselectivity, and the hydrolysis of 3aa led to
4aa in high enantioselectivity (entry 10). The reaction
proceeded at ambient temperature, requiring 4 mol % of
Pd(dba)2 and 8 mol % of ligand L3 ((S)-tBu-PHOX) as the
catalyst, 1.0 equiv of Cs2CO3 as the base, and THF as the
solvent. Some key factors affecting the performance of this
transformation are listed in Table 1 and Tables S2−S4. Among
the ligands screened, L3 was found to be satisfactory in terms
of both yield and selectivity. Further screening of the reaction
conditions revealed that THF served as the best solvent
compared with toluene, EtOAc, 1,4-dioxane, DMA, ether, or
DMSO (entries 3−5 and Table S3 entries 4−7). Besides
Cs2CO3, 1,8-diazabicycloundec-7-ene (DBU, entry 3), 1,1,3,3-
tetramethylguanidine (TMG, entry 6), or K3PO4 (entry 7) also
promoted this reaction but furnished 3aa in lower yields and
the resulting 4aa with lower diastereoselectivity or enantiose-
lectivity. The identity of the palladium salt is critical for the
enantioselectivity of this reaction, as the use of Pd(OAc)2 or
Pd(dppf)Cl2 significantly reduced the ee value of 4aa (entries
8 and 9). If the palladium catalyst was omitted, the reaction did
not proceed (entry 12).
With the optimal conditions established, we proceeded to
explore the scope of this transformation (Scheme 2). It is
noteworthy that the products of these reactions were readily
hydrolyzed to give primary amines. This transformation
demonstrated a broad scope with respect to the allylic acetate
reaction partner. The allylic acetates bearing halogenated (2c−
2e), electron-deficient (2b), and electron-rich (2f) aromatic
rings could all engage in this reaction. The absolute structure
of 4af was confirmed by X-ray crystallographic analysis
(CCDC 1555489). In addition, allylic acetates with sterically
demanding groups (2g and 2h) underwent this transformation
smoothly and gave the products 4ag and 4ah with high
enantioselectivity (>99% ee). The allylic acetate with a
heteroaryl group 2i was also tolerated, leading to the
corresponding product 4ai with good diastereoselectivity
(7.8:1) and moderate enantioselectivity.
Encouraged by these results, we expanded the substrate
scope to 1,3-unsymmetrically substituted 2-propenyl acetates.
Notably, the reaction proceeded to give the desired α-
trifluoromethylamine product in 89% yield and good enantio-
and diastereoselectivity (Scheme S1). However, the regiose-
lectivity of this transformation was low, and only a 1.1:1 ratio
of regioisomers was obtained. To enhance the regioselectivity
of this reaction, we used enantiomerically pure allylic acetates
as substrates.18
To our delight, the reaction between imine 1a and (S,E)-1-
(4-methylphenyl)-3-phenylallylacetate (2j) gave 6aj as the
major regioisomer in 92% yield with high enantio- and
B
https://dx.doi.org/10.1021/acs.orglett.0c01836
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Scheme 2. Pd-Catalyzed Asymmetric Allylic Alkylation of
Trifluoromethyl Imine with 1,3-Diaryl-2-propenyl Acetates
Scheme 3. Regioselective Asymmetric Allylation with Chiral
1,3-Unsymmetrically Allylic Acetates
a
a
a
Conditions: 1a (0.3 mmol), 2 (0.39 mmol), Pd(dba)2 (4 mol %),
(S)-tBu-PHOX (8 mol %), Cs2CO3 (0.3 mmol), THF (1 mL).
Isolated yields (IY) of the amines were reported. The diastereomeric
ratios (dr) were determined by 19F NMR integration of the crude
alkylated products. Enantiomeric excess values of major diastereomers
were determined by HPLC analysis.
a
Conditions: 1a (0.2 mmol), 2 (0.26 mmol), Pd(dba)2 (4 mol %),
(S)- or (R)-tBu-PHOX (8 mol %), Cs2CO3 (0.2 mmol), THF (1
mL). Isolated yields (IY) of the amines were reported; The
diastereomeric ratios (dr) and regioisomeric ratio (rr) were
determined by 19F NMR integration of the crude alkylated products.
Enantiomeric excess values of major diastereomers were determined
by HPLC analysis. 1 mmol scale. Pd(dba)2 (6 mol %), (S)-tBu-
PHOX (12 mol %).
diastereoselectivity when the ligand (S)-tBu-PHOX was used
(Scheme 3). Notably, the regioselectivity increased from 1.1:1
to 94:6 when achiral allylic acetate was replaced with optically
active 2j. Importantly, with the enantiomeric ligand (R)-tBu-
PHOX, the opposite regioisomer 7aj was the major product in
89% yield with more than 99% ee and up to 95:5 rr. These
phenomena demonstrated that the regioselectivity of a reaction
using an optically active substrate could be controlled by the
absolute configuration of the ligand employed. Thus, this
reaction provides a useful strategy for the selective synthesis of
both of the regioisomeric products by adjusting the
configurations of the catalysts and substrates. We were pleased
to find that this method was also applicable with various chiral
1,3-unsymmetrically allylic acetates 2k−2q. The desired
products 6ak−6aq and the regioisomers 7ak−7aq were
generated in good yields with excellent enantio- and
regioselectivities (56−92% yields, up to 99% ee and 99:1 rr).
In addition, allylic acetates 2o and 2p with functional groups
gave the corresponding products 6ao and 6ap and the
regioisomers 7ao and 7ap in good yields with excellent ee
values and rr. Furthermore, allylic acetates with heteroaryl
groups were also tolerated, producing the corresponding
products in good yields with excellent ee. Notably, the
reaction could perform at the 1 mmol scale as demonstrated by
the synthesis of 7aj, which was isolated with 82% yield, 99% ee,
and 95:5 dr.
b
c
Scheme 4. Synthetic Transformations of α-
Trifluoromethylated Amines
To demonstrate the synthetic utility of this method, several
representative transformations of the products were performed
and summarized in Scheme 4. For example, the polysubstituted
lactam 8 was obtained with excellent ee, dr, and rr. Further
transformations of 7aj and 4aa were realized by treatment with
I2 and K2CO3 in CH3CN, providing the synthetically valuable
pyrrolidines 9 and 9′ in 79% and 82% yields with high enantio-
and diastereoselectivities. The absolute configuration of 9 was
established by X-ray crystallographic analysis. In addition, by
treating 7aj with allyl bromide and K2CO3 in DMF, a N-
C
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allylated product was prepared in 55% yield. Subsequently, the
N-allylated product could be further converted to polysub-
stituted tetrahydropyridine 10 via the alkene metathesis
reaction in 75% yield with 16:1 dr.
We performed some preliminary studies to probe into the
mechanism of this Pd-catalyzed transformation. As shown in
Scheme 5a, we found that both our reaction and the reaction
synthesis of both of the regioisomeric products could be
achieved by adjusting the configurations of the catalysts and
substrates. The synthetic utility of the products was
demonstrated by the introduction of additional functionalities
and the resulting formation of chiral lactams, pyrrolidines, and
tetrahydropyridines. Preliminary mechanistic studies showed
that this Pd-catalyzed transformation underwent a distinct
mechanism from our previously reported Ir-catalyzed ones.
Scheme 5. Mechanistic Studies
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01836.
Detailed DFT calculations, experimental procedures,
characterization data, copies of 1H, 13C, 19F NMR
spectra, and HPLC spectra (PDF)
Accession Codes
CCDC 1555442, 1555448−1555449, and 1555489 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.
AUTHOR INFORMATION
■
Corresponding Authors
Jie Liu − State Key Laboratory of Biotherapy and Cancer Center,
West China Hospital, Sichuan University, Chengdu 610041,
P.R. China; Email: liujie2011@scu.edu.cn
Yu Lan − College of Chemistry, and Institute of Green Catalysis,
Zhengzhou University, Zhengzhou 450001, P.R. China; School
of Chemistry and Chemical Engineering, and Chongqing Key
Laboratory of Theoretical and Computational Chemistry,
Chongqing University, Chongqing 400030, P.R. China;
orcid.org/0000-0002-2328-0020; Email: lanyu@
zzu.edu.cn
Xia Zhang − State Key Laboratory of Biotherapy and Cancer
Center, West China Hospital, Sichuan University, Chengdu
610041, P.R. China; orcid.org/0000-0002-5073-0269;
Email: zhang-xia@scu.edu.cn
employing dimethyl malonate afforded C3-alkylated product in
the presence of the same ligand. It was established that in this
transformation the absolute configuration of ligand together
with that of the substrate controls the site of initial C−C bond-
forming event. Therefore, the observed regioselectivity argues
against the involvement of an allylation/2-aza-Cope rearrange-
ment cascade18 indicated by the red arrow shown in Scheme
5b, as this would give the C1-alkylated product. Additionally,
the same regioisomer could be obtained when two
regioisomeric enantiomerically pure allylic acetates ((S)-2o
vs (R)-2o′) were used (Scheme 5c and Scheme S2). To further
understand this outcome, we performed DFT calculations and
located the transition structures leading to C- and C′-
functionalized products, respectively. We found the former D
is ca. 0 kcal/mol more stable than the latter E. The other
calculation details are provided in the Supporting Information.
Thus, this Pd-catalyzed process shows a distinct mechanism
from the previously Ir-catalyzed ones.
Authors
Wei Wang − State Key Laboratory of Biotherapy and Cancer
Center, West China Hospital, Sichuan University, Chengdu
610041, P.R. China; Chemical Synthesis and Pollution Control
Key Laboratory of Sichuan Province/College of Chemistry &
Chemical Engineering, China West Normal University,
Nanchong 637009, P.R. China; orcid.org/0000-0001-
8166-1844
Qin Xiong − College of Chemistry, and Institute of Green
Catalysis, Zhengzhou University, Zhengzhou 450001, P.R.
China; School of Chemistry and Chemical Engineering, and
Chongqing Key Laboratory of Theoretical and Computational
Chemistry, Chongqing University, Chongqing 400030, P.R.
China
In conclusion, we established a general protocol to prepare
α-trifluoromethyl amines with two adjacent stereocenters
through a palladium-catalyzed asymmetric allylation of 2-
azaallyl anions. This reaction permitted the use of a wide range
of substrates and readily available reagents and catalysts,
yielding various homoallylic α-trifluoromethyl amines in high
enantio-, diastereo-, and regioselectivity. Notably, the selective
Liang Gong − State Key Laboratory of Biotherapy and Cancer
Center, West China Hospital, Sichuan University, Chengdu
610041, P.R. China
D
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F. Organocatalytic umpolung: N-heterocyclic carbenes and beyond.
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(e) Tang, S.; Zhang, X.; Sun, J.; Niu, D.; Chruma, J. J. 2-Azaallyl
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Organocatalytic Asymmetric Biomimetic Transamination: From α-
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Ligand-Controlled Asymmetric Arylation of Aliphatic α-Amino Anion
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Yingwei Wang − State Key Laboratory of Biotherapy and
Cancer Center, West China Hospital, Sichuan University,
Chengdu 610041, P.R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01836
Author Contributions
⊥W.W. and Q.X. contributed equally. J.L. and X.Z.
conceptualized and directed the project. X.Z. and W.W.
drafted the paper with assistance from all coauthors. W.W.
conducted most of the experiments. L.G. and Y.W. prepared
some of the starting materials. Q.X. and Y.L. performed the
computational study. All authors contributed to discussions.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Funding from the National Natural Science Foundation (Nos.
21602144, 81803359, 81573290, and U1603123) and start-up
funding from Sichuan University is acknowledged. We thank
Prof. Dawen Niu (SCU) for helpful discussions.
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Walsh, P. J. Synthesis of diarylmethylamines via palladium-catalyzed
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2014, 5, 2383−2391. (h) Liu, X.; Gao, A.; Ding, L.; Xu, J.; Zhao, B.
Aminative Umpolung Synthesis of Aryl Vicinal Diamines from
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Chen, J.; Hu, Y.; Xu, J.; Gong, X.; Xu, D.; Zhao, B.; Li, H. Aminative
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