Palladium-catalyzed asymmetric addition of diarylphosphines to N-tosylimines

Article abstract of DOI:10.1039/c2cc35563a

Bis(phosphine) pincer-Pd complex-catalyzed asymmetric addition of diarylphosphines to N-tosylimines was developed for the synthesis of chiral phosphine sulfides with high stereoselectivities (up to 96% ee) under mild conditions.

Full text of DOI:10.1039/c2cc35563a

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Palladium-catalyzed asymmetric addition of diarylphosphines to N-
tosylimines†
Miao Huang,b Chun Li,b Jian Huang,b Wei-Liang Duan*a and Sheng Xu b
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
A bis(phosphine) pincer Pd complex-catalyzed asymmetric
addition of diarylphosphines to N-tosylimines was developed
for the synthesis of chiral phosphine sulfides with high
stereoselectivities (up to 96% ee) in mild conditions.
continuation of our research, a bis(phosphine) (PCP) pincer
Pd-catalyzed addition of diarylphosphines to N-tosylimines to
produce
chiral
phosphine
sulfides
with
high
50 enantioselectivities and yields is described in this study.
10 The catalytic asymmetric addition of nucleophiles to imines is
one of most important synthesis routes for chiral amines.
Various carbon and heteroatom nucleophiles have been
extensively employed in this process during the past decades.1
Among phosphorus nucleophiles, phosphites are the most
15 frequently used substrates in reactions with imines, which
produce optically active α-amino phosphonic acid derivatives
(eqn (1)).2,3 The obtained α-amino phosphonates and their
derivatives have received a considerable amount of attention
because of their potential biological activity as antibiotics,4
20 anti-viral agents,5 and enzyme inhibitors.6 The use of
Table
1.
Palladium-catalyzed
addition
of
secondary
phosphine
oxides
as
nucleophiles
in
diphenylphosphine to N-tosylimine 1a.
enantioselective addition reactions with imines (eqn (2)) have
only been recently investigated. Particular examples include
that highly enantioselective chiral guanidinium-catalyzed
25 addition of phosphine oxides and H-phosphinates to N-
tosylimines that was reported by Tan et al.,7a the Zn-catalyzed
addition of dialkyl phosphine oxides to chiral (S)-N-tert-
butanesulfinyl imines that was reported by Wang et al.,7b and
the asymmetric addition of diarylphosphine oxides to N-
30 benhydryl imines, which is catalyzed by chiral magnesium
BINOL phosphate, that was reported by Antilla et al..7c
However, investigations on the catalytic asymmetric addition
of trivalent secondary phosphines to imines have not been
reported to date (eqn (3)).8-9 This process can generate
35 optically active α-amino trivalent phosphine, which can serve
as chiral P,N-ligands to transition metals.10 The phosphorus
atom in these compounds can also be functionalized with
reducing reagents or oxidants to produce chiral borane-
phosphine complexes or phosphine sulfides that have α-amino
40 groups. Notably, the potential biological properties of chiral
α-amino borane-phosphines or phosphine sulfides have not
been explored because of the absence of direct synthetic
methods.
55
T (°C)
Entry
Solvent
Time (h) Yielda (%) eeb (%)
rt
rt
rt
rt
rt
rt
rt
rt
−30
−60
1
2
3
4
5
6
7
8
9
CH2Cl2
THF
ClCH2CH2Cl
dioxane
toluene
DME
2
2
81
55
77
89
88
99
91
85
90
53
31
22
26
40
38
61
77
87
93
80
2
2
2
2
Et2O
2
3.5
4
MTBE
MTBE
MTBE
10
6.5
a Isolated yields. b Determined by chiral HPLC with hexane/2-propanol.
The addition reaction of diphenylphosphine to N-tosylimine
1a, with 2 mol% PCP pincer–PdOAc (S,S)-411,12 as the
In our previous study,
45 hydrophosphination of electron-deficient alkenes catalyzed by
Pd catalyst was successfully conducted.8d,8j,8l As
a
highly stereoselective
60 catalyst, was investigated (Table 1). Given the air sensitivity
of the trivalent phosphorus atom, the formed product was
oxidized to the phosphine sulfide using S8 prior to analysis.
a
a
This journal is © The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 00–00 | 1

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Solvent screening at room temperature indicated that methyl
tert-butyl ether (MTBE) is the optimal solvent, affording the
product 3a with 87% ee and 85% yield (Table 1, entry 8). The
phosphine sulfide with the highest stereoselectivity (90%
yield, 93% ee; entry 9) was obtained when the reaction
temperature was decreased to −30 °C.
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5
With optimized conditions obtained, various substrates 1
that bear electron-donating or -withdrawing groups on the
aromatic ring reacted with diphenylphosphine to produce the
10 chiral phosphine sulfides in high yields with good
stereoselectivities (84–99% yield, 78–96% ee; Table 2, entries
1–7).13 It’s worth pointing out that 2-thiofuryl and 3-thiofuryl
substituted N-tosylimines, which show strong ability to
coordinate with late transition metals via the sulfur atom, also
15 can be used as the substrate to afford the corresponding
products with good ee and yields (90–95% yield, 86–91% ee;
entries 8 and 9). With respect to the nucleophilic component,
phosphines that have electron-donating or -withdrawing
groups can be coupled with imines to form products with good
20 yields and enantioselectivities as well (89–97% yield, 84–86%
ee; entries 10 and 11). In addition, secondary phosphines
bearing two different groups, such as phenyl and methyl
moieties, were also employed to react with N-tosylimines. The
corresponding products having both P-stereocenter and C-
25 stereocenter were obtained in good yields, but with low
diastereoselectivities and enantioselectivities (entries 12 and
13).14 The absolute configuration of the product was
determinated to be S through X-ray crystal diffraction analysis
of the phosphine sulfide (Table 2, entry 4; Figure 1).15
Figure 1. X-ray structure of the phosphine sulfide (Table 2, entry 4) with
40 the thermal ellipsoids drawn at the 50% probability level.
The proposed catalytic cycle for this process is shown in
Scheme 1. First, the transphosphination between the
diarylphosphine and the pincer–PdOAc produces a Pd-PAr2
intermediate8d, the similar metal-PAr2 intermediates have been
45 reported in phosphorus-addition reactions of electronic-
deficient alkenes3g,3i, and asymmetric phosphination reactions
of alkyl and aryl halides.9 This Pd-PAr2 species then reacts
with N-tosylimine to generate
a Pd-amido intermediate.
Finally, protonolysis of the amido-Pd bond by AcOH in the
50 system then regenerates the active catalyst and releases the
addition product 3.
HOAc
P
transphosphination
Ar2PH
Ts
N
C
Pd PAr2
P
30 Table 2. Palladium-catalyzed asymmetric addition of secondary
phosphines to N-tosylimines.
R
H
1
2
P
addition
C
Pd OAc
4
P
P
Ts
C
HN
Pd
Ts
N
R
PAr2
Yielda (%) eeb (%)
P
Entry
1
R
Ar2PH
Ph2PH
3
R
PAr2
protonolysis
Ph
90
98
84
93
99
89
86
90
95
97
89
93
96
95
94
86
78
84
91
86
86
84
HOAc
2
p-MeOC6H4
m-MeOC6H4
p-MeC6H4
p-ClC6H4
m-BrC6H4
2-naphthyl
2-thiofuryl
3-thiofuryl
Ph
Ph2PH
3
Ph2PH
Scheme 1. Proposed catalytic cycle for the Pd-catalyzed addition of
55 diarylphosphines to N-tosylimines.
4
Ph2PH
5
Ph2PH
6
Ph2PH
In summary, a PCP pincer palladium-catalyzed asymmetric
addition of diarylphosphines to N-tosylimines was developed
for the synthesis of chiral phosphine sulfides in mild
conditions. Exploration of the obtained phosphorus
60 compounds as the ligand in asymmetric reactions is
undergoing.
7
Ph2PH
8
Ph2PH
9
Ph2PH
10
11
12c
13c
(p-ClC6H4)2PH
(p-MeOC6H4)2PH
Ph(Me)PH
Ph(Me)PH
p-MeOC6H4
m-MeOC6H4
2-thiofuryl
96 (1:0.9)d (0;0)e
87 (1.5:1)d (0;16)e
The NSFC (20902099, 21172238), National Basic
Research Program of China (973 Program 2010CB833300),
and SIOC are greatly acknowledged for funding this work.
a Isolated yields. b Determined by chiral HPLC with hexane/2-propanol. c
d
Ph(Me)PH was used instead of Ph2PH as the nucleophile. the ratios of
1
35 two diastereomers in parentheses were determined by H NMR analysis
e
of the crude products. the ee of the major and minor diastereomers in
65 Notes and references
parentheses.
a State Key Laboratory of Organometallic Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, China. Fax: (+86)-21-6416-6128; Tel: (+86)-21-5492-
5203; E-mail: wlduan@mail.sioc.ac.cn
2
| Chem. Commun., 2012, 48, 00–00
This journal is © The Royal Society of Chemistry 2012

Page 3 of 4
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b School of Chemistry & Molecular Engineering, East China University of
Science and Technology, 130 Meilong Road, Shanghai 200237, China
† Electronic Supplementary Information (ESI) available: Detailed
experimental procedures, and analytical data for all new compounds. See
5 DOI: 10.1039/b000000x/.
9
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This journal is © The Royal Society of Chemistry 20
Chem. Commun., 2012, 48, 00–00 |
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TOC
An asymmetric addition of diarylphosphines to N-tosylimines catalyzed by a
bis(phosphine) pincer–Pd complex has been developed for the synthesis of chiral
phosphine sulfides with high stereoselectivities.