Copper(I)-Catalyzed Asymmetric Alkylation of Unsymmetrical Secondary Phosphines

Article abstract of DOI:10.1021/jacs.1c04112

A copper(I)-catalyzed asymmetric alkylation of HPAr1Ar2 with alkyl halides is uncovered, which provides an array of P-stereogenic phosphines in generally high yield and enantioselectivity. The electrophilic alkyl halides enjoy a broad substrate scope, including allyl bromides, propargyl bromide, benzyl bromides, and alkyl iodides. Moreover, 11 unsymmetrical diarylphosphines (HPAr1Ar2) serve as competent pronucleophiles. The present methodology is also successfully applied to catalytic asymmetric double and triple alkylation, and the corresponding products were obtained in moderate diastereo- and excellent enantioselectivities. Some 31P NMR experiments indicate that bulky HPPhMes exhibits weak competitively coordinating ability to the Cu(I)-bisphosphine complex, and thus the presence of stoichiometric HPAr1Ar2 does not affect the enantioselectivity significantly. Therefore, the high enantioselectivity in this reaction is attributed to the high performance of the unique Cu(I)-(R,RP)-TANIAPHOS complex in asymmetric induction. Finally, one monophosphine and two bisphosphines prepared by the present reaction are employed as efficient chiral ligands to afford three structurally diversified Cu(I) complexes, which demonstrates the synthetic utility of the present methodology.

Full text of DOI:10.1021/jacs.1c04112

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Copper(I)-Catalyzed Asymmetric Alkylation of Unsymmetrical
Secondary Phosphines
Shuai Zhang, Jun-Zhao Xiao, Yan-Bo Li, Chang-Yun Shi, and Liang Yin*
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ABSTRACT: A copper(I)-catalyzed asymmetric alkylation of
HPAr1Ar2 with alkyl halides is uncovered, which provides an
array of P-stereogenic phosphines in generally high yield and
enantioselectivity. The electrophilic alkyl halides enjoy a broad
substrate scope, including allyl bromides, propargyl bromide,
benzyl bromides, and alkyl iodides. Moreover, 11 unsymmetrical
diarylphosphines (HPAr1Ar2) serve as competent pronucleophiles.
The present methodology is also successfully applied to catalytic
asymmetric double and triple alkylation, and the corresponding
products were obtained in moderate diastereo- and excellent enantioselectivities. Some 31P NMR experiments indicate that bulky
HPPhMes exhibits weak competitively coordinating ability to the Cu(I)-bisphosphine complex, and thus the presence of
stoichiometric HPAr1Ar2 does not affect the enantioselectivity significantly. Therefore, the high enantioselectivity in this reaction is
attributed to the high performance of the unique Cu(I)-(R,RP)-TANIAPHOS complex in asymmetric induction. Finally, one
monophosphine and two bisphosphines prepared by the present reaction are employed as efficient chiral ligands to afford three
structurally diversified Cu(I) complexes, which demonstrates the synthetic utility of the present methodology.
transforms 50% racemic phosphine oxides to the desired chiral
products, in which the yield is less than 50%. The third strategy
is more advantageous, as all of the racemic phosphines or
phosphine derivatives are converted to the target chiral
products in high yields. Moreover, various methods could be
employed to accomplish the dynamic kinetic resolution,
including Ni-catalyzed asymmetric allylation of secondary
phosphine oxides,30 palladium- or platinum-catalyzed asym-
metric arylation,31−36 Cu-catalyzed asymmetric arylation of
secondary phosphine oxides with diaryliodonium salts,37
transition-metal-catalyzed asymmetric conjugate addition of
secondary phosphines to α,β-unsaturated compounds,38−44
palladium-catalyzed asymmetric addition of unsymmetrical
diarylphosphines to benzoquinones,45 and transition-metal-
catalyzed asymmetric alkylation of secondary phosphines.46−54
Other notable miscellaneous catalytic asymmetric methods for
accessing P-chiral phosphines include pincer-nickel-complex-
catalyzed asymmetric synthesis of secondary phosphinebor-
anes,55 asymmetric alkylation of phenylphosphine borane
complexes under phase-transfer catalysis,56 Brønsted acid-
catalyzed addition of phosphoramidic acid to alkenes,57
INTRODUCTION
■
P-Chiral stereogenic centers not only exist in pharmaceuticals
(such as sofosbuvir, remdesivir, and cytoxan), pesticides (such
as salithion), and bioactive molecules (such as cyclophostin,
salinipostin A, and phostine), but also exist in powerful
phosphine ligands (such as QUINOXP*, BENZP*, and
DUANPHOS).1−7 The classical synthetic methods mainly
rely on resolution with stoichiometric chiral reagents and
diastereoselective synthesis with chiral auxiliaries. The
continuing flourish of asymmetric catalysis offers an alternative
for the efficient synthesis of P-stereogenic centers, which
enjoys the advantages of chirality economy, diversified
methodologies, and high synthetic efficiency. However, only
limited success has been achieved so far. It is obvious that
more structurally diversified P-chiral phosphines would lead to
the generation of more transition metal complexes, which
would serve as new and efficient chiral metal catalysts in
asymmetric catalysis. Therefore, it is highly desirable to
develop new and powerful methodologies toward the synthesis
of diversified P-chiral phosphines.
The strategies available for the catalytic asymmetric
synthesis of P-chiral phosphines are mainly divided into four
types, including molecular desymmetric reactions,8−24 kinetic
resolution of secondary phosphine oxides,25−29 dynamic
kinetic resolution of secondary phosphines, their oxides, and
their borane complexes,30−54 and other miscellaneous
reactions.55−59 The first strategy usually requires a synthetic
handle on the starting molecules bearing P(V) to enable the
desymmetric functionalization. The second strategy generally
Received: April 19, 2021
Published: June 23, 2021
https://doi.org/10.1021/jacs.1c04112
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© 2021 American Chemical Society
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rhodium-catalyzed asymmetric arylation of phospholene
oxides,58 and Pd-catalyzed asymmetric allylic O-alkylation of
phosphinic acids.59
alkylation in moderate enantioselectivity (Scheme 1b) and
extended the catalytic system to double alkylation later.48−53
Moreover, the Duan group applied a pincer palladium
catalyst in the asymmetric alkylation of HPMePh and achieved
moderate enantioselectivity in 2013 (Scheme 1c).54 Recently,
we have achieved copper(I)-catalyzed asymmetric conjugate
addition of diarylphosphines to α,β-unsaturated phosphine
sulfides and α,β-unsaturated amides with the generation of
[Cu]*-PPh2 species.43,44,60−65 These two reactions were also
used to accomplish the dynamic kinetic transformation of
unsymmetrical diarylphosphines (HPPhAr). A [Cu]*-PPhAr
species was generated as the nucleophile through the
deprotonation of HPPhAr in the presence of a copper(I)
complex and an organic base. This species would be highly
nucleophilic with the assistance of a bisphosphine ligand,66
which inspires us to envision a catalytic asymmetric SN2-type
alkylation of HPAr1Ar2 with various alkyl halides and even
diversified allyl electrophiles (Scheme 1d). Under certain
suitable reaction conditions, a Cu(I)-bisphosphine complex-
catalyzed asymmetric alkylation with the concurrent dynamic
kinetic transformation of HPAr1Ar2 would be achieved in high
yield with satisfactory enantioselecitvity.67,68
Among these powerful methods, catalytic asymmetric
alkylation of secondary phosphines serves as a straightforward
method to access P-stereogenic phosphines. However, both the
starting materials and the products, which contain free
phosphine moieties, could serve as competitive ligands to the
transition metals. Thus, the desired metal catalysts may
decompose partially or even completely. Furthermore, new
but undesired metal complexes may be generated, which would
catalyze the nonenantioselective reaction to erode the
asymmetric induction. In spite of these concerns, transition-
metal-catalyzed asymmetric alkylation of secondary phosphines
achieved some progress with the continuing efforts from the
chemical community.46−54 In 2006, Toste and Bergman
disclosed a Ru-iPr-PHOX complex-catalyzed asymmetric
alkylation of HPMePh with benzyl chlorides and ethyl chloride
in moderate enantioselectivity (Scheme 1a).46 Later, they
Scheme 1. Introduction to Catalytic Asymmetric Alkylation
of Unsymmetrical Secondary Phosphines and Our Work
RESULTS AND DISCUSSION
■
1. Optimization of Reaction Conditions. The model
reaction of HPPhMes (1a) and allyl bromide (2a) was
performed in 1,2-dimethoxyethane (DME) at 0 °C with
(R,RP)-TANIAPHOS as the ligand, with Barton’s base (10 mol
%) as the catalytic base and with Cs2CO3 (1.2 equiv) as the
stoichiometric base to neutralize HBr.69 Tertiary phosphine
sulfide 3aa was afforded in quantitative yield with 94% ee after
quenching the reaction with CH3COOH and S8 (Table 1,
entry 1).70 The reaction results with varied reaction conditions
are shown in entries 2−15. Axially chiral bisphosphine ligands,
such as (R)-TOL-BINAP and (R)-SEGPHOS, showed much
worse asymmetric induction but led to a high yield of 3aa
(entries 2 and 3). Bisphosphines containing chiral carbons,
such as (R,R)-BDPP and (R,R)-Ph-BPE, were not effective in
the control of the enantioselectivity either (entries 4 and 5).
Moreover, a P-chiral bisphosphine, such as (R,R)-QUINOXP*,
was not a suitable ligand as a moderate yield and very low
enantioselectivity were observed (entry 6). (R)-(S)-JOSI-
PHOS, a very common ferrocene-embedded bisphosphine
ligand, did not suit the present reaction either, as very low
enantioselectivity was observed (entry 7). A P,N-bidentate
ligand ((S,S)-iPr-FOXAP) and an N,N,N-tridentate ligand
((S,S)-Ph-PyBOX) were also tried, which resulted in low
enantioselectivity of 3aa (entries 8 and 9).
The alkylation with (R,RP)-TANIAPHOS in tetrahydrofuran
(THF) delivered 3aa in inferior yield but with maintained high
enantioselectivity (entry 10). Moreover, the reaction in more
polar solvent (such as dimethylformamide (DMF)) furnished
3aa in excellent yield but with significantly decreased
enantioselectivity (entry 11). The alkylation without 10 mol
% Barton’s base led to a decreased yield but with high
enantioselectivity maintained (entry 12). However, switching
Cs2CO3 to KOtBu resulted in significantly decreased
enantioselectivity, indicating that mainly the background
reaction promoted by KOtBu occurred (entry 13). A weaker
potassium base (K2CO3) led to a very low yield (20%) and
attenuated enantioselectivity (75% ee) (entry 14). Finally,
decreasing the reaction temperature to −20 °C did not give
improved enantioselectivity (entry 15).
developed a mixed-ligand catalytic system of Ru to achieve the
asymmetric alkylation with benzyl chlorides and alkyl
bromides, which furnished various tertiary phosphines in
moderate enantioselectivity.47 Simultaneously in 2006, Glueck
and co-workers uncovered a platinum-catalyzed asymmetric
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a
a
Table 1. Optimization of the Reaction Conditions
Table 2. Substrate Scope of RBr
yield
ee
(%)
b
c
entry
variations
(%)
1
2
3
4
5
6
7
8
-
100
90
92
87
96
94
5
13
14
48
−3
−18
−36
−23
93
(R)-TOL-BINAP in THF
(R)-SEGPHOS in THF
(R,R)-BDPP in THF
(R,R)-Ph-BPE in THF
(R,R)-QUINOXP* in THF
(R)-(S)-JOSIPHOS in THF
(S,S)-iPr-FOXAP in THF
(S,S)-Ph-PyBOX in THF
THF instead of DME
DMF instead of DME
without 10 mol % Barton’s base in THF
without 10 mol % Barton’s base, 1.5 KOtBu in
45
97
100
100
75
100
60
9
10
11
12
13
9
93
<5
93
THF
14
15
without 10 mol % Barton’s base, 1.5 K2CO3 in
20
46
75
83
THF
−20 °C instead of 0 °C
a
b
1
1a: 0.1 mmol, 2a: 0.15 mmol. Determined by H NMR analysis of
the reaction crude mixture using CH2Br2 as an internal standard.
c
Determined by chiral-stationary-phase HPLC analysis. DME = 1,2-
dimethoxyethane.
a
1a: 0.2 mmol, 2: 0.3 mmol. Isolated yield. Enantioselectivity was
b
determined by chiral-stationary-phase HPLC analysis. With 2 equiv
of Cs2CO3 but without 10 mol % Barton’s base.
induction (3av, 98%, 77% ee). Fortunately, the substrates
with a 3,5-disubstituted phenyl group also successfully reacted
with 1a to deliver the corresponding products in good results
(3aw−3ax, 95%, 82% ee). Moreover, both 2-(bromomethyl)-
naphthalene (2y) and 3-(bromomethyl)thiophene (2z) were
well tolerated in the present reaction, providing the desired
products in high yields with high enantioselectivity (3ay−3az,
85−98%, 83−90% ee). The absolute configuration of 3af was
determined to be S by X-ray analysis of its single crystals (for
the details, see the SI). The stereochemistry in other products
(3) was assigned by analogy.
In the alkylation with alkyl iodide, both 3.0 equiv of alkyl
iodide and 3.0 equiv of Cs2CO3 were required to achieve the
full conversion of 1a, as shown in Table 3. Short alkyls,
including ethyl, n-propyl, n-butyl, and isobutyl were well
tolerated with the corresponding products isolated in high
enantioselectivity (5aa−5ad, 78−95%, 90−92% ee). As for the
yield, 5ad was generated in lower yield possibly due to the
steric hindrance of the bulkier isobutyl group. Moreover, the
reaction with long linear alkyl iodides afforded consistently
good results (5ae−5af, 93−95%, 89−90% ee). The alkyl
iodides containing a functional group were also investigated.
Methyl ether, benzyl ether, TBS-ether, ester, trifluoromethyl,
and alkyl chloride were acceptable with the corresponding
products generated in high yields and high enantioselectivity
(5ag−5ao, 80−98%, 82−90% ee). Noticeably, the wonderful
chemoselectivity between the alkyl iodide moiety and alkyl
2. Investigation of the Substrate Scope. Under the
optimized reaction conditions, the substrate scope of alkyl
bromides including allyl bromides, propargyl bromide, and
benzyl bromides was investigated as shown in Table 2.
Compared to the reaction with allyl bromide 2a (95%, 94%
ee), the reaction with 2b and 2c, bearing a terminal
substituent, generated the corresponding products in lower
yields and enantioselectivity (3ab, 85%, 85% ee; 3ac, 60%, 78%
ee). The allyl bromide bearing 2-methyl (2d) was a suitable
substrate to afford tertiary phosphine sulfide 3ad in 88% yield
with 86% ee. 1-Bromobut-2-yne (2e) was a competent
substrate too, which was transformed to product 3ae in 88%
yield with 94% ee. In this case, Barton’s base was removed
from the reaction mixture to get higher enantioselectivity and 2
equiv of Cs2CO3 was used to get higher yield. Subsequently,
various benzyl bromides (2f−2z) were studied. The reaction
results were not significantly affected by the electronic nature
of a substituent on the para-position of the phenyl group
(3af−3ap, 85−95%, 82−90% ee). Moreover, both yield and
enantioselectivity were not very sensitive to the substituent on
the meta-position of the phenyl group (3aq−3au, 90−96%,
84−87% ee). However, the reaction with benzyl bromide 2v
containing ortho-methyl resulted in lower asymmetric
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a
a
Table 3. Substrate Scope of RI
Table 4. Substrate Scope of HPAr1Ar2
a
1a: 0.2 mmol, 4: 0.6 mmol. Isolated yield. Enantioselectivity was
determined by chiral-stationary-phase HPLC analysis.
chloride moiety was achieved in the synthesis of 5ao, which
allowed further functionalization with the alkyl chloride unit.
Several secondary phosphines (HPAr1Ar2) other than
HPPhMes (1b−1k)71 were also tried (Table 4). When Ar1 =
Ph, the Ar2 group was changed to other 2,4,6-trisubstituted
aryls, such as 4-F-2,6-Me2-C6H2 (1b), 4-Cl-2,6-Me2-C6H2
(1c), and 4-MeO-2,6-Me2-C6H2 (1d). To our joy, four
representative alkylation reactions (allylation, propargylation,
benzylation, and ethylation) proceeded smoothly to furnish the
corresponding products in moderate to high yields with
moderate to high enantioselectivity (3ba−3da, 92−94%, 87−
93% ee; 3be−3de, 58−92%, 83−90% ee; 3bf−3df, 69−92%,
75−84% ee; 5ba−5da, 84−95%, 90−94% ee). It was noted
that moderate yields were observed in the propargylation and
the benzylation of 1d (3de, 58%; 3df, 69%), and moderate
enantioselectivity was obtained in the benzylation of 1c (3cf,
75% ee). Moreover, it was found that the benzylation generally
led to inferior enantioselectivity to the allylation, the
propargylation, and the ethylation. The Ar2 group could also
be extended to 2,6-disubstituted aryls, including 2,6-Me2-C6H3
(1e), 2,6-Et2-C6H3 (1f), and 2-methoxyl-6-methyl-C6H3 (1g)
(3ea−3ga, 88−96%, 82−92% ee; 3ee−3ge, 77−99%, 50−92%
ee; 3ef−3gf, 86−99%, 73−86% ee; 5ea−5ea, 78−95%, 83−
93% ee). As for 1e and 1f, the four alkylation reactions
occurred with satisfactory results. Although satisfying results
were obtained in the allylation and the ethylation of 1g,
propargylation and benzylation delivered the products in
moderate enantioselectivity (3ge, 50% ee; 3gf, 73% ee).
Furthermore, 2,3,5,6-Me4-C6H (1h) served as a competent Ar2
substituent. The four alkylation reactions proceeded in high
yields with high enantioselectivity (3ha, 94%, 91% ee; 3he,
94%, 92% ee; 3hf, 96%, 82% ee; 5ha, 92%, 87% ee).
Remarkably, 2-Me-1-naphthyl (1i) was also an appropriate Ar2
group with the corresponding products of the four alkylation
reactions obtained in good results (3ia, 88%, 86% ee; 3ie, 95%,
90% ee; 3if, 89%, 81% ee; 5ia, 99%, 90% ee). Finally, 4-
a
1b−1k: 0.2 mmol, 2: 0.3 mmol, 4: 0.6 mmol. Isolated yield.
Enantioselectivity was determined by chiral-stationary-phase HPLC
analysis. With 2 equiv of Cs2CO3 but without 10 mol % Barton’s
base. With 3 equiv of Cs2CO3, 40 h.
b
c
methylphenylmesityl phosphine (1j) and 2-thienylmesityl
phosphine (1k) were investigated, and competent results
were obtained (3ja, 82%, 93% ee; 3je, 73%, 89% ee; 3jf, 78%,
84% ee; 5ja, 77%, 93% ee; 3ka, 94%, 90% ee; 3ke, 92%, 90%
ee; 3kf, 99%, 80% ee; 5ka, 99%, 91% ee). Evidently, higher
enantioselectivity was obtained in the alkylation with a larger
steric difference between the two aryl groups (Ar1 = ArS vs Ar2
= ArL).
The present methodology was applied to double and triple
asymmetric alkylation with substrates bearing two or three
alkyl halide units (Table 5). Both (E)-1,4-dibromobut-2-ene
(6a) and 1,4-dichlorobut-2-yne (6b) underwent double
alkylation smoothly to give the desired bisphosphine sulfides
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and the ligand exchange of (R)-BINAP by HPPh2 occurred
completely to deliver some undesired Cu(I)-(HPPh2)x
species.44 Thus, although the asymmetric reaction with
stoichiometric Cu(I)-(R)-BINAP complex delivered the target
product in moderate enantioselectivity, the catalytic version
afforded the racemic product. In view of the above interesting
phenomenon, both the stoichiometric version and the catalytic
version with several Cu(I)-bisphosphine complexes (Cu(I)-
(R)-BINAP, Cu(I)-(R)-TOL-BINAP, Cu(I)-(R,R)-Ph-BPE,
Cu(I)-(R)-(S)-JOSIPHOS, and Cu(I)-(R,RP)-TANIAPHOS)
were investigated in the present asymmetric alkylation as
shown in Scheme 2. Surprisingly, the two versions provided
Table 5. Catalytic Asymmetric Double and Triple
Alkylation
a
Scheme 2. Asymmetric Alkylation with both Catalytic and
Stoichiometric Cu(I)-Bisphosphine Complexes (1H NMR
Yields Are Given)
the desired products in similar enantioselectivity. From these
results, it was speculated that the catalytically active Cu(I)-
bisphosphine complexes remain relatively stable in the
presence of stoichiometric HPPhMes. Thus, stoichiometric
HPPhMes had a weaker effect on the stability of the Cu(I)-
bisphosphine complexes than stoichiometric HPPh2. More-
over, the produced P(allyl)PhMes did not disturb the catalytic
asymmetric induction significantly. Lastly, the low enantiose-
lectivity was attributed to the poor performances of these
Cu(I)-bisphosphine complexes in asymmetric induction except
for the Cu(I)-(R,RP)-TANIAPHOS complex.
a
1a: 0.2 mmol for double alkylation and 0.3 mmol for triple
alkylation, 6: 0.1 mmol. Isolated yield. Both diastereoselectivity and
enantioselectivity were determined by chiral-stationary-phase HPLC
analysis. 15 mol % Cu(CH3CN)4PF6, 15 mol % (R,RP)-
TANIAPHOS, 30 mol % Barton’s base, and 9.0 equiv of Cs2CO3
b
were used.
in high yields with excellent enantioselectivity (7aa−7ab, 80−
95%, 96−97% ee). However, the diastereoselectivity in the
case of 6b was lower than that in the case of 6a (4.8/1 vs 10.7/
1). In the double alkylation of 1,4- and 1,3-bis(bromomethyl)-
benzenes (6c−6e) and 4,4′-oxybis((bromomethyl)benzene)
(6f), the reaction proceeded smoothly with the corresponding
products furnished in high yields with moderate diastereo- and
excellent enantioselectivities (7ac−7af, 88−96%, 5.6/1 to 8.9/
1 dr, 99%−>99% ee). Remarkably, the triple alkylation of
1,3,5-tris(bromomethyl)benzene (6g) was accomplished with
uncompromising yield and enantioselectivity (7ag, 88%, 99%
ee). However, the diastereoselectivity dropped down to 3.2/1
dr. Moreover, by using a series of alkyl diiodides (6h−6l) as
the electrophiles, the double alkylation was successfully carried
out to provide the target bisphosphine sulfides in high yields
with moderate diastereo- and excellent enantioselectivities
(7ah−7al, 80−98%, 6.2/1 to 9.7/1 dr, 98%−>99% ee).
Obviously, the diastereoselectivity increased with the increase
of the alkyl chain length. The absolute configuration of 7ah
was determined by X-ray crystallography. Analogously, the
absolute configurations of 5 and 7ah−7al were assigned
tentatively. The absolute configurations of 7aa−7ag were
assigned by their analogy to the exact structure of 3af.
In order to get some insights on the difference of HPPh2 and
HPPhMes, the 31P NMR experiments of Cu(CH3CN)4PF6
and (R)-BINAP were performed as shown in Figure 1. The 31
P
3. Insights into the Reaction Mechanism and
Proposed Reaction Pathway. Previously, in the copper-
(I)-catalyzed asymmetric addition of HPPh2 to α,β-unsatu-
rated amides, we demonstrated that the Cu(I)-(R)-BINAP
complex was not stable in the presence of 5 equiv of HPPh2
Figure 1. 31P NMR studies with (R)-BINAP
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NMR signals of HPPhMes and (R)-BINAP appeared at δ
−77.12 and δ −15.22 ppm, respectively (Figure 1A and B). A
certain complex formed from Cu(CH3CN)4PF6 and HPPhMes
gave a broad peak at δ −68.25 ppm (Figure 1C). The signal of
Cu(I)-(R)-BINAP was recorded as δ −1.31 ppm (Figure 1D).
When 1 equiv of HPPhMes was added to the solution of
Cu(I)-(R)-BINAP in THF, one new sharp peak (δ 1.36 ppm)
and one new broad peak (δ −63.89 ppm) were observed,
indicating the formation of the Cu(I)-(R)-BINAP-HPPhMes
complex (Figure 1E). When 5 equiv of HPPhMes was added,
the signal at δ −15.26 ppm indicated that some amount of (R)-
BINAP was liberated from the Cu(I) complex (Figure 1F).
However, a substantial amount of Cu(I)-(R)-BINAP complex
remained, which was indicated by the signal at δ 1.47 ppm.
When 20 equiv of HPPhMes was added, although a significant
amount of free (R)-BINAP was detected, a certain Cu(I)-(R)-
BINAP complex still remained (δ 1.14 ppm) (Figure 1G).
These 31P NMR experiments suggested that HPPhMes has a
much weaker competitive coordinating ability toward the
Cu(I)-(R)-BINAP complex than HPPh2 possibly due to its
larger steric hindrance. Previously, it was realized that the
Cu(I)-(R,RP)-TANIAPHOS complex was relatively stable in
the presence of stoichiometric HPPh2.44 Thus, it was
conjectured that the Cu(I)-(R,RP)-TANIAPHOS complex
would be more stable in the presence of stoichiometric
HPPhMes. The high enantioselectivity in the present catalytic
asymmetric alkylation could be attributed to the high
performance of the Cu(I)-(R,RP)-TANIAPHOS complex in
asymmetric induction. Moreover, the 31P NMR experiment of
the mixture of Cu(CH3CN)4PF6 (1 equiv), (R)-BINAP (1
equiv), HPPhMes (1 equiv), and Barton’s base (0.1 equiv) was
performed, which gave the same signals as the mixture without
Barton’s base (0.1 equiv) (Figure 1H vs E). When 1 equiv of
Barton’s base was added, the mixture gave unidentified
multiple signals, suggesting the formation of many copper(I)
complexes (Figure 1I). Definitely, a certain catalytically active
Cu(I)-PPhMes-(R)-BINAP complex existed. However, its 31P
NMR signal was not unambiguously identified. Furthermore, it
should be pointed out that Barton’s base not only worked as an
organic base but also served as a ligand to copper(I), which
was revealed by the presence of a significant amount of free
(R)-BINAP (δ −15.37 ppm).
HPPhMes itself might serve as a ligand to Cu(I). In the
reaction with (R)-TOL-BINAP, the yield in 24 h increased to
73%, indicating that the reaction catalyzed by Cu(I)-(R)-TOL-
BINAP complex was not accelerated significantly. However,
the reactions with (R,R)-Ph-BPE and (R,RP)-TANIAPHOS
were much faster than the background reaction. Evidently, the
moderate enantioselectivity in the reaction with (R,R)-Ph-BPE
was largely due to its unsatisfactory performance in asymmetric
induction. Such an interesting ligand-accelerating effect was
the key to achieve high enantioselectivity.
Except for allyl bromide 2a, a series of other electrophiles
with an allyl group (8−15) was studied as described in Scheme
3. Obviously, allyl chloride 8 was a much less efficient
Scheme 3. Trials with Various Allyl Electrophiles (1H NMR
Yields Are Given)
electrophile under the present reaction conditions, as 3aa was
generated in 24% yield with 85% ee. As for allyl sulfonate, less
bulky allyl mesylate 9 was transformed to 3aa in 22% yield
with 60% ee. Bulky allyl tosylate (10) was an appropriate
substrate, and 3aa was produced in quantitative yield with 85%
ee. Unfortunately, the reaction with much bulkier allyl 2,4,6-
trimethylbenzenesulfonate (11) provided 3aa in slightly
decreased enantioselectivity (80% ee). Subsequently, allyl
methyl carbonate (12), allyl 2,2,2-trichloroethyl carbonate
(13), and allyl acetate (14) were tried, which were widely used
in palladium- or iridium-catalyzed asymmetric allylic alkyla-
tion.73 However, no reaction occurred. Furthermore, allyl
diethyl phosphate (15) frequently used in copper-catalyzed
asymmetric allylic alkylation73−78 was employed. Nevertheless,
only trace 3aa was observed. Therefore, we believe that the
present alkylation proceeds through a simple SN2 substitution
mechanism.
Moreover, the ligand-accelerating effect72 in this reaction
was roughly investigated with HPPhMes and allyl bromide as
shown in Figure 2. Without an external ligand, the copper(I)-
catalyzed nonenantioselective reaction proceeded slowly and
provided the product in 40% yield in 24 h. In this reaction,
With the assistance of the above control experiments and
our previous realization toward the [Cu]*-PPh2 species,43,44
a
plausible mechanism for the copper(I)-catalyzed asymmetric
alkylation is proposed in Scheme 4. As previously reported, the
coordination of HPAr1Ar2 to Cu(I)-(R,RP)-TANIAPHOS
complex (U) results in complex V and thus activates
HPAr1Ar2, which enables its facile deprotonation to afford
two diastereoisomers, Cu(I)-PAr1Ar2-(R,RP)-TANIAPHOS
complexes W and W′. Then in the presence of RBr, the
asymmetric SN2 substitution of W occurs fast to afford the
desired chiral RPAr1Ar2 as the product and the complex U is
regenerated as the catalyst. The asymmetric SN2 substitution of
W′ is very slow, which finally leads to high asymmetric
induction in the present reaction. It should be pointed out that
the bromide anion was finally transformed to CsBr in the
presence of stoichiometric Cs2CO3.
Figure 2. Ligand-accelerating effect in the catalytic asymmetric
allylation of HPPhMes with allyl bromide (1H NMR yields are given).
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was a dimer and iodide worked as a bridged ligand in this case.
Moreover, the solution of chiral bisphosphine 7ab′ and CuCl
(2 equiv) in toluene was stirred at room temperature for 12 h
to give complex 17, which was recrystallized with CH2Cl2/
petroleum ether to afford its crystals in 61% yield. 17 was
identified as a self-assembled coordination cage compound by
X-ray analysis of its single crystals. Interestingly, the classical
interaction between copper(I) and the alkyne group was not
observed, and bisphosphine 7ab′ served as a monodentate
ligand to each copper(I) center. Finally, CuCl (1 equiv) was
subjected to the toluene solution of chiral bisphosphine 7ah′ at
room temperature, and the resulting mixture was stirred at
room temperature for 12 h. Then complex 18 was obtained in
81% yield after recrystallization with CH2Cl2/petroleum ether,
and its exact structure was determined by X-ray diffraction
crystallography. In this complex, bisphosphine 7ah′ worked as
a bidentate ligand. The facile preparation of these copper(I)
complexes demonstrated that the synthesized chiral phos-
phines were versatile ligands toward transition metals.
Scheme 4. Proposed Mechanism for the Copper(I)-
Catalyzed Asymmetric Alkylation
CONCLUSION
■
4. Application of the Present Methodology. Under the
inert atmosphere (Ar), the free phosphines could be obtained
directly in high yields. For example, 3af′, 7ab′, and 7ah′ were
isolated in 97%, 94%, and 97% yields, respectively (for the
details, see the SI). Chiral phosphines are supposed to be
suitable ligands for transition metals.1−7 Here, by using
copper(I) as the metal species, several chiral complexes were
prepared as shown in Figure 3 (for details, see the SI). Treating
monophosphine 3af′ with 1 equiv of CuI in CH3CN at room
temperature in 12 h resulted in chiral complex 16 in 89% yield
after recrystallization with CH3CN and n-pentane, whose
structure was determined by single-crystal X-ray diffraction. 16
In summary, by means of the dynamic kinetic transformation
of HPAr1Ar2, a catalytic asymmetric alkylation was achieved,
which furnished a variety of P-chiral phosphines in moderate to
high yields with moderate to high enantioselectivity. Various
electrophiles, such as allyl bromides, propargyl bromide, benzyl
bromides, and alkyl iodides, served as appropriate substrates,
and 11 secondary phosphines were found as suitable
pronucleophiles. Moreover, the present reaction was success-
fully extended to double alkylation and triple alkylation with
the corresponding products generated in moderate diaster-
eoselectivity and excellent enantioselectivity. Control experi-
ments suggested that bulky HPPhMes exhibited weak
competitive coordinating ability toward the Cu(I)-bisphos-
phine complex and thus stoichiometric HPAr1Ar2 did not have
a significant disturbing effect on the asymmetric induction in
the present alkylation. Lastly, several produced chiral
phosphines worked as wonderful ligands to copper(I) salts,
which provided three structurally diversified chiral copper(I)
complexes. Further efforts on the development of catalytic
asymmetric alkylation of HPRAr (R = alkyl) and the
application of the produced P-chiral phosphines in asymmetric
catalysis with transition metals are in progress.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c04112.
Experimental procedures, characterizations, and analyt-
ical data of new compounds, X-ray diffraction data for
3af, 7ah, 16, 17, and 18, and spectra of NMR and HPLC
for new compounds (PDF)
Accession Codes
CCDC 2020486, 2020488, 2020490, 2021216, and 2025208
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge via www.ccdc.ca-
m.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.
Figure 3. Three copper(I) complexes prepared with the produced P-
chiral phosphines.
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(6) Zhu, R.-Y.; Liao, K.; Yu, J.-S.; Zhou, J. Recent Advances in
Catalytic Asymmetric Synthesis of P-Chiral Phosphine Oxides.
Huaxue Xuebao 2020, 78, 193−216.
(7) Glueck, D. S. Catalytic Asymmetric Synthesis of P-Stereogenic
Phosphines: Beyond Precious Metals. Synlett 2021, 32, 875−884.
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lective Synthesis of P-Stereogenic Alkynylphosphine Oxides by Rh-
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3410−3413.
AUTHOR INFORMATION
■
Corresponding Author
Liang Yin − CAS Key Laboratory of Synthetic Chemistry of
Natural Substances, Centre for Excellence in Molecular
Synthesis, Shanghai Institute of Organic Chemistry,
University of Chinese Academy of Sciences, Chinese Academy
of Sciences, Shanghai 200032, China; orcid.org/0000-
0001-9604-5198; Email: liangyin@sioc.ac.cn
(9) Harvey, J. S.; Malcolmson, S. J.; Dunne, K. S.; Meek, S. J.;
Thompson, A. L.; Schrock, R. R.; Hoveyda, A. H.; Gouverneur, V.
Enantioselective Synthesis of P-Stereogenic Phosphinates and
Phosphine Oxides by Molybdenum-Catalyzed Asymmetric Ring-
Closing Metathesis. Angew. Chem., Int. Ed. 2009, 48, 762−766.
(10) Du, Z.-J.; Guan, J.; Wu, G.-J.; Xu, P.; Gao, L.-X.; Han, F.-S.
Pd(II)-Catalyzed Enantioselective Synthesis of P-Stereogenic Phos-
phinamides via Desymmetric C-H Arylation. J. Am. Chem. Soc. 2015,
137, 632−635.
(11) Lin, Z.-Q.; Wang, W.-Z.; Yan, S.-B.; Duan, W.-L. Palladium-
Catalyzed Enantioselective C-H Arylation for the Synthesis of P-
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(12) Xu, G.; Li, M.; Wang, S.; Tang, W. Efficient Synthesis of P-
Chiral Biaryl Phosphonates by Stereoselective Intramolecular
Cyclization. Org. Chem. Front. 2015, 2, 1342−1345.
(13) Sun, Y.; Cramer, N. Rhodium(III)-Catalyzed Enantiotopic C−
H Activation Enables Access to P-Chiral Cyclic Phosphinamides.
Angew. Chem., Int. Ed. 2017, 56, 364−367.
Authors
Shuai Zhang − CAS Key Laboratory of Synthetic Chemistry of
Natural Substances, Centre for Excellence in Molecular
Synthesis, Shanghai Institute of Organic Chemistry,
University of Chinese Academy of Sciences, Chinese Academy
of Sciences, Shanghai 200032, China
Jun-Zhao Xiao − CAS Key Laboratory of Synthetic Chemistry
of Natural Substances, Centre for Excellence in Molecular
Synthesis, Shanghai Institute of Organic Chemistry,
University of Chinese Academy of Sciences, Chinese Academy
of Sciences, Shanghai 200032, China
Yan-Bo Li − CAS Key Laboratory of Synthetic Chemistry of
Natural Substances, Centre for Excellence in Molecular
Synthesis, Shanghai Institute of Organic Chemistry,
University of Chinese Academy of Sciences, Chinese Academy
of Sciences, Shanghai 200032, China
Chang-Yun Shi − CAS Key Laboratory of Synthetic Chemistry
of Natural Substances, Centre for Excellence in Molecular
Synthesis, Shanghai Institute of Organic Chemistry,
University of Chinese Academy of Sciences, Chinese Academy
of Sciences, Shanghai 200032, China
(14) Jang, Y.-S.; Dieckmann, M.; Cramer, N. Cooperative Effects
between Chiral Cpx−Iridium(III) Catalysts and Chiral Carboxylic
Acids in Enantioselective C−H Amidations of Phosphine Oxides.
Angew. Chem., Int. Ed. 2017, 56, 15088−15092.
(15) Wang, Z.; Hayashi, T. Rhodium-Catalyzed Enantioposition-
Selective Hydroarylation of Divinylphosphine Oxides with Aryl
Boroxines. Angew. Chem., Int. Ed. 2018, 57, 1702−1706.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c04112
́
(16) Jang, Y.-S.; Wozniak, Ł.; Pedroni, J.; Cramer, N. Access to P-
and Axially Chiral Biaryl Phosphine Oxides by Enantioselective
CpxIrIII-Catalyzed C−H Arylations. Angew. Chem., Int. Ed. 2018, 57,
12901−12905.
Notes
The authors declare no competing financial interest.
(17) Sun, Y.; Cramer, N. Tailored Trisubstituted Chiral CpxRhIII
Catalysts for Kinetic Resolutions of Phosphinic Amides. Chem. Sci.
2018, 9, 2981−2985.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support from the
National Natural Science Foundation of China (No. 21871287
and No. 21922114), the Science and Technology Commission
of Shanghai Municipality (No. 20JC1417100), the Strategic
Priority Research Program of the Chinese Academy of
Sciences (No. XDB20000000), CAS Key Laboratory of
Synthetic Chemistry of Natural Substances, and Shanghai
Institute of Organic Chemistry.
(18) Zheng, Y.; Guo, L.; Zi, W. Enantioselective and Regioselective
Hydroetherification of Alkynes by Gold-Catalyzed Desymmetrization
of Prochiral Phenols with P-Stereogenic Centers. Org. Lett. 2018, 20,
7039−7043.
(19) Zhang, Y.; Zhang, F.; Chen, L.; Xu, J.; Liu, X.; Feng, X.
Asymmetric Synthesis of P-Stereogenic Compounds via Thulium-
(III)-Catalyzed Desymmetrization of Dialkynylphosphine Oxides.
ACS Catal. 2019, 9, 4834−4840.
(20) Fernández-Pérez, H.; Vidal-Ferran, A. Stereoselective Catalytic
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K. Catalytic Asymmetric P−C Bond Formation Via Chiral Copper(I)-
or Nickel(II)-Phosphido Complexes. Ph.D. Thesis, Dartmouth
College, 2019.
(69) Due to Barton’s base’s excellent performance in our previous
two reactions (copper(I)-catalyzed asymmetric additions of diary-
lphosphines to α,β-unsaturated phosphine sulfides and to α,β-
unsaturated amides), it was used as the catalytic base in the present
reaction.
(70) For the ease of manipulation in purification and analysis,
tertiary phosphines were oxidized by S8 to the corresponding
phosphine sulfides.
(71) Secondary phosphines, such as HPMePh and HPiPrPh, were
studied in the present allylation with allyl bromide (2a). However,
racemic products were afforded in high yields, indicating that a new
catalytic system is required.
(72) Berrisford, D. J.; Bolm, C.; Sharpless, K. B. Ligand-Accelerated
Catalysis. Angew. Chem., Int. Ed. Engl. 1995, 34, 1059−1070.
(73) Kazmaier, U. Transition Metal Catalyzed Enantioselective
Allylic Substitution in Organic Synthesis. Top. Organomet. Chem.
2012, 38, 1−340.
̀
(74) Alexakis, A.; Bäckvall, J. E.; Krause, N.; Pamies, O.; Diéguez, M.
Enantioselective Copper-Catalyzed Conjugate Addition and Allylic
Substitution Reactions. Chem. Rev. 2008, 108, 2796−2823.
(75) Harutyunyan, S. R.; den Hartog, T.; Geurts, K.; Minnaard, A. J.;
Feringa, B. L. Catalytic Asymmetric Conjugate Addition and Allylic
Alkylation with Grignard Reagents. Chem. Rev. 2008, 108, 2824−
2852.
(76) Falciola, C. A.; Alexakis, A. Copper-Catalyzed Asymmetric
Allylic Alkylation. Eur. J. Org. Chem. 2008, 2008, 3765−3780.
(77) Geurts, K.; Fletcher, S. P.; van Zijl, A. W.; Minnaard, A. J.;
Feringa, B. L. Copper-Catalyzed Asymmetric Allylic Substitution
Reactions with Organozinc and Grignard Reagents. Pure Appl. Chem.
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(78) Alexakis, A.; Krause, N.; Woodward, S. Copper-Catalyzed
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