P-Chiral Phosphines Enabled by Palladium/Xiao-Phos-Catalyzed Asymmetric P-C Cross-Coupling of Secondary Phosphine Oxides and Aryl Bromides

Article abstract of DOI:10.1021/jacs.9b11938

The development of transition-metal-catalyzed methods for the synthesis of P-chiral phosphine derivatives poses a considerable challenge. Herein, we present a direct Pd/Xiao-Phos-catalyzed cross-coupling reaction of easily accessible secondary phosphine o

Full text of DOI:10.1021/jacs.9b11938

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Article
P-Chiral Phosphines Enabled by Palladium/Xiao-Phos-Catalyzed Asymmetric
P–C Cross-Coupling of Secondary Phosphine Oxides and Aryl Bromides
Qiang Dai, Wenbo Li, Zhiming Li, and Junliang Zhang
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 02 Dec 2019
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Journal of the American Chemical Society
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P-Chiral Phosphines Enabled by Palladium/Xiao-Phos-Catalyzed
Asymmetric P–C Cross-Coupling of Secondary Phosphine Oxides and
Aryl Bromides
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Qiang Dai†, Wenbo Li†, Zhiming Li§, and Junliang Zhang*,†,§
†Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular
Engineering, East China Normal University, Shanghai 200062, China
§Department of Chemistry, Fudan University, 2005 Songhu Road, Shanghai, 200438, China
ABSTRACT: The development of transition metal-catalyzed methods for the synthesis of P-chiral phosphine derivatives
pose considerable challenge. Herein we present a direct Pd/Xiao-Phos-catalyzed cross-coupling reaction of easily accessible
secondary phosphine oxides and aryl bromides, which provides a rapid access to P-chiral phosphine oxides. The reaction
proceeds efficiently with a wide array of reaction partners to deliver various tertiary phosphine oxides in up to 96% yield
and 97% ee. Moreover, the synthesis of DiPAMP ligand and its analogues was also realized, which demonstrates a suitable
pathway to switching the branched chain of DiPAMP.
salts to access P-stereogenic tertiary phosphine oxides
(TPOs)
INTRODUCTION
Chiral phosphine compounds have seen widespread
applications in chiral introduction. They can be used as a
ligand for metal catalysts1 or directly as an organocatalyst2.
However, the great majority of chiral phosphines
commonly used today are axial-chiral or planar-chiral or C-
stereogenic phosphines. The lack of concise and efficient
methods for their enantioselective synthesis inhibits P-
stereogenic phosphines to continue their early promising
applications.3 Classical synthetic methods usually rely on
resolution processes or the use of chiral auxiliaries.4 In past
years, alternative methods such as desymmetrization,
addition of specified phosphine derivatives to alkenes or
benzoquinones have been developed.5 Besides, employing
alkene, alkyne and imine hydrophosphination to build
phosphine compounds have also been realized,6 while
most of them are not for building P-chirality or hampered
in selectivity. In addition, general methods relying on P–C
cross-coupling events catalyzed by transition metals have
been the object of extensive investigations for some time.7,8
The difficulties encountered in this process are that the
initial and final phosphorus compounds coordinate to
metal catalysts competitively with chiral ligands, thus
eroding the enantioselectivity. Bulky substrates or the
ortho-functionalized coupling partners are usually
required to compensate for the insufficient coordination
capacity of the chiral ligands. Therefore, it is still highly
desirable to develop alternative strategies for synthesis of
P-stereogenic phosphine compounds.
Scheme 1. Enantioselective synthesis of
P-chiral
phosphines.
a) Gaunt's work: Enantioselective Cu-Catalyzed Arylation
O
N
Cu
P
R
O
N
N
Ar
P
H
Ar
F3BF
+
R
Ar
L* = tridentate pybox
I
(±)
(SP)-TPOs
50-98% ee
M
b) Tautomerism of SPO and Formation of SPO- Complexes
Potential hydrogen
bonding site
R1
R2
R1
R1
O
O
O
P
OH
M
Pd Pt
,
=
P
P
M
H
R2
base
R2
(PIII
H
Binding site to
late-transition
metals
P
(Pv)
)
R2
R1
M
SPO- complexes
Versatile catalysts
c) This work: Pd-Catalyzed Asymmetric P-C Cross-Coupling
O
O
Ar1
P
P
Pd
NH
R
Ar2
P
H
Br
Ar1
P
R
L*
Ar1
Ar2
Ar2
+
P
Ar2
(R = Me)
Ar1
(±)
Ar2 = aryl, naphthyl, pyridyl
(RP or SP)-TPOs
DiPAMP-type ligands
(Scheme 1a). The rigid chelation of tridentate pybox with
copper provides favorable condition for high
a
enantioselectivity. The air stability of SPOs10 used in this
reaction largely stems from the unique tautomerism
between the pentavalent and the trivalent tautomer.11 The
tautomeric equilibrium can be shifted toward to the
trivalent phosphinous acid form in the presence of bases or
transition metals.12 Either of the chelating sites (O, P) could
coordinate with transition metal, whereas the phosphorus
atom coordinates well to the soft metal ions (M) and the
Recently, Gaunt and co-workers9 reported an elegant
copper/pybox-catalyzed enantioselective arylation of
secondary phosphine oxides (SPOs) with diaryliodonium
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oxygen atom can act as a potential hydrogen bond acceptor of X4 as ligand, lowering the reaction temperature from 90
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2
3
4
5
6
7
8
(Scheme 1b). The resulting SPO-M complexes are known
as versatile catalysts in transition metal-catalyzed cross-
coupling reactions.13 In view of the possibility that the
excessive SPOs competitively bind to the metals with chiral
ancillary ligands, using racemic SPOs as cross-coupling
partners to implement a palladium catalyzed asymmetric
process might be very difficult. The tight binding of the
chiral ligand to the metal, as with Gaunt’s work, is indeed
an effective method. However, choosing a flexible chiral
ancillary ligand to deftly circumvent this effect is also an
alternative pathway. Having this in mind, we report here
our efforts to develop a Pd-catalyzed asymmetric P–C
cross-coupling of easily available racemic SPOs and aryl
halides (Scheme 1c). The chiral sulfinamidephosphine
(Sadphos) type ligands (Xiao-Phos) used here belong to
a class of hemilabile ligands.14 The coordination of its
sulfinamide moiety is highly fluxional and labile in nature,
thus providing a dynamic environment for metal-catalyzed
reactions. In addition, Xiao-Phos was previously used as
an organocatalyst15 in our group and it’s the first time
acting as chiral ancillary ligand in asymmetric metal-
catalysis.
to 80 °C slightly decreased the yield but improved the ee
from 75% to 85%
Table 1. Optimization of reaction conditions.a
Me
O
P
O
P
H
Me
Me
5 mol% Pd2(dba)3
11 mol% Ligand
Me
Br
+
2.5 equiv Cs2CO3
Solvent, Ar, 90 o
Me
C
1a
(±)- (2 equiv)
2a
Me
3aa
Ad
HN
9
tBu
Ph2P
Ph
O
S
O
S
10
11
12
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S
tBu
N
tBu
N
H
O
O
H
PPh2
Ming-Phos
PPh2
Wei-Phos
PPh2
PC1
(R, RS)-
M1:
(S, RS)-
(R, RS)-
49% yield, 0% ee
M1:
35% yield, 0% ee
W1:
(S, RS)-
83% yield, 8% ee
22% yield, 0% ee
X1:
(S, RS)-
(S, RS)-
(S, RS)-
(S, RS)-
(S, RS)-
(S, RS)-
(S, RS)-
(S, RS)-
(S, RS)-
(S, RS)-
R = H
Ph2P
X2:
X3:
X4:
X5:
X6:
X7:
X8:
X9:
R = Ph
O
S
R
R
R
= 2-naphthyl
= 9-anthracenyl
= 9-(10-phenyl)anthracenyl
Ph2P
O
tBu
N
Me
S
N
tBu
R = 2,4,6-(iPr)3-C6H2
R = 2,4,6-(Cy)3-C6H2
R = 2,6-(Me)2-C6H3
R= 2,6-(Ph)2-C6H3
Ar
Ar = 9-anthracenyl
H
R
X4
N-Me-(S, RS)-
Xiao-Phos
trace
R = 2,6-(iPr)2-C6H3
X10:
Entry
Ligand
Solvent
yield (%)b
ee (%)c
1
2
(S,RS)-X1
(S,RS)-X2
(S,RS)-X3
(S,RS)-X4
(S,RS)-X4
(S,RS)-X4
/
toluene
toluene
toluene
toluene
toluene
PhCF3
52
38
43
39
31
19
66
69
75
85
71
RESULT AND DISSCUSION.
3
Optimization of Reaction Conditions. Our initial
ligand screening was performed by using racemic SPO ()-
1a and 4-bromotoluene 2a as model reaction. Tridentate
pybox and bidentate N, N-ligands (L1−L4) all failed to
promote the reaction (Figure S1, supporting information).
Other commercially available ligands such as bidentate N,
P-ligands (L5−L8), P, P-ligands (L10−L12) as well as
monodentate binol-derived phosphoramidite (L9) were
also examined. Unfortunately, very low ee was observed in
some cases, indicating the asymmetric P–C cross-coupling
reaction is indeed very challenging (for more details, please
see Supporting Information). Over the past 6 years, a series
of novel chiral ligands (Sadphos) have been developed in
our laboratory, which showed good performance in
asymmetric metal catalysis (Au, Cu, Pd).16 However, (R,
RS)-PC1, which worked well in asymmetric palladium-
catalyzed arylation of general sulfenate anions for the
synthesis of chiral sulfoxides,16g was found inefficient in
this palladium-catalyzed reaction. (R, RS)-M1 and (S, RS)-
M1 also gave racemic product in low yield. Bisphosphine
(S, RS)-W1 provided excellent conversion, but only 8% ee
was obtained. The ee was slightly increased to 19% when
Xiao-Phos ((S, RS)-X1) was used (Table 1, entry 1). Of
interest, the introduction of a phenyl group at ortho-
position of the side aryl ring ((S, RS)-X2) significantly
improved the ee to 66% but only a modest yield was
obtained (Table 1, entry 2). Having observed the ortho-
substituent effect, we next focused on variation of the
ortho-aryl group. Further increasing the steric hindrance
of ortho-aryl group, structured as X3, X4, both allowing
enantioselectivity increasing (Table 1, entries 3−4).
Interestingly, no product of 3aa was formed when using N-
methylated ligand N-Me-X4, which indicated that the NH
might play some role for the catalytic activity. With the use
4
5d
6d
7d
90
13
PhCF3
/
8e
9e
(S,RS)-X4
(S,RS)-X5
(S,RS)-X6
(S,RS)-X7
(S,RS)-X8
(S,RS)-X9
(S,RS)-X6
(S,RS)-X6
(S,RS)-X6
(S,RS)-X10
PhCF3
87
94
66
68
69
62
97
83
73
70
74
75
87
84
80
73
54
84
90
92
PhCF3
10e
11e
12e
13e
14e,f
15e
16g,h
17g
PhCF3
PhCF3
PhCF3
PhCF3
acetone
anisole
anisole
anisole
aReactions performed at 0.2 mmol scale in solvent (2 mL) for 40
h. bIsolated yield. cEnantiomeric excesses were determined by
HPLC on chiral stationary phases. d80 oC. e70 oC. fFor 10 h. g35 oC.
hFor 60 h.
(Table 1, entries 5). However, further screening of
conditions including aryl electrophile 2, palladium sources,
and bases could not bring both better results in yield and
selectivity (for additional details, please see Supporting
Information). A reverse trend of ee value and yield was
observed in solvent screening under the same catalytic
system conditions, which is largely due to the different
catalytic activities of SPO-M complexes in different
solvents (for additional details, please see Supporting
Information, Table S1). Although the background reaction
was still high in trifluorotoluene solvent, 3aa was afforded
with very high yield and maintained a relatively good ee
value (Table 1, entry 6−7). Further lowering the
temperature to 70 °C slightly increase the ee to 74% (Table
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1, entry 8). Continuing to change the substitution pattern temperature. Product (RP)-3aj−3al were obtained in 57-71%
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5
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7
8
of ortho-aryl group found that a relatively better result
(66% yield, 87% ee) could be obtained when X6 (with
2,4,6-(iPr)3-C6H2 as the ortho-aryl group) was used (Table
1, entries 9−13). Interestingly, when using X6 as the chiral
ligand, 3aa was isolated in 97% yield after only 10 hours in
acetone albeit with moderate ee (Table 1, entry 14). Further
investigation of the reaction time and temperature in
acetone could not bring better results (for additional
details, please see Supporting Information, Table S2).
There was also a dramatic increase in the yield of 3aa and
the selectivity was maintained when using anisole as
solvent (Table 1, entry 15). Moreover, 90% ee and 73% yield
was obtained in anisole when lowering the reaction
temperature from 70 °C to 35 °C with elongated reaction
time (Table 1, entry 16). Besides, compared with X6, ligand
X10 slightly enhanced the activity in the absence of para-
isopropyl in the side aryl group (Table 1, entry 17).
yield with 90-95% ee. Besides, using a mixture of solvent
(anisole/acetone = 4/1) could improve the yield of (RP)-
3am to 61% yield with 90% ee. In addition, the steric
hindrance effect appeared again when1-bromonaphthalene
was examined. Increasing the equivalents of 1a was
necessary, delivering (RP)-3an in 97% yield with 90% ee.
Remarkably, this reaction produced (RP)-3cj−3co18 in 50-
82% yield with 90-94% ee, which provided a rapid access
to useful enantioenriched PAMP and analogues.
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Table 2. Scope of the SPOs and aryl bromides.
O
O
R1
R1
5 mol% Pd2(dba)3
Br
P
P
X10
11 mol% (S, RS)-
R2
R2
+
H
Cs2CO3 (2.5 equiv)
anisole, 35 oC, Ar
1
3
(±)- (2 equiv)
2
Me
Me
O
O
P
Me
3db:
(RP)-
R = Ethyl, 24 h
O
P
Me
R
69%; 91% ee
(RP)-3eb: R = nPropyl, 32 h
81%; 91% ee
3fb:
Me
P
Me
Me
5 mol% Pd2(dba)3
O
Me
O
P
X6
11 mol% (S, RS)-
P
Br
R = nButyl, 32 h
2.5 equiv Cs2CO3
(RP)-
Ph
Me
, 40 h
+
OH
(1)
Ph
47%; 93% ee
anisole (2 mL)
35 oC, Ar, 40 h
3aa
(RP)-3gb, 32 h
(RP)-
Me Me
Me
70%; 92% ee
71%; 91% ee
Me
68% yield; 88% ee
3aa
Me
Me
Me
Me
O
Me
Me
1b
(±)- (2 equiv)
2a
(0.2 mmol)
Me
Me
O
O
O
P
P
P
P
With the fact that SPO 1a could react with acetone to
form adduct 1b under basic conditions.11,17 A control
experiment was carried out using the adduct 1b instead of
1a with anisole as solvent. A comparable yield of 3aa was
obtained with slightly reduced ee value after 40 hours,
which might be attributed to the in-situ generated acetone
during the reaction (eq 1).
Ph
Ph
Me
Me
, 60 h
54%; 92% ee
3ha
3ia
3jb
3kb a
, 24 h
(RP)-
(RP)- , 40 h
66%; 88% ee
(RP)- , 44 h
64%; 93% ee
(RP)-
58%; 81% ee
Me
O
Me
O
P
P
Me
(RP)-
R = OPh,c 58 h
O
3ed:
Me
P
55%; 93% ee
3ee:
(RP)-
R = NHBoc, 40 h
Scope of the SPOs and Aryl Bromides. With the
optimal reaction conditions in hand, we firstly investigated
the scope of the SPO by changing the alkyl substituent on
the phosphine atom (Table 2). The desired TPOs (RP)-
3db−3gb bearing linear alkyl chain were obtained from
moderate to high yield with 91−93% ee when ()-1d−1g
were used. SPOs with cyclohexylmethyl and neopentyl
group were also suitable substrates to give moderate yields
of (RP)-3ha and (RP)-3ia with 92% ee and 88% ee,
respectively. With steric hindrance closely adjacent to P
atom, isopropyl-derived SPO ()-1j is applicable to this
asymmetric cross coupling process, delivering the desired
(RP)-3jb in 64% yield and 93% ee. The bulky tert-butyl-
substituted SPO ()-1k, a previously reported challenging
substrate,9 also worked to afford the desired product (RP)-
3kb in moderate yield with 81% ee. The effect of
substituent on the aryl bromide was then investigated. Aryl
bromides with a variety of substituents at the para-position
was transformed to the corresponding product (RP)-3ac
and (RP)-3ed−3eh in moderate yield with high
enantioselectivity (90−95% ee) under modified conditions.
Meta-substituted aryl bromide showed relatively low
reaction efficiency but still in high enantioselectivity under
the reaction conditions. For example, product (RP)-3ei was
afforded in 48% yield and 94% ee. When the scope was
extended to ortho-substituted aryl bromides, (S, RS)-X6
showed better enantioselectivity even in higher
X
X = Cl, 72 h
59%; 93% ee
3eh:
59%; 93% ee
R = tBu, 48 h
OMe
3eg:
(RP)-
3ef:
(RP)-
R
65%; 91% ee
3ac b
, 88 h
(RP)-
(RP)-
X = F, 72 h
64%; 90% ee
61%; 95% ee
Me
Me
Cl
O
P
Me
Me
Me
R
3aj:
(RP)-
R = Me,b,d 23 h
O
P
71%; 90% ee
3ak:
O
(RP)-
R = OMe,b,c 48 h
P
Me
67%; 95% ee
3al:
(RP)-
R = Ph,b,c 48 h
3am a,b,e
3ei
(RP)- , 60 h
48%; 94% ee
(RP)-
,
35 h
57%; 93% ee
61%; 90% ee
Me
Me
O
O
O
Me
Me
Me
O
P
P
Me
P
OMe
P
OiPr
3an
3cj a,b,e
3ck a,b,e
3co a,b,e
(RP)-
, 40 h
(RP)-
,
40 h
(RP)-
,
40 h
(RP)-
,
40 h
97%; 90% ee
50%; 90% ee
77%; 93% ee
82%; 94% ee
amixed solvent (anisole/acetone) was used, for details, see
supporting information. b(S, RS)-X6 was used. c50 oC. d70 oC. e80
oC.
The introduction of an ortho-methyl group to the
aromatic ring of SPOs led to a great improvement in
enantioselectivity and activity (Table 3). Electron-
withdrawing groups, such as trifluoromethyl and ester
group, in the para position of aryl bromides were well
tolerated, and the coupling products (SP)-3mq−3mr were
isolated in moderate to good yield with excellent
enantioselectivity. Meta-substituted aryl bromides were
also applicable to this process. For example, methyl,
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chloro, methoxy substituted and disubstituted aryl
Page 4 of 11
1
2
3
4
5
6
7
8
bromides were all compatible, delivered the desired
product (SP)-3mi−3mw in excellent yield and ee. Sterically
bulky substrates such as ortho-acetal substituted and
naphthalene both gave very good results ((RP)-3mx, 71%
yield, 95% ee and (RP)-3mn, 70% yield, 95% ee). The acetal
group provided a handle for the further transformations.
Pyridine group was also suitable coupling partner to
furnish SPO (RP)-3my in 61% yield with 94% ee. Similarly,
(SP)-PAMP analogues (SP)-3cj18 and (SP)-3nb were both
achieved in 91-92% yields and 91-93% ee.
9
Figure 1. X-ray structure of 4ck confirmed the absolute
stereochemistry.
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Table 3. Scope of the SPOs and aryl bromides.
Me
Me
O
O
R1
R1
5 mol% Pd2(dba)3
Br
P
P
X10
11 mol% (S, RS)-
R2
R2
+
Gram-scale Synthesis and Synthetic Applications.
To demonstrate the practicability of our method, gram
H
Cs2CO3 (2.5 equiv)
anisole, 35 oC, Ar
1
3
(±)- (2 equiv)
2
scale
preparation
of
enantioenriched
tertiary
3mp:
(SP)-
84%; 96% ee
3mb
R = H, 40 h
3mi:
95%; 96% ee
3ms:
93%; 92% ee
3mt:
64%; 96% ee
(SP)-
R = Me, 50 h
Me
methylphosphine oxides was conducted under modified
conditions, delivered the corresponding product without
loss of the enantioselectivity (Scheme 2). Further
transformation of these enantioenriched tertiary
methylphosphine oxides to DiPAMP ligands and its
analogues was then carried out.19 The dimerization of the
enantioenriched product 3 gave the chiral bisphosphine
oxides (4ck, 4co and 4cj) in almost enantiomerically pure
level, and only minor amount of meso compounds
remained after recrystallization. Subsequent stereo-
controlled reduction took place with inversion of
configuration at the P-center and efficiently delivered the
DiPAMP−BH3 adducts after borane protection (5ck, 5co
and 5cj) with very high enantioselectivity.20 Thus providing
a facile route to vary the branched chain of DiPAMP. In
addition, the absolute configuration of product 4ck was
unambiguously determined to be (R, R) by single crystal
XRD analysis (Figure 1),21 from which we can determine the
absolute configuration of the product 3ck and then
tentatively assign other TPOs a relative configuration by
analogy to 3ck.
Me
(SP)-
87%; 95% ee
3mq:
: R = Ph, 40 h
O
P
O
(SP)-
R = Cl, 55 h
Me
Me
P
R
(SP)-
R = CF3, 60 h
(SP)-
R = OMe, 50 h
46%; 90% ee
R
3mr:
(SP)-
R = CO2Me, 50 h
76%; 92% ee
Me
O
O
Me
3mu:
(SP)-
68%; 97% ee
3mv:
R = Me, 50 h
O
O
Me
P
Me
P
R
(SP)-
96%; 93% ee
3mw:
R = OMe, 55 h
(SP)-
R = Ph, 50 h
92%; 92% ee
3mx a
R
(RP)-
,
50 h
71%; 95% ee
Me
Me
O
Me
Me
Me
P
O
O
O
Me
P
Me
P
Me
P
N
Ph
3cj a
3nb a
, 35 h
3mn
3my b
(SP)-
,
40 h
(SP)-
92%; 91% ee
(RP)-
, 45 h
(RP)-
,
45 h
91%; 93% ee
70%; 95% ee
61%; 94% ee
amixed solvent (anisole/acetone) was used, for details, see
supporting information. b60 oC.
Scheme 2. Gram-Scale Synthesis and Synthetic
Applications: DiPAMP type ligands.
R1
O
R1
O
P
H
Me
P
R2
Pd2(dba)3 (5-7 mol%)
X6 X10
Br
R2
Mechanistic Studies. With the facts that the product ee
was influenced by the amount of SPOs and the SPOs are
configurationally stable according to the literature, the
possible mechanism was initially thought to be a kinetic
resolution process. To probe this hypothesis, we firstly
tested the stability of enantioenriched SPO (SP)-1e under
reaction systems and a very low degree of racemization was
observed in the presence of palladium (Scheme 3a). We
also showed that the reaction of (SP)-1e with (R, SS)-
X10·Pd2(dba)3 leads to the productive, matched formation
of the product (SP)-3eb with higher enantioselectivity.
While under the mismatched conditions (with (S, RS)-
X10·Pd2(dba)3), the enantiomer (RP)-3eb was obtained in
greatly reduced yield and enantioselectivity from the fewer
matched (RP)-1e and the possible weak racemization of
(SP)-1e (Scheme 3b). We then turned our attention to the
basic piece of data (yield and ee) of both recovered starting
materials and products under their respective standard
conditions (Scheme 3c). The ees of recovered ortho-
substituted aryl SPOs (SP)-1m and 1n are higher than 1a
and 1e (for more basic data, please see Supporting
or
(11-15.4 mol%)
Me
+
anisole/acetone, Cs2CO3
35 oC or 80 oC, 20-40 h
3ck:
3co:
3cj:
(RP)-
(RP)-
(SP)-
87%; 91% ee
83%; 94% ee
82%; 92% ee
1 (
(±)- 2 equiv)
R1 = H, Me
2
(6.0 mmol)
R2 = H, OMe, OiPr
LDA, CuCl2,THF
recrystallation
R1
O
R1
MeOTf, DME, rt
then LiAlH4, -70 o
C
BH3
R2
R2
P
P
R2
R2
P
P
then BH3 THF
H3B
R1
O
R1
5ck:
5co:
5cj:
(R,R)-
(R,R)-
(S,S)-
69%; 99% ee
76%; 99% ee; dl/meso =17:1
74%; 99% ee; dl/meso = 9:1
4ck:
4co:
4cj:
(R,R)-
(R,R)-
(S,S)-
63%; >99% ee; dl/meso >99:1
62%; >99% ee; dl/meso >97:3
70%; >99% ee; dl/meso >99:1
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Information, Section 10), these results might indicate that
the reactions of the ortho-substituted aryl SPOs might
1
2
3
4
5
6
7
8
100
s = 12
90
80
70
60
50
40
30
20
10
0
undergo the kinetic resolution process, but simple aryl
alkyl SPOs might undergo very minor dynamic kinetic
resolution. We also performed the reaction by using
stoichiometric catalysts (Scheme 3d), and were surprised
to find that almost no target product 3mb was detected,
instead, a large number of Michael-addition type product
6ma was obtained. The low ee value of 6ma indicated that
it might stem from palladium-catalyzed enantioselective
hydrophosphination reaction, which can also be
demonstrated by enantiomeric excess of recovered 1m.
Given that the enantioselective hydrophosphination
reaction must also occurred in the catalytic system, and
was obviously prior to the target coupling reaction, which
might explain why only a very weak racemization was
observed in scheme 3a (mismatched condition under (SP)-
1e and (S, RS)-X10).
conversion ≈ 10%
conversion > 50%
9
0
10 20 30 40 50 60 70 80 90 100
eeX10 (%)
10
11
12
13
14
15
16
17
18
19
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22
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
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60
Figure 2. Product ee (ee3mb) as a function of catalyst ee
(eeX10). selectivity factors: s = ln[(1 − C)(1 – ee1m)]/ln[(1 − C)(1
+ ee1m)]. C represents conversion of 1m.
As Xiao-Phos was firstly used as chiral ancillary ligand in
Pd-catalyzed asymmetric reaction. We were very
interested in its coordination pattern, and we managed to
get its palladium complex by using Pd(CH3CN)2Cl2 ((S, RS)-
X10)2·PdCl2, Scheme 4a)22. The formation of intermolecular
hydrogen bonds between NH and Cl might helped stabilize
the complex. However, the palladium complex prepared
with palladium (0) was very unstable and difficult to
separate. In addition, it is worth noting that although the
palladium (II) could also perform good enantioselectivity,
the catalytic efficiency was very low (for additional details,
please see Supporting Information, Table S3 and Section
10). Therefore, we speculated that the complex obtained
above is a stable form but was not really a catalytic active
species and the stable coordination modes of palladium
with different valence states may be different in our system.
The nonlinear effect studies have also shown that the
obtained complex might not really an active species in the
reaction process (Figure 2, for additional details, please see
Supporting Information, Section 10). The observed
negative nonlinear effect at high conversion was due to the
intrinsic kinetics of the enantioconvergent process, rather
than to the presence of more than one unit of the chiral
ligands in coordination with palladium.23 Because almost
no nonlinear effect was detected at low conversion, we
hinted the opportunity that the sulfinamide moiety might
occupy one coordination site of palladium in a very flexible
manner during the reaction.14 And it was precisely the
highly fluxional and labile in nature that made such
palladium complex cannot be isolated in a stable form.
Scheme 3. Mechanistic Research Experiments.
(a)
O
X10
11 mol% (S, RS)-
1e
1e
95%
73%
remaining, 74% ee
P
H
Cs2CO3, anisole, 35 oC, Ar, 18 h
Me
X10
5 mol% Pd2(dba)3, 11 mol% (S, RS)-
1e
(SP)-
remaining, 70% ee
O
Cs2CO3, anisole, 35 oC, Ar, 18 h
74% ee
(b)
Me
P
X10
11 mol% (S, RS)-
O
P
4-Ph-C6H4Br (0.2 mmol)
5mol% Pd2(dba)3
Cs2CO3 (2.5 equiv)
anisole, Ar, 35 oC, 32 h
3eb
39%; 66% ee
(RP)-
Ph
Me
H
O
P
Me
1e
74% ee
(SP)- (2 equiv)
X10
11 mol% (R, SS)-
3eb
(SP)-
Ph
89%; 99% ee
O
R1
(c)
R2
O
R1
R2
P
Under respective
standard conditions
P
R3
Ar Br
2 (0.2 mmol)
1
(±)-
(2 equiv)
+
H
+
1
Recovered
3
Me
O
P
O
P
Me
Me
Me
3mb
(SP)-
3aa
(RP)-
H
H
87%; 95% ee
75%; 95% eea
61%; 95% eeb
70%; 92% ee
63%; 92% eea
50%; 92% eeb
+
+
1m
(SP)-
1a
(SP)-
40%; 89% ee
29%; 89% eea
28%; 96% eeb
45%; 48% ee
41%; 49% eea
40%; 52% eeb
(d)
Pd2(dba)3
O
nPr
P
O
4-Ph-C6H4Br (0.1 mmol)
X10
Cs2CO3 (0.25 mmol)
3mb
Trace
(SP)-
2-Me-C6H4
Ph
(S, RS)-
(0.11 mmol)
(0.05 mmol)
Ph
+
+
Scheme 4. Study on coordination pattern of Xiao-Phos.
1m
(SP)-
6ma
(62%, 20%ee, 12%ee, dr = 1:1)c
m
()-1
(0.2 mmol)
anisole, 35 oC, Ar, 5 h
22%; 27% ee
a1.8 equivalents of ()-1 were used. b1.5 equivalents of ()-1 were
c
used. Isolated yield was based on Dibenzylideneacetone (dba)
and contained a small amount of double hydrophosphination
product.
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(a)
equilibrium might exist and the palladium complex A
having the P atom and sulfinamide moiety coordinate to
O
R
1
Ph2
P
S
tBu
Cl
Pd
NH
2
3
4
5
6
7
8
9
palladium participated in the catalytic cycle. Following the
classical coupling steps (path a), the oxidative addition of
aryl bromide to palladium complex A leaded to the
formation of intermediate C, which further evolved into
intermediate D through transmetalation. Our initial
assumption was that the hydrogen bond interactions
between sulfinamide NH and the oxygen of the SPO might
exist in the resulting intermediate D and contribute to the
stability of the transition state. On the other hand, the
more competitive hydrophosphination reaction (scheme
3d) indicated that the reaction preferred the b route to
some extent. The coordination of SPO to palladium center
(intermediate B) through the trivalent phosphinous acid
form took precedence over oxidative addition step of aryl
bromide. In this case, the sulfonamide might temporarily
leave to provide a vacant coordination site for incoming
aryl bromide to give the same intermediate D. The
instability of D(RP) might due to the steric effect between
two aromatic rings in the approximately planar
coordination of Pd. Reductive elimination from the more
favored intermediate D(SP) gave the corresponding (SP)-3cj
(Bromobenzene, ()-1n along with the Pd0−(S, RS)-X10
chiral system was selected as model), which was in
agreement with the formation of the major experimental
enantiomer.
HN
P
Ph2
tBu
Cl
S
R
O
X10
((S, RS)-
)
2 PdCl2 (R = 2,6-(iPr)2-C6H3)
(b)
Me
O
P
Me
O
P
H
Me
Br
+
Standard conditions
Me
Me
Me
3aa
1a
()- (2equiv)
2a
10
11
12
13
14
15
16
17
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Ph2P
O
S
O
S
O
O
tBu
iPr
N
Me
i
H
Pr
N
tBu
N
N
Bn
N
H
Me
H
H
Me
iPr
(S,RS)-
X6
73% yield, 90% ee
X6
3aa
P1
P2
P3
(S)-
N-Me-
trace of
(S)-
(S)-
3aa
33% yield, 61% ee 25% yield, 59% ee
trace of
In order to gain insight into the coordination properties
of the sulfinamide moiety and its role in the reaction, the
modification of (S, RS)-X6 was investigated (Scheme 4b).
Both N-methylated ligand N-Me-X6 and further removal
of the sulfinyl group P1 blocked the reactions, suggested
that these two parts play a crucial role in the catalytic
activity. We next used acyl instead of chiral sulfinyl group,
the ligands P2 and P3 both led to significantly low yield
and enantioselectivity which showed the importance of
sulfinamide moiety again. Due to the diversity of
coordination modes (O, S or N) of sulfinamide moiety, we
were not sure what the actual coordination pattern existed
in the reaction, but it did play a very important role in the
efficiency and enantioselectivity of the reaction. On the
other hand, according to our previous studies on the
coordination pattern of palladium with chiral
sulfinamidephosphine ligands,16g,i we speculated that was
the oxygen atom in sulfinamide moiety coordinate with
palladium.
(b)
(a)
D'
en-
D'
G = 3.8 kcal/mol
G = 3.8 kcal/mol
iPr
iPr
iPr
iPr
(c)
(d)
O
N
S
N
S
Ph
Ph
Ph
P
Me
Ph
Ph
H
tBu
P
Me
H
tBu
O
P
O
Pd
O
Pd
O
P
Me
P
3cj
Me
Me
(SP)-
Me
[RE]
Vs.
P
D
D
(RP)
(SP
favored
)
disfavored
N
H
H
N
X10
N
H
(S, RS)-
P
Pd
R2
Pd
P
SPO
Ph
P
Pd
N
H
O
P
R1
PhBr
D'-H
D'-H
en-
P
Pd
Base
G = 5.2 kcal/mol
G = 7.8 kcal/mol
N
Pd
[OA]
P
Ph
H
Br
D
path a
C
N
A
[OA']
H
(e)
(ML*2, inactive species)
N
P
ArBr
Base
H
R1
R2
Pd
R2
P
R1
O
O
P
R1
OH
H
[SPO]
P
path b
R2
H
B
Figure 3. Tentative mechanism.
As to the possible mechanism of the stereoselective
cross-coupling process (Figure 3), a dynamic coordination
D'-O
G = 16.6 kcal/mol
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AUTHOR INFORMATION
Figure 4. The optimized structures of intermediate D at
1
2
3
4
5
6
7
8
B3LYP/6-31G(d)-SDD level in anisole (bromobenzene, ()-
1n along with the Pd0−(S, RS)-X10 chiral system was
selected as the model).
Corresponding Author
jlzhang@chem.ecnu.edu.cn; junliangzhang@fudan.edu.cn
Author Contributions
DFT calculations at B3LYP/6-31G(d)-SDD level were
then carried out to locate intermediate D using Gaussian
09 software.24 The reaction of bromobenzene, ()-1n along
with the Pd0−(S, RS)-X10 chiral system was selected as the
model, which has shown good performance in the reaction
(Tables 3). The solvent effects, anisole, were included with
the SMD approach.25 The other calculation details were
provided in the supporting information. Both
intermediates D' and en-D' corresponding to each product
(SP and RP) were located, in which divalent Pd coordinates
with P and O atom in (S, RS)-X10, aromatic ring from
bromobenzene, and 1n (Figure 4). The relative free
energies based on the initial structures (int-A + ()-1n +
PhBr) are both 3.8 kcal/mol for D' and en-D'. Another pair
of D intermediates with H-bond interactions were located
as well (Figure 4), the bond distances between NH group
and O atom in SPO are 2.06 Å for D'-H (corresponds to
D(SP) in figure 3) and 2.11 Å for en-D'-H (corresponds to
D(RP) in figure 3). However, they are less stable
conformations compared to D' and en-D', the relative free
energies are 5.2 and 7.8 kcal/mol. Since N-Me-X6 is not
active and only gives a trace amount of the product, while
the X6 gives 73% yield and 90% ee (Scheme 4), the
intermediate D containing the H-bond interactions (D’-H
and en-D’-H) should be invoked to account for the
observed enantioselectivity, as it does show some energy
bias towards the right enantiomer. This might be
indicative that the NH moiety functions as a proton shuttle
in the reaction. The O atom in SPO as coordination site
with palladium was also considered, and the higher
instability of D'-O (relative free energy 16.6 kcal/mol) rules
out the O-coordination possibility of SPO (For additional
details, please see Supporting Information, Section 10).
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
9
We gratefully acknowledge the funding support of NSFC
(21425205, 21672067), 973 Program (2015CB856600), the
Program of Eastern Scholar at Shanghai Institutions of Higher
Learning and the Innovative Research Team of Ministry of
Education.
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CONCLUSION
In summary, we have developed an asymmetric Pd/Xiao-
phos-catalyzed P–C cross-coupling for the efficient
synthesis of highly enantioenriched P-stereogenic
phosphine oxides. Xiao-Phos contributes significantly to
the catalytic activity and enantioselectivity control.
Moreover, this method could be applied to the
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facile route to DiPAMP-type ligands with diverse branched
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asymmetric catalysis of these ligands. The further
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course.
ASSOCIATED CONTENT
Supporting Information
Experimental
procedure,
optimization
tables,
characterization data for all the products (PDF).
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O
P
Ar1
O
R
N
Br
R
P
H
P
O
P
[Pd]/L*
H
R
Ar1
Ar2
Ar1
Pd
R
Pd
R
H
+
Ar2
Ar2
O
P
O
P
Aryl,
Ar1
Ar1
Naphthyl,
Pyridyl
()-SPO
(Rp or Sp)-TPOs
46- 96% yield
81- 97% ee
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