Highly effective chiral phosphorus amidite-olefin ligands for palladium-catalyzed asymmetric allylic substitutions

Article abstract of DOI:10.1039/c1ob05803g

This paper describes the development of a type of novel P-olefin hybrid ligand by the incorporation of terminal olefins onto phosphorus amidite ligands for palladium-catalyzed asymmetric allylic alkylations of indoles and substitutions with amines to give the desired products in 70-97% yield with 91-98% ee.

Full text of DOI:10.1039/c1ob05803g

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Highly effective chiral phosphorus amidite–olefin ligands for
palladium-catalyzed asymmetric allylic substitutions†
Zhaoqun Liu, Ziping Cao and Haifeng Du*
Received 23rd May 2011, Accepted 14th June 2011
DOI: 10.1039/c1ob05803g
This paper describes the development of a type of novel P–
olefin hybrid ligand by the incorporation of terminal olefins
onto phosphorus amidite ligands for palladium-catalyzed
asymmetric allylic alkylations of indoles and substitutions
with amines to give the desired products in 70–97% yield with
91–98% ee.
Chiral olefins as steering ligands for transition-metal-catalyzed
asymmetric reactions have received intensive attention, and con-
siderable progress has been made in this lately emerging area.1,2
Besides the rapid growth of chiral diene ligands,3 several hybrid
ligands combining olefins with heteroatoms such as phosphorus4
or nitrogen5 have also been well developed since Gru¨tzmacher and
co-workers reported the first phosphane–olefin ligand for iridium-
catalyzed asymmetric hydrogenation.4a Especially, in some cases,
the olefin moieties were found to be essential for the high reactivity
and enantioselectivity. However, compared with the phosphorus
and nitrogen ligands, the quantity and the application scope of the
hybrid olefin ligands are still very limited. Further efforts on the
design of highly active and selective hybrid ligands are therefore
of great importance.1
Fig. 1 Strategy for the development of chiral P–olefin ligands.
During the course of exploring novel and easily synthesized
chiral diene ligands, we found that flexible ligands incorporating
terminal olefins as binding elements were effective for rhodium-
catalyzed asymmetric reactions.6 A strategy for the development of
P–olefin ligands by the incorporation of terminal olefin and phos-
phorus atom was then adopted in our group, and ligands 1 and 2
were successfully developed for palladium-catalyzed asymmetric
substitutions (Fig. 1).7 Due to their ease of synthesis, their good
stability and their wide application, chiral phosphorus amidites
have become one class of “privileged ligands” in asymmetric
catalysis.8 Olefin moieties have also been introduced into this type
of ligands by Carreira and co-workers via a one-step synthesis
(Scheme 1).4e Inspired by this beautiful work and the wonderful
characters of chiral phosphorus amidite ligands, we envisioned
that the combination of terminal olefins with phosphoramidite
ligands would provide a good opportunity for the development of
Scheme 1 Initial studies on Pd-catalyzed asymmetric alkylation of indole
with the use of P–olefin ligands.14
highly active and selective P–olefin hybrid ligands (Fig. 1). Herein,
we wish to report our preliminary results on this subject.
Palladium-catalyzed asymmetric allylic alkylations9 of indoles
provide an efficient approach to the synthesis of optically active
indoles, which are widely present in various biologically and
medically important compounds.10–12 However, to the best of
our knowledge, only a few chiral ligands including P/S ligands
developed by Chan and co-workers,13a binaphthyl-based P/S
Beijing National Laboratory of Molecular Sciences, CAS Key Laboratory
of Molecular Recognition and Function, Institute of Chemistry, Chi-
nese Academy of Sciences, Beijing, 100190, China. E-mail: haifengdu@
iccas.ac.cn; Fax: 0086-10-62554449; Tel: 0086-10-62652117
† Electronic supplementary information (ESI) available: Experimental
details, spectroscopic data, data for the determination of ee and copies
of NMR spectra. See DOI: 10.1039/c1ob05803g
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ligands developed by Hagiwara’s group,13b and P–olefin ligands
2 developed by us7b were found to be effective for this asymmetric
transformation. Therefore, further searching for other highly
effective ligands is still desirable.
Table 1 Optimization of reaction conditions and evaluation of chiral
ligandsa
Entry Ligand Solvent
Base
Conv (%)b ee (%)c
Initially, we subjected phosphorus amidite–olefin ligands to the
palladium-catalyzed asymmetric alkylation of indole (4a) with
1,3-diphenyl-2-propenyl acetate (5) to examine the reactivity and
enantioselectivity for this type of ligands (Scheme 1). It was found
that Carreira’s ligand4e gave 12% conversion with 20% ee and (S)-
BINOL derived ligand 3a bearing a terminal double bond gave
75% conversion with 76% ee. We were pleased to find that ligand
3b incorporating chiral amine moieties was more effective for this
reaction. Control experiments employing 3c and 3d as ligands led
to extremely low reactivity or enantioselectivity, which strongly
indicated that both the terminal olefin moieties and the binaphthyl
backbone of ligand 3b were essential for the observed high activity
and selectivity.
With these promising results in hand, several new ligands
were synthesized (Fig. 2) and the reaction conditions such as
base or solvent were optimized in order to further improve the
enantioselectivity. As shown in Table 1, the base and solvent
were found to have an obvious effect on both reactivity and
enantioselectivity (entries 1–9). Interestingly, ligand 3e derived
from (S)-BINOL and a racemic amine led to a reasonable
conversion with 87% ee (Table 1, entry 10). While ligands 3f and
3g with different axial chiralities showed similar activity, ligand 3f
gave a much better ee (Table 1, entries 11 vs. 12), which suggested
that the absolute configuration of product was controlled by the
ligand’s axial chirality rather than the amine chirality. Ligand 3h
incorporating internal olefin moieties was less effective than ligand
3f (Table 1, entries 13 vs. 11). Overall, ligand 3f gave the best
conversion and enantioselectivity (Table 1, entry 11).
1
2
3
4
5
6
7
8
3b
3b
3b
3b
3b
3b
3b
3b
3b
3e
3f
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
toluene
Et2O
K2CO3
Na2CO3 NR
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
92
84
ND
82
83
86
86
92
89
90
87
95
-74
63
90
91
92
74
44
92
91
68
95
93
52
THF
CH2Cl2/THF (2/1) K2CO3
CH2Cl2/THF (1/1) K2CO3
CH2Cl2/THF (2/1) K2CO3
CH2Cl2/THF (2/1) K2CO3
CH2Cl2/THF (2/1) K2CO3
CH2Cl2/THF (2/1) K2CO3
9
10
11
12
13
3g
3h
a All reactions were carried out with indole (4a) (0.20 mmol), 5 (0.24
mmol), Pd/L = 1/1 (3 mol% Pd), base (0.60 mmol), and solvent (1.0 mL,
entries 1–7, 1.2 mL, entries 8–13) at 15 ◦C for 12 h. b The conversion was
determined by crude 1H NMR. c The ee values were determined by chiral
HPLC with the N-Boc-protected derivative of 6a.
8 in 95–97% yield with 91–94% ee (Scheme 2). A control experi-
ment employing ligand 3c for the palladium-catalyzed asymmetric
amination reaction of 1,3-diphenyl-2-propenyl acetate (5) with
benzylamine (7a) only led to product 8a in 85% yield with 7%
ee, which further demonstrated the importance of the terminal
olefin moieties of ligand 3f.
Scheme 2 Pd/3f catalyzed asymmetric allylic amination.
Hydroxylamine hydrochloride (9) is a cheap and low-molecular-
weight nitrogen source. However, to the best of our knowledge,
the successful utilization of hydroxylamine hydrochloride (9) as
a nitrogen source for Pd-catalyzed asymmetric allylic amination
has seldom been reported. Under our catalytic system, the
reaction of 1,3-diphenyl-2-propenyl acetate (5) and hydroxylamine
hydrochloride (9) catalyzed by 2.5 mol% Pd/3f complex went
efficiently to give the desired product 10 in 70% yield with 95%
ee (Scheme 3). The ee can be further improved to >99% after
a recrystallization in hexanes. The hydroxyl group was easily
removed by treating with Zn/HOAc according to the reported
method15 to give a free amine 1116 in quantitative yield without
losing any ee value.
Fig. 2 Selected phosphorus amidite–olefin ligands.14
Under the optimal conditions involving
3 mol% Pd,
CH2Cl2/THF (2/1) as a solvent and K2CO3 as a base, we examined
the substrate scope for ligand 3f in the palladium-catalyzed allylic
alkylations of indoles 4 with 1,3-diphenyl-2-propenyl acetate (5).
It was found that different substituents on the indoles were well
tolerated, and all the reactions proceeded smoothly to give the
desired products 6 in 72–96% yield with 91–98% ee (Table 2, entries
1–10). Compared with the previously reported ligand 2,7b ligand
3f showed a better selectivity in most cases.
Conclusion
In summary, we have successfully developed a novel type of
P–olefin ligand by the incorporation of a terminal olefin onto
chiral phosphorus amidite ligands. Ligand 3f was highly effective
for palladium-catalyzed asymmetric allylic alkylations of indoles,
The application of ligand 3f can be extended to palladium-
catalyzed asymmetric allylic amination to give the desired products
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Table 2 Pd/3f catalyzed asymmetric allylic alkylation of indolesa
Entry Indole
1
Productb
Yield (%)c ee (%)d
94
84
72
77
88
91
96
95
95
94
92
91
98
95
95
96
Scheme 3 Pd/3f catalyzed asymmetric allylic amination with hydroxy-
lamine hydrochloride (9).
2
3
4
5
6
7
8
and aminations as well, to give the corresponding products
in high yields with excellent ee’s. It is noteworthy that the
asymmetric allylic amination with hydroxylamine hydrochloride
as a nitrogen source has been achieved with 95% ee for the
first time. Importantly, the terminal olefin moieties proved
to be essential for the observed high activity and selectivity.
Further application of this ligand class in other transition-
metal-catalyzed asymmetric reactions is underway in our
laboratory.
Acknowledgements
The authors are thankful for the financial support from the
National Science Foundation of China (20802079, 21072194),
the National Basic Research Program of China (973 program,
2010CB833300), and the Scientific Research Foundation for the
Returned Overseas Chinese Scholars.
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