The design and synthesis of a novel chiral 1,1′-disubsitituted ruthenocenyl phosphine–oxazoline ligand

Article abstract of DOI:10.1007/s11164-020-04253-1

Chiral ferrocene-based phosphine–oxazoline ligands have shown efficient asymmetric catalytic behaviors in asymmetric catalysis; however, the design and synthesis of the corresponding chiral ruthenocenes have not been widely explored. In this article, we report the synthesis of a chiral ruthenocene-based 1,1′-phosphine–oxazoline ligand, based on careful design and experimental exploration. The experimental results here reveal again that the synthetic preparation of 1,1′-disubstituted chiral ruthenocenyl ligands differs from the corresponding ferrocenes. The current method provides a feasible and practical strategy for the synthesis of 1,1′-disubstituted ruthenocene-based ligands.

Full text of DOI:10.1007/s11164-020-04253-1

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-020-04253-1
The design and synthesis of a novel chiral
1,1′‑disubsitituted ruthenocenyl phosphine–oxazoline
ligand
Jianxun Ye1 · Yunnan Xu1 · Jingjing Li1 · Delong Liu1 · Wanbin Zhang1,2
Received: 14 July 2020 / Accepted: 13 August 2020
© Springer Nature B.V. 2020
Abstract
Chiral ferrocene-based phosphine–oxazoline ligands have shown efcient asymmet-
ric catalytic behaviors in asymmetric catalysis; however, the design and synthesis
of the corresponding chiral ruthenocenes have not been widely explored. In this
article, we report the synthesis of a chiral ruthenocene-based 1,1′-phosphine–oxa-
zoline ligand, based on careful design and experimental exploration. The experi-
mental results here reveal again that the synthetic preparation of 1,1′-disubstituted
chiral ruthenocenyl ligands difers from the corresponding ferrocenes. The current
method provides a feasible and practical strategy for the synthesis of 1,1′-disubsti-
tuted ruthenocene-based ligands.
Keywords 1,1′-disubstituted ruthenocene · Phosphine–oxazoline ligand · Chirality ·
Synthesis
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s1116
4-020-04253-1) contains supplementary material, which is available to authorized users.
*
Delong Liu
dlliu@sjtu.edu.cn
Wanbin Zhang
wanbin@sjtu.edu.cn
1
2
Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School
of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240,
People’s Republic of China
School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative
Molecules, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240,
People’s Republic of China
Vol.:(0123456789)
1 3

J. Ye et al.
Introduction
The enantioselectivity and reactivity of asymmetric catalytic reactions mainly
depend on the properties of the chiral catalyst. The performance of the chiral
metal complex catalyst is largely determined by the chiral ligand [1–16]. There-
fore, to some extent, the design, synthesis, and application of chiral ligands are
pivotal to the research and development of asymmetric catalysis. Compared with
ligands bearing central chirality and axial chirality, ligands with planar chirality
have received less attention. However, planar chiral ligands have been shown to
exhibit very efcient asymmetric catalytic efects in many asymmetric catalytic
reactions and have attracted increasing attention [1, 17–24]. Some commonly
encountered planar ligands include planar chiral arene chromium complexes
[25–27], paracyclophane complexes (PhanePhos) [28], ferrocene complexes
(FcPHOX) [29], and cyclopentadienone-ligated dimeric ruthenium complexes
(Shvo catalysts) [30], among others. Ferrocene, which has greatly promoted the
advancement of modern organometallic chemistry due its special structure, plays
a very important role in the design and synthesis of planar chiral ligands. Many
excellent ferrocene-based chiral ligands have been synthesized and applied to var-
ious asymmetric synthetic reactions. Some of them (such as Josiphos) have been
successfully used in the industrial manufacture of optically pure compounds,
including drugs and materials [31–33].
Compared with chiral ferrocene-based ligands, the synthesis and application
of chiral ruthenocene-based ligands that also belong to the metallocene group
have received little attention. It has been reported that the distance between the
two cyclopentadienyl rings in ferrocene and ruthenocene is 0.332 and 0.368 Ǻ,
respectively [34, 35]. The approximately 10% longer distance between the two
rings in ruthenocene is expected to present diferent electronic and steric efects
compared with those exhibited by ferrocene ligands [36]. As a result, the develop-
ment of chiral ruthenocene ligands will greatly expand the application of planar
chiral metallocene ligands. Our group has a long-standing interest in the design
and synthesis of chiral ferrocene and ruthenocene [37–51] ligands of which the
1,2′-disubstituted phosphine–oxazoline ligand RuPHOX exhibits highly efcient
asymmetric catalytic behaviors in several types of reactions. During the synthe-
sis of ruthenocene-based ligands, we have found that the methods and conditions
needed for introducing groups onto the ruthenocene rings difer signifcantly from
the corresponding ferrocenes [40].
In 1998, Zhang and Ikeda’s group reported a 1,1′-disubstituted ferrocene-
based phosphine–oxazoline ligand (1, Fig. 1), which gave the desired products
in 91% ee for an enantioselective Pd-catalyzed asymmetric allyl alkylation reac-
tion [52]. In particular, the ligand showed very high reactivity, and the reaction
went to completion at room temperature within 30 min. In 2001, Hou and Dai
developed a new type of 1,1′-disubstituted ferrocene phosphine–oxazoline ligand
(2) by introducing an axial chiral BINOL molecule to the phosphorus atom of
1. The ligands 2 showed excellent enantioselectivity and diastereoselectivity in
a series of asymmetric catalytic reactions [53]. Encouraged by these results, we
1 3

The design and synthesis of a novel chiral 1,1′-disubsitituted…
Fig. 1 Metallocene-based 1,1′-phosphine–oxazoline ligands
intended to explore the synthetic preparation of 1,1′-disubstituted ruthenocene
phosphine–oxazoline ligand 3 with the aim of providing the synthetic method of
such ligands and expanding to planar chiral ruthenocene ligands by further deri-
vatization of 3. Herein, we report a new and efcient method for the synthesis of
1,1′-disubstituted ruthenocene phosphine-oxazolines 3, which is largely distinct
from the synthesis of the corresponding ferrocene ligands.
Experiment
1,1’‑dibromoruthencene (4) [54, 55]
The synthesis of 4 was accomplished following the previously published procedure
with slight modifcations. A mixture of n-butyllithium (2.5 M in n-hexane, 16 mL,
39.8 mmol) and PMDTA (N,N,N′,N′′,N′′-pentamethyldiethylenetriamine, 8.3 mL,
39.8 mmol) in n-hexane (50 mL) was added dropwise to the solution of ruthenocene
(4 g, 17.3 mmol) in n-hexane (100 mL) at room temperature, and the mixture was
then stirred for an additional 24 h to a slurry of dilithiated ruthenocene species. This
n-hexane slurry was treated with 1,2-dibromotetrachloroethane (14 g, 43.3 mmol)
at−78 °C and then stirred at room temperature overnight. The reaction mixture
was washed with water and brine and dried over anhydrous Na2SO4. The solvent
was removed under reduced pressure, and the residue was purifed by column chro-
matography using petroleum ether as the eluent to aford 4 as a yellow green solid
(4.8 g, 72% yield).
1H NMR (400 MHz, CDCl3): δ 4.88 (t, J=1.8 Hz, 4H), 4.52 (t, J=1.8 Hz, 4H).
1‑bromo‑1′‑isopropylester ruthenocene (5)
To a solution of 4 (3 g, 7.7 mmol) in THF (60 mL) was added dropwise n-butyl-
lithium (2.5 M in n-hexane, 3.1 mL, 7.7 mmol) at−78 °C. After stirring for 0.5 h,
1 3

J. Ye et al.
isopropyl chloroformate (1.3 mL, 11.6 mmol) was slowly added to the above solu-
tion at−78 °C. The reaction mixture was warmed to room temperature and stirred
overnight. After quenching with water, the solution was extracted with ethyl ace-
tate (10 mL×3). The organic phases were combined, washed with brine, dried over
Na2SO4, and evaporated in vacuum. The residue was purifed by column chromatog-
raphy using petroleum ether/ethyl acetate (14:1, v/v) as the eluent to give 5 (1.5 g,
50% yield).
1H NMR (400 MHz, CDCl3): δ 5.17 (t, J=1.8 Hz, 2H), 5.13–5.06 (m, 1H),
4.86 (t, J=1.7 Hz, 2H), 4.73 (t, J=1.8 Hz, 2H), 4.48 (t, J=1.7 Hz, 2H), 1.27 (d,
J=6.2 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 168.5, 79.1, 76.5, 75.0, 74.7, 74.0,
71.4, 67.7, 22.1; HRMS (ESI, m/z): Calcd. for C14H15BrO2Ru [M+H]+ 396.9371
found, 396.9361.
1‑bromo‑1′‑carboxy ruthenocene (6)
5 (1.5 g, 3.8 mmol) and NaOH (4.2 g, 76.7 mmol) were stirred at refux temperature
in mixed solvents of EtOH (140 mL) and H2O (14 mL). After TLC indicated 5 had
been consumed, the reaction was evaporated to dryness. The crude obtained was
dissolved in H2O (200 mL) and washed with Et2O (15 mL×3). The aqueous layer
was acidifed with aq. HCl solution (1 M) to pH=2. After fltration and drying in
vacuo, 1-bromo-1′-carboxy ruthenocene (6) was obtained (1.3 g, 97% yield).
1H NMR (400 MHz, DMSO-d6): δ 12.21 (brs, 1H), 5.08 (t, J=1.8 Hz, 2H),
4.99 (t, J=1.7 Hz, 2H), 4.81 (t, J=1.8 Hz, 2H), 4.60 (t, J=1.7 Hz, 2H); 13C NMR
(100 MHz, DMSO-d6): δ 169.1, 79.1, 76.0, 74.8, 74.1, 73.7, 71.4; HRMS (ESI,
m/z): Calcd. for C11H9BrO2Ru [M-H]− 352.8755 found, 352.8752.
1‑bromo‑1′‑[tert‑butyloxazolin‑2‑yl] ruthenocene (7)
To a solution of 6 (0.7 g, 2.0 mmol) in DCM (50 mL) was added oxalyl chloride
(0.64 mL, 7.9 mmol) and pyridine (0.1 mL) at 0 °C. The mixture was heated at
refux for 5 h and then evaporated to dryness. The residue was washed with Et2O
(15 mL×3), and the solvent was evaporated in vacuo. The resulting crude product
was used directly in the next step without another further purifcation. To a solu-
tion of (S)-tert-leucinol (255.5 mg, 2.2 mmol) and DIPEA (N,N-diisopropylethyl-
amine, 1.0 mL, 6.0 mmol) in DCM (dichloromethane, 20 mL) was added dropwise
the solution of the above 1-bromo-1′-chlorocarbonyl ruthenocene in DCM (20 mL)
at 0 °C. The reaction mixture was stirred at room temperature overnight. To this
solution was added dropwise MsCl (methanesulfonyl chloride, 0.25 mL, 3.2 mmol)
and DIPEA (1.3 mL, 8.0 mmol) at 0 °C, and then the solution was stirred at room
temperature for another 4 h. The reaction mixture was washed with water and brine
and dried over anhydrous Na2SO4. The solvent was removed under reduced pres-
sure, and the residue was purifed by column chromatography using petroleum ether/
ethyl acetate (6:1, v/v) as the eluent to aford 7 as a yellow green solid (0.39 g, 58%
yield for three steps).
1 3

The design and synthesis of a novel chiral 1,1′-disubsitituted…
1H NMR (400 MHz, CDCl3): δ 5.20–5.16 (m, 2H), 4.88–4.87 (m, 2H), 4.72–4.69
(m, 2H), 4.47 (t, J=1.8 Hz, 2H), 4.21 (dd, J=8.6, 10.0 Hz, 1H), 4.11 (dd, J=7.2,
8.6 Hz, 1H), 3.88 (dd, J=7.2, 10.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 164.5,
76.0, 74.6, 74.44, 74.41, 74.39, 73.3, 73.1, 71.29, 71.27, 68.6, 58.6, 34.0, 26.1, 18.6;
HRMS (ESI, m/z): Calcd. for C17H20BrNORu [M+H]+ 435.9844 found, 435.9841.
1‑[tert‑butyloxazolin‑2‑yl]‑2‑diphenylphosphino ruthenocene (8) [40]
To a solution of 7 (0.5 g, 1.14 mmol) in THF (20 mL) was added dropwise n-butyl-
lithium (2.5 M in n-hexane, 0.78 mL, 1.95 mmol) at−78 °C. The reaction mix-
ture was stirred for an additional 0.5 h and then trapped with ClPPh2 (chlorodi-
phenylphosphine, 0.42 mL, 2.25 mmol) at this temperature. After stirring at room
temperature overnight, TLC indicated that most of the raw material 7 was still pre-
sent. After evaporation, the residue was purifed by column chromatography using
petroleum ether/ethyl acetate (8:1, v/v) as the eluent to aford unexpected product 8
(70 mg, 11% yield).
1H NMR (CDCl3, 400 Hz): δ 7.27–7.38 (m, 10H), 5.28 (brs, 1H), 4.66 (brs, 1H),
4.59 (s, 5H), 4.10 (dd, J=8.4, 10 Hz, 1H), 3.95 (brs, 1H), 3.85 (dd, J=7.6, 8.4 Hz,
1H), 3.69 (dd, J=7.2, 10 Hz, 1H), 0.77 (s, 9H).
1‑bromo‑1′‑diphenylphosphino ruthenocene
To a solution of 4 (0.25 g, 0.6 mmol) in THF (25 mL) was added dropwise n-butyl-
lithium (2.5 M in n-hexane, 0.3 mL, 0.6 mmol) at−78 °C. After stirring for 0.5 h,
ClPPh2 (0.13 mL, 0.7 mmol) was slowly added to the solution at−78 °C. The reac-
tion mixture was warmed to room temperature and stirred overnight. The solvent
was removed under reduced pressure, and the residue was purifed by column chro-
matography using petroleum ether/ethyl acetate (6:1, v/v) as the eluent to aford a
yellow green solid (154 mg, 48.5% yield).
1H NMR (CDCl3, 400 Hz): δ 7.40–7.35 (m, 4H), 7.34–7.30 (m, 6H), 4.75 (dd,
J=1.5, 1.7 Hz, 4H), 4.54 (q, J=1.7 Hz, 2H), 4.33 (t, J=1.7 Hz, 2H); 13C NMR
(CDCl3, 100 Hz): δ 133.8 (d, Jpc =9.7 Hz), 133.2 (d, Jpc =19.1 Hz), 128.3, 128.0
(d, Jpc =6.7 Hz), 82.0 (d, Jpc =10.9 Hz), 76.7 (d, Jpc =31.8 Hz), 75.9, 75.3 (d,
Jpc =3.4 Hz), 74.1, 71.2; 31P NMR (CDCl3, 162 Hz): δ -17.43; HRMS (ESI, m/z):
Calcd. for C22H18BrPRu [M+H]+ 494.9447 found, 494.9445.
Sodium carbomethoxycyclopentadienide (9) [56]
To a slurry of sodium (1.15 g, 50 mmol) in THF (60 mL) was added freshly cracked
cyclopentadiene (10.3 mL, 125 mmol) at 0 °C. The mixture was magnetically stirred
until the sodium was consumed. To the resulting pink solution of sodium cyclopen-
tadienide was added dimethyl carbonate (13.1 mL, 155 mmol). The reaction mixture
was stirred at room temperature for 10 min and subsequently heated at refux for 4 h.
The solvent was removed under reduced pressure, and the residue was washed with
1 3

J. Ye et al.
Et2O (20 mL×3) until the fltrate was clear and dried to aford 9 as a cream-colored
solid (6.83 g, 93% yield).
1H NMR (400 MHz, acetone-d6): δ 6.31 (t, J=2.8 Hz, 2H), 5.69 (t, J=2.8 Hz,
2H), 3.52 (s, 3H); 13C NMR (100 MHz, CD3COCD3): δ 168.4, 112.3, 110.1, 109.0,
49.2.
[(η5‑C5H4COOMe)Ru(η6‑C6H6)]PF6 (10) [57]
The synthesis of 10 was accomplished following the previously published proce-
dure with slight modifcations. To a solution of benzeneruthenium (II) chloride
dimer (3 g, 6 mmol) in acetonitrile (300 mL) was added the solution of 9 (2.1 g,
14.4 mmol) in THF (20 mL) at room temperature. The reaction mixture was heated
at refux and stirred for 18 h. The resulting suspension was fltered through celite,
and the solvent was evaporated in vacuo. The residue was dissolved in water fol-
lowed by the addition of KPF6. The resulting of-white precipitate was collected by
fltration, washed with water, and dried under a high vacuum (12.3 g, 76% yield).
1H NMR (400 MHz, CD3CN): δ 6.16 (s, 6H), 5.79–5.78 (m, 2H), 5.46–5.45 (m,
2H), 3.81 (s, 3H); 13C NMR (100 MHz, CD3CN) δ: 166.1, 88.3, 86.3, 83.1, 81.7,
53.5.
[(η5‑C5H4COOMe)Ru(CH3CN)3]PF6 (11)
A 250-mL fask was charged with 10 (2.32 g, 5.2 mmol), and degassed acetonitrile
(150 mL) was added. The reaction mixture was irradiated with a medium-pressure
mercury lamp for 12 h. Evaporation of the solvent yielded 11 (2.5 g, 98%, NMR
yield) as a black green solid. The product was directly used in the next step without
any further purifcation.
[boranatodiphenylphosphino]cyclopentadiene (13)
To a solution of freshly cracked cyclopentadiene (1.66 mL, 20 mmol) in Et2O
(20 mL) was added dropwise n-butyllithium (2.5 M in n-hexane, 8.8 mL, 22 mmol)
at−78 °C. After stirring for 3 h, ClPPh2 (4.13 mL, 23 mmol) was added to the
solution at−78 °C. The reaction mixture was warmed to room temperature and
stirred overnight. To the above solution was added slowly BH3·THF (1 M, 24 mL,
24 mmol) at−78 °C and stirred for 2 h at this temperature. The reaction mixture
was quenched by 1 N HCl, diluted with ethyl acetate (30 mL), and washed with
water and then with brine. The organic layer was dried over anhydrous Na2SO4 and
removed under reduced pressure. The residue was purifed by column chromatog-
raphy using petroleum ether/ethyl acetate (10:1, v/v) as the eluent to aford 12 as a
white solid (4.3 g, 81% yield).
1H NMR (400 MHz, CDCl3): δ 7.65–7.58 (m, 4H), 7.51–7.40 (m, 6H), 6.96–6.91
(m, 1H), 6.89–6.80 (m, 1H), 6.62–6.58 (m, 1H), 3.23 (s, 2H), 1.41–0.77 (m, 3H);
13C NMR (100 MHz, CDCl3): δ 147.0 (d, JPC =8.8 Hz), 141.1 (d, JPC =6.3 Hz),
134.2 (d, JPC =64.4 Hz), 132.7 (d, JPC =9.8 Hz), 132.4 (d, JPC =13.2 Hz), 131.2
1 3

The design and synthesis of a novel chiral 1,1′-disubsitituted…
(d, JPC =2.4 Hz), 129.8 (d, JPC =59.0 Hz), 128.7 (d, JPC =10.2 Hz), 44.2 (d,
JPC =11.4 Hz); 31P NMR (162 MHz, CDCl3): δ 10.83 (d, JPB =75.9 Hz); HRMS
(ESI, m/z): Calcd. for C17H18BP [M+Na]+ 287.1135 found, 287.1134.
1‑methoxycarbonyl‑1′‑boranatodiphenylphosphino ruthenocene (14)
To a solution of 13 (2.83 g, 10.72 mmol) in THF (50 mL) was added dropwise
n-butyllithium (2.5 M in n-hexane, 4.5 mL, 11.17 mmol) at 0 °C, and the solution
was stirred for 3 h at this temperature. The above solution was slowly added to the
solution of 11 in THF (200 mL) at 0 °C. After stirring overnight at this temperature,
the reaction mixture was quenched by the addition of water. The organic solvent
was evaporated in vacuo, and the residue was diluted with DCM. The organic layer
was washed with brine and dried over anhydrous Na2SO4. The residue was purifed
by column chromatography using petroleum ether/dichloromethane (1:1, v/v) as the
eluent to aford 14 as a slight orange solid (3.13 g, 72% yield).
1H NMR (400 MHz, CDCl3): δ 7.61–7.56 (m, 4H), 7.50–7.45 (m, 2H), 7.44–7.39
(m, 4H), 5.04 (t, J=2.0 Hz, 2H), 4.84–4.83 (m, 2H), 4.78 (q, J=1.7 Hz, 2H), 4.63
(t, J=2.0 Hz, 2H), 3.65 (s, 3H), 1.24–0.67 (m, 3H); 13C NMR (100 MHz, CDCl3):
δ 170.0, 132.8 (d, JPC =9.7 Hz), 131.2 (d, JPC =2.6 Hz), 130.9 (d, JPC =59.1 Hz),
128.6 (d, JPC =10.0 Hz), 77.4, 76.2 (d, JPC =10.5 Hz), 75.8, 75.5 (d, JPC =6.9 Hz),
75.4 (d, JPC =64.7 Hz), 73.8, 51.8; 31P NMR (162 MHz, CDCl3) δ: 15.90 (d,
JPB =77.3 Hz); HRMS (ESI, m/z): Calcd. for C24H24BO2PRu [M+Na]+ 511.0554
found, 511.0554.
1‑carboxy‑1′‑boranatodiphenylphosphino ruthenocene (15)
A solution of 14 (2.2 g, 4.51 mmol) and NaOH (1.8 g, 45.1 mmol) in a mixed sol-
vent system of THF, MeOH, and H2O (30 mL, 30 mL and 30 mL, respectively)
was stirred at room temperature. After TLC indicated 14 had been consumed, the
reaction was evaporated to dryness. The obtained crude product was dissolved in
H2O (300 mL) and washed with Et2O (30 mL×3). The aqueous layer was acidifed
with aq. HCl solution (1 M) to pH=2. After fltration and drying in vacuo, 15 was
obtained as a slight yellow solid (2.07 g, 97% yield).
1H NMR (400 MHz, DMSO-d6): δ 12.24 (brs, 1H), 7.59–7.50 (m, 10H),
4.94–4.92 (m, 2H), 4.88 (t, J=1.8 Hz, 2H), 4.82 (q, J=1.7 Hz, 2H), 4.48 (t,
J=1.8 Hz, 2H), 1.28–0.65 (m, 3H); 13C NMR (100 MHz, DMSO-d6): δ 169.7,
132.2 (d, JPC =9.6 Hz), 131.3 (d, JPC =2.4 Hz), 130.4 (d, JPC =58.8 Hz), 128.7 (d,
JPC =10.1 Hz), 78.1, 75.63 (d, JPC =22.4 Hz), 75.61 (d, JPC =4.8 Hz), 75.1, 74.3 (d,
JPC =64.8 Hz), 73.4; 31P NMR (162 MHz, DMSO-d6): δ 14.60; HRMS (ESI, m/z):
Calcd. for C23H22BO2PRu [M-H]− 473.0432 found, 473.0428.
Amide intermediate (16)
A mixture of 15 (1.5 g, 3.17 mmol), EDCI [1-(3-dimethylaminopropyl)-3-ethylcar-
bodiimide hydrochloride, 1.34 g, 6.97 mmol], and HOBt (N-hydroxybenzotriazole,
1 3

J. Ye et al.
0.64 g, 4.76 mmol) was dissolved in DMF (50 mL). DIPEA (1.1 mL, 6.66 mmol)
was added to this mixture, and the reaction was stirred at room temperature for
0.5 h. To this solution was added (S)-tert-leucinol (0.46 g, 3.96 mmol) at room tem-
perature. The reaction mixture was stirred overnight at room temperature. After the
solvent was removed in vacuo, the residue was dissolved in DCM (150 mL), washed
with water (150 mL) and brine (150 mL), and dried over anhydrous Na2SO4. The
solvent was removed under reduced pressure, and the residue was purifed by col-
umn chromatography using petroleum ether/ethyl acetate (4:1, v/v) as the eluent to
aford 16 as a yellow green solid (1.6 g, 88% yield).
1H NMR (400 MHz, CDCl3): δ 7.63–7.54 (m, 4H), 7.51–7.39 (m, 6H), 6.23
(d, J=9.4 Hz, 1H), 5.13–5.11 (m, 2H), 4.96–4.94 (m, 1H), 4.89–4.87 (m, 1H),
4.85–4.83 (m, 1H), 4.52–4.50 (m, 2H), 4.38–4.36 (m, 1H), 3.96–3.86 (m, 2H), 3.65
(dd, J=11.1, 8.6 Hz, 1H), 1.68 (s, 1H), 1.58–1.03 (m, 3H), 0.98 (s, 9H); 13C NMR
(100 MHz, CDCl3): δ 169.7, 132.8 (dd, JPC =20.0, 9.6 Hz), 131.4 (d, JPC =2.4 Hz),
131.3 (d, JPC =2.4 Hz), 128.7 (t, JPC =10.3 Hz), 82.6, 77.7 (d, JPC =13.3 Hz), 75.6
(dd, JPC =9.4, 7.6 Hz), 75.2 (d, JPC =6.4 Hz), 74.4 (d, JPC =2.7 Hz), 73.7, 72.6,
63.2, 59.9, 33.9, 27.3; 31P NMR (162 MHz, CDCl3) δ: 15.58; HRMS (ESI, m/z):
Calcd. for C29H35BNO2PRu [M+Na]+ 596.1447 found, 596.1456.
1‑tert‑butyloxazolinyl‑1′‑boranatodiphenylphosphino ruthenocene (17)
To a solution of 16 (1.35 g, 2.36 mmol) in DCM (50 mL) was added DIPEA
(1.17 mL, 7.08 mmol) and MsCl (0.28 mL, 3.54 mmol) at 0 °C. The reaction mix-
ture was warmed to room temperature and stirred until TLC indicated 16 had been
consumed. After evaporation, the residue was purifed by column chromatography
using petroleum ether/ethyl acetate (8:1, v/v) as the eluent to aford 17 as a yellow
green solid (1.18 g, 90% yield).
1H NMR (400 MHz, CDCl3): δ 7.62–7.57 (m, 4H), 7.49–7.44 (m, 2H), 7.43–7.38
(m, 2H), 5.05–5.04 (m, 1H), 4.99–4.98 (m, 1H), 4.81–4.79 (m, 2H), 4.78–4.74 (m,
2H), 4.59–4.56 (m, 2H), 4.09 (dd, J=10.0, 8.6 Hz, 1H), 4.01 (dd, J=8.6, 7.1 Hz,
1H), 3.78 (dd, J=10.0, 7.1 Hz, 1H), 1.50–0.90 (m, 3H), 0.85 (s, 9H); 13C NMR
(100 MHz, CDCl3): δ 163.8, 132.8 (dd, JPC =9.5, 1.4 Hz), 131.12 (dd, JPC =8.4,
2.5 Hz), 131.09 (dd, JPC =58.7, 5.1 Hz), 128.6 (d, JPC =10.0 Hz), 77.4, 76.5,
76.1 (d, JPC =10.7 Hz), 75.9, 75.8 (d, JPC =10.4 Hz), 75.4 (t, JPC =6.7 Hz), 75.1
(d, JPC =1.9 Hz), 74.8 (d, JPC =65.1 Hz), 73.2, 72.9, 68.4, 34.0, 25.9; 31P NMR
(162 MHz, CDCl3) δ: 15.93 (d, JPB =58.3 Hz); HRMS (ESI, m/z): Calcd. for
C29H33BNOPRu [M+H]+ 556.1522 found, 556.1522.
1‑tert‑butyloxazolinyl‑1′‑boranatodiphenylphosphino ruthenocene (3)
A mixture of 17 (600 mg, 1.1 mmol) and DABCO (triethylenediamine, 2.42 g,
22 mmol) was dissolved in degassed dioxane (30 mL) and stirred at refux tempera-
ture overnight. After careful removal of the volatile solvent, the residue was purifed
by fash chromatography on silica gel using petroleum ether/ethyl acetate (10:1, v/v)
as the eluent to aford 3 as a yellow green solid (572 mg, 97.7% yield).
1 3

The design and synthesis of a novel chiral 1,1′-disubsitituted…
1H NMR (400 MHz, CDCl3): δ 7.39–7.33 (m, 4H), 7.33–7.30 (m, 6H), 5.05–5.03
(m, 1H), 5.00–4.98 (m, 1H), 4.72–4.70 (m, 2H), 4.52–4.47 (m, 4H), 4.14 (dd,
J=10.0, 8.6 Hz, 1H), 4.06 (dd, J=8.6, 7.1 Hz, 1H), 3.82 (dd, J=10.0, 7.1 Hz, 1H),
0.87 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 164.1, 139.1 (dd, JPC =9.8, 7.8 Hz),
133.5 (dd, JPC =19.1, 10.5 Hz), 128.6 (d, JPC =10.7 Hz), 128.2 (d, JPC =6.6 Hz),
81.6 (d, JPC =10.8 Hz), 76.5 (dd, JPC =27.6, 15.9 Hz), 75.9, 75.8, 74.4 (d, JPC =7.8,
3.4 Hz), 73.7, 72.2 (d, JPC =7.1 Hz), 68.4, 34.0, 26.0; 31P NMR (162 MHz, CDCl3):
δ -16.93; HRMS (ESI, m/z): Calcd. for C29H30NOPRu [M+H]+ 542.1189 found,
542.1187.
Results and discussion
Generally, the synthetic method for the preparation of 1,1′-disubstituted ferrocene
is realized via the introduction of active groups, such as halogen or organotin com-
pounds, to the two Cp rings (Fig. 2). Zhang and Ikeda’s group synthesized 1,1′-dis-
ubstituted ferrocene phosphine–oxazoline ligand 1 via an organotin intermediate.
First, the lithiation of ferrocene forms 1,1′-dilithiated ferrocene, which is trapped
with tributyltin chloride to generate a 1,1′-ditributyltin ferrocene intermediate. The
organotin intermediate is lithiated sequentially followed by phosphonylation with
Ph2PCl and the formation of the oxazoline ring, respectively, to provide 1 [52].
Using 1,2-dibromotetrafuoroethane instead of tributyltin chloride, Hou’s group
synthesized a halogen intermediate 1,1′-dibromoferrocene via a lithium–halogen
exchange reaction. Ferrocene phosphine–oxazoline ligand 1 was then obtained using
a similar process to that described above. Further derivation of 1 resulted in a series
of planar chiral 1,1′-phosphine-oxazoline based ligands [58–60].
Similar to the synthetic strategy of ferrocene-based ligand 1, we frst intended
to synthesize the target product 3 by introducing active groups to the two Cp rings
in ruthenocene, followed by functionalization and formation of the oxazoline ring.
Fig. 2 The synthetic strategy for 1,1′-phosphine-oxazoline 1
1 3

J. Ye et al.
Fig. 3 The retrosynthesis of 1,1′-phosphine-oxazoline ruthenocene 3
Fig. 4 The frst synthetic route to 3
Bromide was selected as the active group, and the retrosynthetic route is shown
below: The target product 3 could be obtained via two types of intermediates,
1-bromo-1′-oxazolinyl ruthenocene or 1-bromo-1′-diphenylphosphino ruthenocene,
which could be formed by functionalization of 1,1′-dibromoruthenocene (Fig. 3).
An attempt on the synthesis of 3 was frst conducted via the 1-bromo-1′-
oxazolinyl ruthenocene intermediate (Fig. 4). Using ruthenocene as the start-
ing material, n-BuLi and PMDTA were added to n-hexane, and the brominated
reagent 1,2-dibromotetetrachloroethane was added after stirring for 18 h at room
1 3

The design and synthesis of a novel chiral 1,1′-disubsitituted…
temperature. 1,1′-dibromoruthenocene (4) can be obtained in 75% yield. After
lithium–halogen exchange, 4 was treated with isopropyl chloroformate to give 5
in 50% yield. Then, 6 was obtained conveniently in 93% yield after hydrolysis
of 5 under alkaline conditions. According to our previous methods [52], the key
intermediate 1-bromo-1′-oxazolinyl ruthenocene (7) was obtained easily. Accord-
ing to the synthesis of the corresponding ferrocene ligand 1, target compound
3 could be obtained through lithium–bromide exchange of 7 followed by phos-
phonylation. However, the unexpected formation of 1,2-disubstituted ruthenocene
phosphine–oxazoline ligand 8 instead of 3 was observed in this reaction.
We speculate that the formation of the unexpected product 8 may be due to the
diferent distances between the two Cp rings of ruthenocene and ferrocene. The
complexation and induction of the oxazoline group result in the stability of the
negative ion in the 1′-position being far less stable than the anion formed in the
2-position after lithiation; this result in the negative charge is transferred to the
ortho position of the oxazoline. Changing the solvent from THF to ether gave the
same result.
In order to avoid the formation of the 1,2-substituted product due to the
induction of the oxazoline group, the alternative route shown in Fig. 3 was
chosen to introduce the diphenylphosphine group frst to give the 1-bromo-1′-
diphenylphosphino ruthenocene intermediate. This then undergoes lithium–bro-
mide exchange and esterifcation to provide the target product 3 (Fig. 5). The frst
phosphonylation proceeded smoothly. However, the subsequent esterifcation was
not successful with no reaction occurring. Extending the lithiation time, increas-
ing the temperature and changing the solvent were tried but were also unsuccess-
ful. It appears that the large steric hindrance and electron donating ability of the
diphenylphosphine group make the lithium–halogen exchange difcult.
We also attempted to use sec-BuLi or add TMEDA (N,N,N’,N’-tetramethyl-
ethylenediamine) during lithiation with the aim of improving the lithiation step.
However, debrominated products were formed with large amounts of starting
materials remaining.
The negative results concerning the introduction of groups into the rutheno-
cene ring prompted us to explore a new synthetic strategy. We envisioned a more
diferent pathway. First, derivatization of cyclopentadiene would aford two func-
tionalized cyclopentadienes which could then react with the ruthenium species in
a proper sequence to generate the key 1,1′-disubstituted ruthenocene backbone
intermediate. Finally, the target product 3 could be obtained through further con-
ventional derivatization.
Fig. 5 The second synthetic route of 3
1 3

J. Ye et al.
Thus, the reaction between sodium and cyclopentadiene in THF was carried out
followed by the addition of dimethyl carbonate. The reaction proceeded under refux
conditions, and compound 9 was obtained in more than 90% yield. Treating 9 with
benzeneruthenium(II) chloride dimer in acetonitrile under refux conditions for 18 h,
followed by addition to a saturated aqueous solution of KPF6, gave [Cp(C6H6)Ru]
PF6 (10) in 76% yield, which was used in the next step without further purifca-
tion. The dissociation of the benzene ring from the Ru atom in 10 was conducted
by irradiation using a medium-pressure mercury lamp (UV light with wavelength
of 310 nm) in acetonitrile. Then, three acetonitrile molecules combine with the Ru
atom to generate [CpRu(CH3CN)3]PF6 (11). After the solvent was evaporated in
vacuo, the brown-black powder 11 was obtained and used directly in the subsequent
reaction without further purifcation (Fig. 6).
On the other hand, cyclopentadiene was reacted with n-BuLi to generate lithium
cyclopentadiene, which was then reacted with ClPPh2 to give compound 12. With-
out additional workup, BH3·THF was added to the reaction system at−78 °C and a
relatively stable compound 13 was obtained in 82% overall yield. Then, 13 was lithi-
ated in THF and the reaction system was added to a solution of the above ruthenium
complex 11 in THF. After reaction at 0 °C overnight, the key intermediate 14 was
obtained in 72% yield (Fig. 6). The results reveal again that the method of introduc-
ing groups to the ruthenocene ring is quite diferent to that of the corresponding fer-
rocene. Although a total of 7 steps were used to obtain the key intermediate 14, the
current methodology provides a feasible and practical strategy for the synthesis of
novel ruthenocene-based ligands.
The hydrolysis of 14 was carried out using a mixed solvent system of THF-
MeOH-H2O at room temperature, providing the carboxylic acid 15. This was then
condensed with amino alcohol in the presence of EDCI and HOBt to generate the
Fig. 6 The synthetic strategy for the key intermediate 14
1 3

The design and synthesis of a novel chiral 1,1′-disubsitituted…
Fig. 7 The synthetic strategy for 1,1′-phosphine-oxazoline 3
amide intermediate 16. The formation of the oxazoline ring was realized by treat-
ing 16 with MsCl to give the ligand precursor 17 in 90% yield. Finally, the target
product 3 was obtained via the removal of borane using DABCO in near quantitative
yield (Fig. 7).
Conclusion
In conclusion, we have developed a novel chiral ruthenocene-based 1,1′-phos-
phine–oxazoline ligand 3 based on careful design and experimental exploration.
First, a key intermediate 1-ester-1′-boranediphenylphosphine ruthenocene was
obtained by using cyclopentadiene as a starting material, followed by functionali-
zation and metallocene-forming steps. Next, the formation of the oxazoline ring
was realized according to our previous method. Finally, 1,1′-disubstituted ruthe-
nocene phosphine–oxazoline ligand 3 was obtained conveniently after the removal
of borane. The experimental results indicate that the synthesis of 1,1′-disubstituted
ruthenocene phosphine–oxazoline ligands is, to a great extent, diferent from the
corresponding ferrocene ligands. The work provides crucial guidance and assis-
tance for the synthesis of novel chiral ruthenocene-based ligands, especially for fur-
ther derivatization to synthesize a broader array of planar chiral ruthenocene-based
ligands.
Acknowledgements This work was supported by National Natural Science Foundation of China
(No. 21672142, 21971162, 21831005, and 21620102003) and Shanghai Municipal Education Com-
mission (No. 201701070002E00030). We also thank the Instrumental Analysis Center of SJTU for
characterization.
1 3

J. Ye et al.
References
1. N.A. Butt, D. Liu, W. Zhang, Synlett 25, 615 (2014)
2. Z. Zhang, N.A. Butt, W. Zhang, Chem. Rev. 116, 14769 (2016)
3. J.-H. Xie, D.-H. Bao, Q.-L. Zhou, Synthesis 47, 460 (2015)
4. T.G. Saint-Denis, R.-Y. Zhu, G. Chen, Q.-F. Wu, J.-Q. Yu, Science 359, 759 (2018)
5. M.A. Divakar, S. Shanmugam, Res. Chem. Intermed. 43, 6863 (2017)
6. M.J. Nasab, A.R. Kiasat, Res. Chem. Intermed. 44, 2719 (2018)
7. Y. Wang, G. Yang, F. Xie, W. Zhang, Org. Lett. 20, 6135 (2018)
8. Á. Pálvölgyi, Z. Rapi, O. Ozohanics, G. Tóth, G. Keglevich, P. Bako, Res. Chem. Intermed. 44,
1627 (2018)
9. F.Z. Belkacemi, M. Merabet-Khelassi, L. Aribi-Zouioueche, O. Riant, Res. Chem. Intermed. 44,
6847 (2018)
10. M. Kooti, F. Kooshki, E. Nasiri, Res. Chem. Intermed. 45, 2641 (2019)
11. J. Chen, N.A. Butt, W. Zhang, Res. Chem. Intermed. 45, 5959 (2019)
12. K. Yao, Q. Yuan, X. Qu, Y. Liu, D. Liu, W. Zhang, Chem. Sci. 10, 1767 (2019)
13. K.O. Aghbash, N.N. Pesyan, E. Şahin, Res. Chem. Intermed. 45, 2079 (2019)
14. C. Mei, Y. Zhao, K. Zou, C. Cao, G. Pang, Y. Shi, Res. Chem. Intermed. 44, 2179 (2018)
15. H. Liu, Z. Sun, K. Xu, Y. Zheng, D. Liu, W. Zhang, Org. Lett. 22, 4980 (2020)
16. M.D. Prabhakara, B. Maiti, Res. Chem. Intermed. 46, 2381 (2020)
17. L.-X. Dai, X.-L. Hou, Eds., VCH: Weinheim, Germany, 2010 Chapter 14, pp 175–214
18. Y. Wang, A. Zhang, L. Liu, J. Kang, F. Zhang, W. Ma, Chin. J. Org. Chem. 35, 1399 (2015)
19. J. Huang, Q. Gu, S. You, Chin. J. Org. Chem. 38, 51 (2018)
20. K. Yoshida, R. Yasue, Chem. Eur. J. 24, 18575 (2018)
21. X.-H. Yan, P. Xue, Res. Chem. Intermed. 44, 4295 (2018)
22. M. Merabet-Khelassi, L. Aribi-Zouioueche, O. Riant, Res. Chem. Intermed. 43, 5293 (2018)
23. K.O. Aghbash, N.N. Pesyan, G. Marandi, N. Dege, E. Şahin, Res. Chem. Intermed. 45, 4543 (2019)
24. R. Yuan, M.-Q. Li, X.-X. Ren, W. Chen, H. Zhou, Y. Wan, P. Zhang, H. Wu, Res. Chem. Intermed.
46, 2275 (2020)
25. E.P. Kundig, A. Quattropan, M. Inage, A. Ripa, C. Duprue, A.F. Cunningham Jr., B. Bourdin, Pure
Appl. Chem. 68, 97 (1996)
26. C. Bolm, K. Muniz, Chem. Soc. Rev. 28, 51 (1999)
27. C.A. Merlic, M.M. Miller, Organometallics 20, 373 (2001)
28. P.J. Pye, K. Rossen, R.A. Reamer, N.N. Tsou, R.P. Volane, P.J. Reider, J. Am. Chem. Soc. 119, 6207
(1997)
29. T. Sammakia, H.A. Latham, D.R. Schaad, J. Org. Chem. 60, 10 (1995)
30. X. Doua, T. Hahashi, Adv. Synth. Catal. 358, 1054 (2016)
31. H.U. Blaser, F. Spindler, Chimia 51, 297 (1997)
32. R. Imwinkelried, A.G. Lonza, S. Visp, Chimia 51, 300 (1997)
33. E.N. Jacobsen, A. Pfaltz, H. Yamamoto, Comprehensive asymmetric catalysis [M] (Springer, New
York, 1999)
34. J. Dunirz, L. Orgel, A. Rich, Acta Crystallogr. 9, 373 (1956)
35. G. Hardgrove, D. Templeton, Acta Crystallogr. 12, 28 (1959)
36. B. Wbi, S. Li, H.K. Lee, T.S.A. Hor, J. Organomet. Chem. 527, 133 (1997)
37. N.A. Butt, W. Zhang, Chem. Soc. Rev. 44, 7929 (2015)
38. J. Fu, X. Huo, B. Li, W. Zhang, Org. Biomol. Chem. 15, 9747 (2017)
39. D. Liu, F. Xie, W. Zhang, Tetrahedron Lett. 48, 7591 (2007)
40. D. Liu, F. Xie, W. Zhang, Tetrahedron Lett. 48, 585 (2007)
41. D. Liu, F. Xie, W. Zhang, Tetrahedron Lett. 49, 1012 (2008)
42. X. Zhao, D. Liu, F. Xie, W. Zhang, Tetrahedron 65, 512 (2009)
43. X. Zhao, D. Liu, Y. Liu, W. Zhang, Org. Biomol. Chem. 9, 1871 (2011)
44. J. Wang, D. Liu, Y. Liu, W. Zhang, Org. Biomol. Chem. 11, 3855 (2013)
45. J. Wang, Y. Wang, D. Liu, W. Zhang, Adv. Synth. Catal. 357, 3262 (2015)
46. Q. An, D. Liu, J. Shen, Y. Liu, W. Zhang, Org. Lett. 19, 238 (2017)
47. X. Huo, R. He, J. Fu, J. Zhang, G. Yang, W. Zhang, J. Am. Chem. Soc. 139, 9819 (2017)
48. Y. Ma, J. Li, J. Ye, D. Liu, W. Zhang, Chem. Commun. 54, 13571 (2018)
49. K. Yao, H. Liu, Q. Yuan, Y. Liu, D. Liu, W. Zhang, Acta Chim. Sinica 77, 993 (2019)
1 3

The design and synthesis of a novel chiral 1,1′-disubsitituted…
50. K. Xu, H. Liu, Y. Hou, J. Shen, D. Liu, W. Zhang, Chem. Commun. 55, 13295 (2019)
51. K. Xu, J. Ye, H. Liu, J. Shen, D. Liu, W. Zhang, Adv. Synth. Catal. 362, 2059 (2020)
52. W. Zhang, Y.-I. Yoneda, T. Kida, Y. Nakatsuji, I. Ikeda, Tetrahedron Asymmetry 9, 3371 (1998)
53. S.-L. You, X.-Z. Zhu, Y.-M. Luo, X.-L. Hou, L.-X. Dai, J. Am. Chem. Soc. 123, 7471 (2001)
54. Y. Habata, S. Akabori, M. Sato, Bull. Chem. Soc. Jpn. 58, 3540 (1985)
55. S. Dey, J.W. Quail, J. Müller, Organometallics 34, 3039 (2015)
56. W.P. Hart, D. Shihua, M.D. Rausch, J. Organomet. Chem. 282, 111 (1985)
57. G.E. Atilla-Gokcumen, D.S. Williams, H. Bregman, N. Pagano, E. Meggers, ChemBioChem 7,
1443 (2006)
58. W.-P. Deng, X.-L. Hou, L.-X. Dai, X.-W. Dong, Chem. Commun. 16, 1483 (2000)
59. W.-P. Deng, X.-L. Hou, L.-X. Dai, Y.-H. Yu, W. Xia, Chem. Commun. 4, 285 (2000)
60. W.-P. Deng, S.-L. You, X.-L. Hou, L.-X. Dai, Y.-H. Yu, W. Xia, J. Sun, J. Am. Chem. Soc. 123,
6508 (2001)
Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published
maps and institutional afliations.
1 3