Spiro indane-based phosphine–oxazoline ligands for palladium-catalyzed asymmetric arylation of cyclic N-sulfonyl imines

Article abstract of DOI:10.1007/s11243-019-00329-z

Palladium complexes of indane-based phosphine–oxazoline ligands with a spirocarbon stereogenic center were examined for asymmetric addition of arylboronic acids to cyclic N-sulfonyl imines. Excellent reaction activities (up to 99% yield) and enantioselect

Full text of DOI:10.1007/s11243-019-00329-z

Transition Metal Chemistry
https://doi.org/10.1007/s11243-019-00329-z
Spiro indane‑based phosphine–oxazoline ligands
for palladium‑catalyzed asymmetric arylation of cyclic N‑sulfonyl
imines
Zhongxuan Qiu1 · Yanshun Li1 · Zhenqing Zhang1 · Dawei Teng1
Received: 30 March 2019 / Accepted: 23 April 2019
© Springer Nature Switzerland AG 2019
Abstract
Palladium complexes of indane-based phosphine–oxazoline ligands with a spirocarbon stereogenic center were examined
for asymmetric addition of arylboronic acids to cyclic N-sulfonyl imines. Excellent reaction activities (up to 99% yield) and
enantioselectivities (up to 99% ee) were obtained with a broad scope of substrate.
Introduction
tuned [13, 14]. However, reports of P,N-ligands for the
Pd-catalyzed asymmetric addition of arylboronic acids to
cyclic N-sulfonyl imines are rare. Recently, Hayashi reported
PHOX and phosphine–imine ligands (P,N-ligands) dem-
onstrated high performance in the asymmetric reaction of
arylboronic acids with cyclic N-sulfonyl imines (Scheme 1,
Eq 2) [15, 16].
Chiral benzylic amines containing the N-substituted stereo-
genic carbon center constitute an important structural motif
in drugs and natural products [1–3]. Asymmetric arylation
of imines with arylboronic acid derivatives catalyzed by
transition metals is an efective strategy to produce these
chiral amines [4–9]. Palladium catalysis is an attractive area
for both theoretical study and practical applications. The
design and synthesis of efective chiral ligands are essen-
tially important. Zhang initially reported the efective use
of palladium catalysts coordinated with pyridine–oxazolines
(N,N-ligands) for the asymmetric addition of arylboronic
acids to cyclic N-sulfonyl ketimines in unpurifed trifuoro-
ethanol (TFE) (Scheme 1, Eq 1) [10, 11]. Pyridine–hydra-
zone ligands (N,N-ligands) reported by Lassaletta also dem-
onstrated excellent catalytic performance for this reaction
under similar conditions (Scheme 1, Eq 1) [12]. The P,N-
ligands are another important class of ligands and have been
successfully applied in a large scope of reactions because
the steric and electronic characters of ligands can be fnely
By taking advantage of the chelating units of PHOX
and the spiro backbone, spiro phosphine–oxazoline ligands
exhibit impressive catalytic performance in many cases.
So far, there are four kinds of spiro phosphine–oxazoline
ligands reported, including SIPHOX by Zhou [17–22],
SpinPHOX by Ding [23–26], HMSI-PHOX by Lin [9] and
SMI-PHOX (an abbreviation for spiro mono-indane-based
phosphine–oxazoline ligands L1–L4 in Scheme 1) [27, 28].
Compared with the other three ligands, SMI-PHOX ligands
possess potentially distinct features: (1) frst spiro indane-
based phosphine–oxazoline ligand with non-C2-symmetric
skeleton in asymmetric metal catalysis; (2) better stability
and higher rigidity; (3) only one chiral center avoiding the
complex stereochemistry; (4) modularity by changing eas-
ily accessible carboxylic acid and ClPR2. Because of the
above-mentioned properties, SMI-PHOX ligands have
demonstrated excellent catalytic performance in palladium-
catalyzed asymmetric allylic alkylation and amination reac-
tions [27, 28].
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s11243-019-00329-z) contains
supplementary material, which is available to authorized users.
To fully explore the potential of these ligands, we
employed them in the asymmetric addition of arylbo-
ronic acids to cyclic N-sulfonyl aldimines and ketimines
(Scheme 1, Eq 3). The ligands exhibited excellent perfor-
mance under mild conditions. Herein, we reported our pre-
liminary results on this subject.
* Dawei Teng
dteng@qust.edu.cn
1
State Key Laboratory Base of Eco-chemical Engineering,
College of Chemical Engineering, Qingdao University
of Science and Technology, 53 Zhengzhou Road,
Qingdao 266042, People’s Republic of China
Vol.:(0123456789)
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Transition Metal Chemistry
Scheme 1 Pd-catalyzed asymmetric arylation of cyclic N-sulfonyl imines
A range of arylboronic acids 2 were examined in addi-
tion to the cyclic N-sulfonyl aldimines 1 (Table 2). Nota-
bly, excellent yields and enantioselectivities were obtained
in all cases (Table 2, entries 1–11). Both electron-rich and
electron-defcient arylboronic acids aford the correspond-
ing products with excellent enantioselectivities (98–99% ee,
entries 1–6). Fused-ring aryl and di-substituted aryl boronic
acids also gave excellent results (entries 7–9). In addition,
the scope of N-sulfonyl aldimines with diferent electronic
nature was also examined. Both substrates were converted to
the desired addition products in excellent yields and enanti-
oselectivities (entries 10 and 11).
Results and discussion
Initially, the model reaction of cyclic N-sulfonyl aldimines
1a and phenylboronic acid 2a was performed in the pres-
ence of Pd(TFA)2 (5 mol%, TFA trifuoroacetate) and four
representative spiro phosphine–oxazoline ligands L1-L4
(7.5 mol%) in unpurifed TFE at 40 °C (Table 1, entries
1–4). We were pleased to fnd that all the ligands proved
to be suitable for the reaction, giving the desired product
3aa in high yields (87–99% yields) with excellent enanti-
oselectivities (97–99% ee). Taking into account the cata-
lytic activity and enantioselectivity, L1 was chosen as the
ideal ligand for further intensive study. Both the enantiose-
lectivity and yield decreased when Pd(OAc)2 was tested
(entry 5) instead of Pd(TFA)2. No reaction occurred with
[Pd(C3H5)Cl]2 as the Pd source. Several solvents were then
examined. The reaction proceeded smoothly in TFE with
99% yield and 99% ee (entry 1), which might be ascribed
to TFE’s benefcial efect on the rate of the transmetala-
tion and protonation steps of the catalytic cycle [10, 29].
Only trace amounts of the desired product were detected
when methanol and 1,2-dichloroethane were applied as the
solvents (entries 7–8).
Encouraged by these results, the present catalyst sys-
tem Pd(TFA)2/L1 for asymmetric arylation was applied to
the more challenging substrates, namely cyclic N-sulfonyl
ketimines. The addition of various arylboronic acids 2 to a
range of cyclic N-sulfonyl ketimines 2 was further investi-
gated (Table 3).
Five-membered ring ketimine bearing ethyl (1d),
methyl (1e), n-butyl (1f), phenyl (1g) and ester (1h)
reacted with various arylboronic acids bearing diferent
substituents to give the corresponding products in good to
excellent yields with excellent enantioselectivities. Moreo-
ver, di-substituted arylboronic acids (2i and 2j) were also
suitable substrates for this reaction. High yields and high
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Transition Metal Chemistry
Table 1 Optimization of the reaction conditions to synthesize product 3aa
Entry
Ligand
Pd precursor
Solvent
Time (h)
Yielda (%)
eeb,c (%)
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L1
L1
L1
L1
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(OAc)2
[Pd(C3H5)Cl]2
Pd(TFA)2
Pd(TFA)2
TFE
TFE
TFE
TFE
TFE
TFE
MeOH
DCE
2
5
12
2
24
24
24
24
99
93
87
99
99
99
98
97
93
ND
–
76
NR
Trace
Trace
–
Unless otherwise noted, reactions were performed with 1a (0.2 mmol), 2a (0.3 mmol), Pd precursor (5 mol%), Ligand (7.5 mol%) in a unpurifed
solvent (2 mL) at 40 °C which was opened to air
aIsolated yield
bDetermined by HPLC using a chiral IC column
cThe absolute confgurations were assigned as S via comparison of specifc rotations with the literature data [16]
Table 2 Pd-catalyzed asymmetric addition of arylboronic acids to cyclic N-sulfonyl aldimines
Entry
R
Ar
Product
Yielda (%)
eeb,c (%)
1
2
3
4
5
6
7
8
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
6-Me (1b)
6-Cl (1c)
Ph (2a)
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
99
99
98
99
99
98
99
99
98
99
99
99
99
99
99
99
99
98
99
99
99
99
4-MeOC6H4 (2b)
4-MeC6H4 (2c)
4-FC6H4 (2d)
4-ClC6H4 (2e)
3-MeOC6H4 (2f)
1-naphthyl (2g)
2-naphthyl (2h)
3,4-(OCH2O)C6H3 (2i)
Ph (2a)
9
10
11
3ba
3ca
Ph (2a)
Unless otherwise noted, reactions were performed with 1 (0.2 mmol), 2 (0.3 mmol), Pd(TFA)2 (5 mol%), L1 (7.5 mol%) in unpurifed TFE
(2 mL) at 40 °C which was opened to air
aIsolated yield
bDetermined by HPLC using a chiral column
cThe absolute confgurations were assigned as S via comparison of specifc rotations with the literature data [16]
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Transition Metal Chemistry
Table 3 Pd-catalyzed asymmetric addition of arylboronic acids to cyclic N-sulfonyl ketimines
Unless otherwise noted, reactions were performed with 1 (0.2 mmol), 2 (0.3 mmol), Pd(TFA)2 (5 mol%), L1 (7.5 mol%) in unpurifed TFE
(2 mL) at 40 °C which was opened to air
aReaction temperature was 75 °C and reaction time was 24 h
ee values were obtained. The ligand L1 also exhibited high
catalytic performance for the addition of phenylboronic
acid to six-membered ring ketimine bearing ester group
(1i). For methyl-substituted ketimine (1j), excellent enanti-
oselectivity was also observed (99%) but the yield slightly
decreased.
Mechanism
The stereochemical outcome can be explained using a
model shown in Scheme 2. Thus, for example, the imine
2a bound to the Pd center is trans to the diphenylphosphine
group of L1, and the nucleophilic phenyl group is cis to the
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Transition Metal Chemistry
Scheme 2 Stereochemical
pathway giving (S)-3aa
diphenylphosphine group. The sterically favored transition
state B, minimizing unfavorable steric interaction between
the tertiary butyl group attached to the oxazoline ring and
the sulfonyl of imine substrate, leads to the product 3aa with
the S confguration that we obtained.
General procedure for the synthesis of product 3
Ligand L1 (6.2 mg, 7.5 mol%) and Pd(TFA)2 (3.4 mg,
5 mol%) were dissolved in unpurifed TFE (1.5 mL) in a
Schlenk tube. After 0.5 h of stirring at room temperature,
N-sulfonyl imine 1 (0.2 mmol) and arylboronic acid 2
(0.3 mmol) were added into the tube. The wall of the tube
was rinsed with an additional of TFE (0.5 mL). The mixture
was stirred at 40 °C for 2 h and then was diluted with EtOAc
and washed with saturated NH4Cl (aq). The organic layers
were dried over MgSO4 and fltered, and the solvents were
evaporated in vacuum. The residue was purifed by fash
column chromatography, eluting with petroleum ether and
ethyl acetate to aford the corresponding product 3.
Conclusions
In summary, palladium complexes generated in situ from
trifuoroacetate and SMI-PHOX ligand exhibited excellent
catalytic performance in Pd-catalyzed asymmetric arylation
of cyclic N-sulfonyl imines. Further application of these
ligands in other asymmetric transformations is currently
under development in our laboratory.
Compliance with ethical standards
Experimental sections
Conflict of interest There are no conficts to declare.
General
All air- and moisture-sensitive manipulations were carried
out with standard Schlenk techniques under argon. Commer-
cially available reagents were used without further purifca-
tion. Melting points were recorded on a RY-1 microscopic
melting apparatus and uncorrected. 1H and 13C NMR spec-
tra were recorded on a Bruker Avance 500 spectrometer.
Chemical shifts were reported in parts per million (δ) rela-
tive to tetramethylsilane (TMS). HRMS were performed on
an Ultima Global spectrometer with an ESI source. High-
performance liquid chromatography (HPLC) was performed
on a Shimadzu LC-20 Liquid Chromatograph using chiracel
OD-H, AD-H, AS-H, IA and IC columns. Ligands L1–L4
were prepared according to the reported procedure [17].
Cyclic N-sulfonyl imines 1a–c [4], 1d [30], 1e [31], 1f–g
[32], 1h [5], 1i [11], 1j [33] were synthesized by the known
procedures.
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