Synthesis and application of a new chiral monodentate spiro phosphoramidite ligand based on hexamethyl-1,1′-spirobiindane backbone in asymmetric hydroamination/arylation of alkenes

Article abstract of DOI:10.1039/c8ob01785a

The design and synthesis of a new chiral monodentate spiro phosphoramidite ligand based on a hexamethyl-1,1′-spirobiindane scaffold has been accomplished. The ligand could serve as an elegant chiral monodentate ligand in the Pd-catalyzed asymmetric hydroamination/arylation of alkenes leading to chiral imidazolidin-2-ones with good enantioselectivities.

Full text of DOI:10.1039/c8ob01785a

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Synthesis and application of a new chiral
monodentate spiro phosphoramidite ligand based
on hexamethyl-1,1’-spirobiindane backbone in
asymmetric hydroamination/arylation of alkenes†
Cite this: DOI: 10.1039/c8ob01785a
Received 25th July 2018,
Accepted 13th August 2018
DOI: 10.1039/c8ob01785a
rsc.li/obc
Huanyu Shan, Rihuang Pan and Xufeng Lin
*
The design and synthesis of a new chiral monodentate spiro phos- methodology to construct chiral imidazolidin-2-one moie-
phoramidite ligand based on
a
hexamethyl-1,1’-spirobiindane ties.5a–c Gong’s group reported Pd-catalyzed asymmetric oxi-
scaffold has been accomplished. The ligand could serve as an dative 1,2-diamination of conjugated dienes with ureas.5d
elegant chiral monodentate ligand in the Pd-catalyzed asymmetric Trost’s group developed asymmetric Pd-catalyzed addition of
hydroamination/arylation of alkenes leading to chiral imidazolidin- vinylaziridines to isocyanates for direct synthesis of chiral imi-
2-ones with good enantioselectivities.
dazolinones.5e Recently, Wolfe’s group described the first cata-
lytic asymmetric hydroamination/arylation of alkenes for pro-
viding a simple route to enantiomerically enriched 4-substi-
tuted imidazolidin-2-ones.5f
The development of highly efficient chiral ligands for tran-
sition-metal-catalyzed organic transformations has become
one of the most challenging goals in chemical synthesis.1
Research advances indicated that chiral monodentate phos-
Chiral spiro backbone has been recognized as one of the
privileged structures for chiral ligands and catalysts in asym-
metric calalysis.6,7 During the past few years, our group has
developed chiral spirocyclic phosphoric acids (SPAs) that
derived from axially chiral 1,1′-spirobiindane-7,7′-diol
(SPINOL) with conformational rigidity, and found good utility
in over 100 asymmetric reactions.8,9 In searching for new struc-
tural backbones, we found that hexamethyl-1,1′-spirobiindane-
6,6′-diol 1 (6,6′-HMSIOL) was first reported in the 1936, and no
further attempts had been made to synthesize chiral ligand.10
More recently, we utilized 6,6′-HMSIOL as a precursor to
develop new types of chiral phosphine-oxazoline ligands
(HMSI-PHOX) and bisphosphine ligands (HMSI-PHOS), and
demonstrated their successful application in asymmetric cata-
lysis.11 Herein we report the facile resolution of 6,6′-HMSIOL
and the first synthesis of chiral monodentate spiro phosphora-
midite ligand based on the hexamethyl-1,1′-spirobiindane
backbone (HMSI-PPA). To demonstrate its potential role in
asymmetric catalysis, chiral monodentate spiro phosphorami-
dite ligand 8 was prepared, and exhibited excellent enantio-
selectivity (up to 93% ee) in Pd-catalyzed asymmetric alkene
carboamination reaction, as shown in Scheme 1.
phorus ligands can be effective for asymmetric catalysis.2
A
large number of monodentate ligands, especially those mono-
dentate phosphoramidite ligands with C2 symmetry, have been
developed for highly efficient asymmetric catalysis. Ligand
design based on a chiral backbone plays a crucial role and has
remarkable influence on catalytic performance in some cases
in this area. Notably, monodentate phosphoramidite ligands
have been prepared from BINOL and SPINOL, and represented
the great success of the promising class of ligands. These
ligands have led to excellent enantioselectivities in many tran-
sition-metal-catalyzed asymmetric reactions.3 Despite these
achievements, there remains a significant need to develop
novel monodentate phosphoramidite ligands with excellent
catalytic activities in
transformations.
a
diverse range of asymmetric
Substituted imidazolidin-2-ones is well-known for its sig-
nificant biological and pharmacological properties.4 However,
over the past decade, only several asymmetric catalysis strat-
egies have been developed for preparing chiral 4-substituted
imidazolidin-2-ones.5 For instance, Shi’s group discovered Cu
(I)-catalyzed asymmetric diamination of olefins as an efficient
The preparation of racemic 6,6′-HMSIOL was carried out by
following the previous reported method by us in 92% yield
from the commercially available Bisphenol C in one step by
acid-catalyzed rearrangement.11 Next, we attempted to resolve
the racemic 6,6′-HMSIOL, and found the two optical spiro
diols could be obtained in good yields through highly efficient
chromatography resolution of the corresponding diastereo-
meric diester derived from N-tosyl-L-phenylalanine acid chlor-
Laboratory of Asymmetric Catalysis and Synthesis, Department of Chemistry,
Zhejiang University, Hangzhou 310027, China. E-mail: lxfok@zju.edu.cn
†Electronic supplementary information (ESI) available: Experimental details,
characterization and analytical data, NMR and HPLC spectra. CCDC 1857510
[(S)-1]. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c8ob01785a
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Scheme 1 Palladium-catalyzed asymmetric alkene carboamination
reaction.
ide and then hydrolysis of each pure diastereomer with hydra-
zine hydrate under reflux in THF (Scheme 1). The absolute
configuration of (S)-1 was confirmed by its single-crystal X-ray
diffraction structure analysis (Fig. 1 and Scheme 2).
With enantiopure 1 in hand, we extended its application to
the synthesis of a new type of C2-symmetric monodentate
spiro phosphoramidite ligand 8. As shown in Scheme 3, the
chiral ligand (Sa,R,R)-8 could be conveniently synthesized from
(S)-1. The chiral spiro dibromides (S)-5 was obtained in high
yield from (S)-1 in three steps, including bromination with
NBS, esterification with Tf2O and the following Pd-catalyzed
selective reduction with HCOOH.11 Then, the spiro dialde-
hydes 6 was successfully accomplished in 92% yield by a
simple Br/Li exchange followed treatment with DMF and
hydrolysis. The subsequent Baeyer–Villiger oxidation
rearrangement and subsequent hydrolysis provided chiral 7,7′-
HMSIOL 7 in 82% yield. Finally, the desired chiral monoden-
tate spiro phosphoramidite ligand (Sa,R,R)-8 was prepared by
substitution reaction of 7 with dichloro-phosphanamine. The
different diastereomer (Ra,R,R)-8 was also prepared by using
another enantiomer (R)-1.
Scheme 2 Resolution of 6,6’-HMSIOL.
Next, the efficiency of new ligand was tested in the Pd-cata-
lytic asymmetric hydroamination/arylation of alkenes between
Scheme 3 Synthesis of spiro phosphoramidite ligand.
N-allyl urea derivatives and aryl halides using optimized condi-
tions,5f as shown in Table 1. We initially examined the use of
the chiral ligand (Sa,R,R)-8 and [Pd2(dba)3] for the asymmetric
reaction of 1-allyl-3-(4-methoxyphenyl)-1-methyl urea 9a and
1-bromo-4-(tert-butyl)benzene 10a, and found the desired imi-
dazolidin-2-one 11a could be obtained in 94% yield with 54%
ee (Table 1, entry 1). The absolute configuration of (S)-11a was
confirmed in comparation with the known data.5f The use of
the diastereomeric ligand (Ra,R,R)-8 gave poor result in 80%
yield and −7% ee (Table 1, entry 2). The decrease of the phos-
phoramidite ligand loading of (Sa,R,R)-8 to 4 mol% led to a sig-
nificant drop in yield but did not compromise the enantio-
selectivity (Table 1, entry 3, 62% yield, 53% ee). Notably, nitro-
gen nucleophilicity of N-allyl urea derivatives 9 on asymmetric
induction had remarkable effect. The increasing electron-with-
drawing ability of the p-substituent on the N-aryl moiety of 9
Fig. 1 X-ray crystal structure of (S)-1.
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Table 1 Asymmetric hydroamination/arylation of alkenesa
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We appreciate the National Natural Science Foundation of
China (21572200) and the Fundamental Research Funds for
the Central Universities (2017QNA3013) for financial support.
Entry
X
R
11
Yieldb (%)
eec (%)
1
OMe
OMe
OMe
H
Br
CN
CN
CN
CN
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
4-tBu
4-tBu
4-tBu
4-tBu
4-tBu
4-tBu
4-Me
4-MeO
4-CF3
4-tBu
H
4-CF3
3-CF3
4-F
4-Cl
4-PhCO
4-Morpholino
11a
11a
11a
11b
11c
11d
11e
11f
11g
11h
11i
11j
11k
11l
94
80
62
91
63
89
85
77
63
87
75
75
67
57
77
62
83
54
−7
53
66
79
83
87
86
87
91
84
93
91
93
90
83
91
2d
3e
4
Notes and references
5
6
7
8
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11
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11m
11n
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a Reactions were performed with 9 (0.05 mmol), 10 (0.1 mmol),
NaOtBu (0.1 mmol), 2 mol% [Pd2(dba)3], 6 mol% (S,R,R)-8, H2O
(0.1 mmol) in toluene (0.05 M) under reflux for 20 h. b Isolated yields.
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4 mol% (S,R,R)-8.
could increase with the level of asymmetric induction (Table 1,
entries 1, 4–6 and 10). p-Cyanophenyl-substituted N-allyl urea
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bromides gave the corresponding imidazolidin-2-one products
with excellent enantioselectivies in most cases (Table 1, entries
10–17). The electronic property of the substituents on the
aromatic rings of 10 had a very limited effect on the
enantioselectivity.
In summary, a new type of hexamethyl-1,1′-spirobiindane-
based chiral monodentate spiro phosphoramidite (HMSI-PPA)
ligand has been developed. The rigid and unique spiro core
structure is the notable feature of HMSI-PPA. The new
HMSI-PPA ligand (Sa,R,R)-8 was applied in Pd-catalyzed asym-
metric hydroamination/arylation of alkenes of N-allyl urea
derivatives with aryl bromides to afford chiral imidazolidin-2-
ones in moderate to high yields with excellent enantioselectivi-
ties. Further investigations to expand this promising chiral
monodentate spiro phosphoramidite ligand in transition-
metal-catalyzed asymmetric reaction for constructing other
chiral carbon–carbon and carbon–heteroatom bonds are cur-
rently under development.
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