Asymmetric synthesis of P -stereogenic diarylphosphinites by palladium-catalyzed enantioselective addition of diarylphosphines to benzoquinones

Article abstract of DOI:10.1021/ja501007t

The reaction of phenyl(2,4,6-trimethylphenyl)phosphine with a substituted benzoquinone in the presence of a chiral phosphapalladacycle complex as a catalyst and triethylamine in chloroform at -45 °C proceeded in a new type of addition manner to give a high yield of a 4-hydroxyphenyl phenyl(2,4,6-trimethylphenyl)phosphinite with 98% enantioselectivity, which is a versatile intermediate readily convertible into various phosphines and their derivatives with high enantiomeric purity.

Full text of DOI:10.1021/ja501007t

Communication
pubs.acs.org/JACS
Asymmetric Synthesis of P‑Stereogenic Diarylphosphinites by
Palladium-Catalyzed Enantioselective Addition of Diarylphosphines
to Benzoquinones
Yinhua Huang,†,‡ Yongxin Li,† Pak-Hing Leung,*,† and Tamio Hayashi*,‡,§
†Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
‡Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore
§Institute of Materials Research and Engineering, A*STAR, 3 Research Link, Singapore 117602, Singapore
S
* Supporting Information
Scheme 1. Catalytic Asymmetric Synthesis of P-Stereogenic
Phosphines
ABSTRACT: The reaction of phenyl(2,4,6-trimethyl-
phenyl)phosphine with a substituted benzoquinone in
the presence of a chiral phosphapalladacycle complex as a
catalyst and triethylamine in chloroform at −45 °C
proceeded in a new type of addition manner to give a
high yield of a 4-hydroxyphenyl phenyl(2,4,6-trimethyl-
phenyl)phosphinite with 98% enantioselectivity, which is a
versatile intermediate readily convertible into various
phosphines and their derivatives with high enantiomeric
purity.
t has been well documented that chiral phosphorus
Icompounds with high enantiomeric purities are a very
important class of compounds, typically as chiral ligands for
metal-catalyzed asymmetric reactions.1 Of the chiral phospho-
rus compounds, P-stereogenic ones have attracted considerable
attention owing to their excellent enantioselectivities observed
in the catalytic asymmetric reactions.1 Asymmetric synthesis of
P-stereogenic compounds is one of the most challenging
subjects in synthetic organic chemistry as well as in organo-
phosphorus chemistry,2,3 and their synthesis by asymmetric
catalysis has been extensively studied because of its high
efficiency.4 The dynamic kinetic resolution of racemic
secondary phosphines HPR1R2 upon P−C bond formation
with alkyl or aryl halides X−R3 giving P-stereogenic chiral
phosphines P*R1R2R3 has been studied with chiral palladium,5
platinum,6 and ruthenium7 complexes as catalysts (Scheme 1a).
Catalytic asymmetric conjugate addition of racemic secondary
phosphines to electron-deficient olefins has been also reported
to produce P-stereogenic phosphines by the dynamic kinetic
resolution.8 In this Communication, we report a new type of
catalytic asymmetric reaction where the P−H bond in
diarylphosphines HPR1R2 is converted into a P−O bond by
the Pd-catalyzed reaction with a benzoquinone to give
diarylphosphinites with high enantiomeric purity (Scheme
1b). The resulting chiral diarylphosphinites are readily
convertible into chiral tertiary phosphines and so on.
of a palladium catalyst proceeds in a 1,6-addition manner to
give a high yield of O-phosphination product with high
enantioselectivity. Thus, phenyl(2,4,6-trimethylphenyl)-
phosphine (rac-1a) was allowed to react with 2,5-diphenylben-
zoquinone (2m) (1.05 equiv to 1a) in the presence of a
phosphapalladacycle complex PdL1* 9b,11 (5 mol%), which is
one of the most catalytically active and enantioselective
catalysts for asymmetric hydrophosphination of α,β-unsatu-
rated ketones,9 and triethylamine in chloroform at −45 °C for
12 h (entry 1 in Table 1). The 31P{1H} NMR analysis of the
reaction mixture showed that all of the phosphine 1a (δ −75.9
ppm in CHCl3) was selectively converted into a new
compound which has a new 31P resonance at 115.7 ppm. It
turned out that the reaction product is 2,5-diphenyl-4-
hydroxyphenyl phenyl(2,4,6-trimethylphenyl)phosphinite
(3am).12 Isolation of the phosphinite 3am in a chemically
pure form is difficult due to its oxidation during the workup,
and hence the reaction mixture was treated with sulfur to allow
us to isolate the reaction product as sulfide 4am in 96% yield.
The enantioselectivity of the reaction is very high, the sulfide
being obtained with 98% ee. The reaction product, phosphinite
3am, can be also isolated pure as phosphinate 5am by oxidation
with H2O2. The absolute configuration of phosphinite 3am was
determined to be (S) by X-ray crystal structure analysis of
During our studies on the Pd-catalyzed asymmetric hydro-
phosphination of electron-deficient olefins,9,10 it was found that
the addition of a racemic diarylphosphine, where one of the two
aryl groups is sterically demanding, to quinones in the presence
Received: January 29, 2014
Published: March 17, 2014
© 2014 American Chemical Society
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Journal of the American Chemical Society
Communication
The phosphorus−oxygen bond formation producing phos-
phinite was also observed in the Pd-catalyzed reaction of
phosphine 1a with other quinones, but the reaction was slower
with 2,5-dimethylbenzoquinone (2n) at −45 °C (Table 1, entry
2). The enantioselectivity was lower with unsubstituted
benzoquinone 2o and dichloro-substituted 2p, although they
gave high yields of the corresponding phosphinites (entries 3
and 4). Screening of reaction conditions in the reaction of
phosphine 1a with 2,5-diphenylbenzoquinone (2m) showed
that the presence of base is essential for the reaction to proceed
(entries 5−8).14 Diisopropylethylamine and potassium carbo-
nate can be used as well as triethylamine. Chloroform is a
solvent of choice. The yield and/or enantioselectivity was lower
in the reactions in dichloromethane, THF, and acetonitrile
(entries 9−11). The enantioselectivity was not strongly
dependent on the reaction temperature between −30 and
−60 °C (entries 1, 12, and 13). Use of azapalladacycle
PdL2* 9a,15 in place of phosphapalladacycle PdL1* gave poor
results, with low conversion and almost no enantioselectivity
(entry 14).16
The selective formation of 2,5-diphenyl-4-hydroxyphenyl
phosphinite in the present Pd-catalyzed oxidation with quinone
2m was observed only with diarylphosphines where one of the
aryl groups is a sterically demanding aryl group. The reaction of
diphenylphosphine with 2m under the conditions used in entry
1 of Table 1 gave a mixture consisting mainly of diphosphinite
9 (24%), diphosphine (Ph2P-PPh2, 10; 27%), and hydro-
quinone 11 (52%), together with a trace amount of 4-
hydroxyphenyl phosphinite 8 (eq 1).17 Thus, quinone 2m
Table 1. Palladium-Catalyzed Asymmetric Addition of
Diarylphosphine 1a to Benzoquinones 2
a
b
temp
% yield
c
entry quinone 2
base
Et3N
solvent
(°C) product
(% ee)
1
2
3
4
5
6
7
2m
2n
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
−45
−45
−45
−45
−45
−45
−45
3am
3an
3ao
96 (98)
43 (87)
95 (68)
92 (7)
Et3N
Et3N
Et3N

2o
2p
3ap
2m
2m
2m
3am
3am
3am
<3 ()
95 (97)
47 (78)
i-Pr2NEt
Proton
Sponge
8
2m
2m
2m
2m
2m
2m
2m
K2CO3
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
CHCl3
CH2Cl2
THF
−45
−45
−45
−45
−60
−30
−45
3am
3am
3am
3am
3am
3am
3am
95 (97)
96 (89)
74 (78)
96 (89)
96 (98)
96 (95)
40 (2)
9
10
11
12
13
14
MeCN
CHCl3
CHCl3
CHCl3
d
a
Reaction conditions: 1a (0.30 mmol), 2 (0.32 mmol), Pd catalyst
PdL1* (5 mol%), base (0.30 mmol), solvent (7.5 mL) for 12 h.
b
oxidized the secondary phosphine into diphosphinite and
diphosphine rather than into the expected phosphinite in the
reaction of diphenylphosphine. The Pd-catalyzed oxidation
with quinone derivatives did not proceed for tert-butyl(phenyl)-
phosphine, the starting phosphine being recovered unreacted.
The results obtained for the reaction of diarylphosphines 1,
which gave the corresponding diarylphosphinites 3 in high
yields, are summarized in Table 2. The enantioselectivity is high
(≥95% ee) in the reaction of phenyl(aryl)phosphines 1a−1e,
where the aryl group is 2,6-disubstituted phenyl or a 2-
substituted 1-naphthyl group (entries 1−5). The enantiose-
lectivity was much lower for those substituted with ortho-
monosubstituted aryl groups, although the yields giving the
phosphinites are high (entries 6 and 7). The reaction of
aryl(2,4,6-trimethylphenyl)phosphines 1h and 1i also pro-
ceeded with high selectivity to give high yields of the
corresponding diarylphosphinites with 81−91% ee (entries 8
and 9).
Isolated yield of sulfide 4 after treatment of the reaction mixture with
c
d
sulfur. Determined by chiral HPLC analysis of sulfide 4. Reaction
with PdL2* (5 mol%) as a catalyst.
palladium complex 7 formed by addition of enantiomerically
pure palladacycle chloro-bridge dimer 613 to the reaction
mixture (Figure 1).
The present catalytic asymmetric transformation, where the
racemic starting compound forms the nonracemic product,
should involve a kinetic resolution or dynamic kinetic
resolution mechanism. The reaction of 1a with 2m giving
3am was quenched before completion by addition of mCPBA
to the reaction mixture to see the enantiomeric purity of
unreacted diarylphosphine 1a (eq 2). The diarylphosphine
Figure 1. X-ray structure of palladacycle−phosphinite complex 7.
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Journal of the American Chemical Society
Communication
Table 2. Palladium-Catalyzed Asymmetric Addition of
a
Diarylphosphines 1 to 2,5-Diphenylbenzoquinone 2m
b
c
entry
phosphine 1
product 3
yield (%) of 4
ee (%) of 4
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
3am
3bm
3cm
3dm
3em
3fm
3gm
3hm
3im
96
95
95
95
94
96
95
93
94
98 (S)
98
conditions and prevents the product from being racemized by
further ester exchange reaction.23
In summary, we have developed a new type of catalytic
asymmetric transformation where diarylphosphines are con-
verted into enantiomerically enriched diarylphosphinites in the
reaction with 2,5-diphenylbenzoquinone catalyzed by a chiral
phosphapalladacycle complex.
97
97
95
43
1g
1h
1i
24
d
8
91
9
81
a
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, compound characterization data, and
crystallographic data (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
Reaction conditions: 1 (0.30 mmol), 2m (0.32 mmol), PdL1* (5 mol
■
b
%), Et3N (0.30 mmol), CHCl3 (7.5 mL) at −45 °C for 20 h. Isolated
S
yield of sulfide 4 after treatment of the reaction mixture with sulfur.
c
d
Determined by chiral HPLC analysis of sulfide 4. At 0 °C.
AUTHOR INFORMATION
Corresponding Authors
pakhing@ntu.edu.sg
■
tamioh@imre.a-star.edu.sg or chmtamh@nus.edu.sg
Notes
The authors declare no competing financial interest.
oxide 12 and phosphinate 5am obtained by stopping the
reaction at 63% conversion18 of 1a were 26% ee and 98% ee,
respectively. The low ee of 12 and the same ee of 5am as that at
full conversion demonstrate that the present reaction is
classified as a dynamic kinetic resolution. Although the catalytic
reaction pathway remains to be clarified, the P-stereogenic
center of diarylphosphine undergoes racemization on the
palladium catalyst under the present conditions.19
The phenyl(2,4,6-trimethylphenyl)phosphinite (S)-3am ob-
tained with high enantiomeric purity (98% ee) by the present
catalytic asymmetric reaction was subjected to reaction with
alkyllithiums to demonstrate its synthetic utility (eq 3). The
reaction with methyllithium proceeded with perfect inversion of
configuration20 to give a high yield of (R)-methyl(phenyl)-
(2,4,6-trimethylphenyl)phosphine (R)-13a with 98% ee, whose
absolute configuration was determined by X-ray analysis of the
sulfide (S)-14a.21 The reaction with butyllithium also took
place with high stereospecificity. The inversion of stereo-
chemistry was also observed in the methylation of thiophos-
phinate (R)-4am with methyllithium to give (S)-14a of 94% ee
(eq 4).22 Ester exchange proceeded successfully with high
stereospecificity in the reaction of phosphinate (S)-15, which
was obtained by methylation of the phenol oxygen in 5am, to
give methyl phosphinate 16 with 94% ee (eq 5). The high
stereospecificity may be ascribed to the phenoxide being a good
leaving group, which promotes the reaction under mild
ACKNOWLEDGMENTS
We thank Nanyang Technological University and National
University of Singapore for supporting this research.
■
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