Modular bisphosphine ligands: Preparation and application in enantioselective catalytic reactions

Article abstract of DOI:10.1016/j.jorganchem.2017.05.059

A set of six chiral modular C₂-symmetric bisphosphine ligands have been synthesized in a straightforward manner through a two-step reaction from the corresponding diols with moderate yields. The applicability of these chiral ligands was evaluated in ruthenium(II)-catalyzed transfer hydrogenation reactions (up to >99% conversion) and palladium(0)-catalyzed enantioselective allylic substitution reactions (up to 70% chemical yield and 43% ee).

Full text of DOI:10.1016/j.jorganchem.2017.05.059

Accepted Manuscript
Modular bisphosphine ligands: Preparation and application in enantioselective
catalytic reactions
Yaşar Gök, İlker Ümit Karayiğit, Halil Zeki Gök
PII:
S0022-328X(17)30374-1
10.1016/j.jorganchem.2017.05.059
JOM 19985
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 14 May 2017
Revised Date: 27 May 2017
Accepted Date: 27 May 2017
Please cite this article as: Yaş. Gök, İ.Ü. Karayiğit, H.Z. Gök, Modular bisphosphine ligands: Preparation
and application in enantioselective catalytic reactions, Journal of Organometallic Chemistry (2017), doi:
10.1016/j.jorganchem.2017.05.059.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Modular bisphosphine ligands: Preparation and application in
enantioselective catalytic reactions
Yaşar Gök, İlker Ümit Karayiğit, Halil Zeki Gök
Department of Chemistry, Faculty of Arts and Sciences, Osmaniye Korkut Ata University, 80000 Osmaniye, Turkey
Abstract
A set of six chiral modular C2-symmetric bisphosphine ligands have been synthesized in a
straightforward manner through a two-step reaction from the corresponding diols with moderate
yields. The applicability of these chiral ligands was evaluated in ruthenium(II)-catalyzed transfer
hydrogenation reactions (up to >99% conversion) and palladium(0)-catalyzed enantioselective
allylic substitution reactions (up to 70% chemical yield and 43% ee).
Keywords: Bisphosphine; C2-symmetric; Enantioselective; Allylic alkylation; Transfer
hydrogenation
1. Introduction
In the past decades, chiral C2-symmetric bidentate phosphorous ligands have received
considerable attention in asymmetric transition metal catalysis due to their great success in a wide
range of catalytic reactions [1-4]. Although, numerous chiral phosphine ligands have been
Corresponding author. Tel.: + 90 (328)-827 1000-3027; fax: +90 (328)-825 0097; e-mail: halilzekigok@gmail.com,
Department of Chemistry, Faculty of Arts and Sciences, Osmaniye Korkut Ata University, 80000, Osmaniye, Turkey
1

ACCEPTED MANUSCRIPT
significantly developed, it is still strongly required suitable electronic and steric needs of an
appropriate ligand for the success of an enantioselective transition metal-catalyzed reaction.
Given the complexity of most catalytic processes, the rational design of a chiral ligand is seldom
straightforward. For this reason, we introduce a modular C2-symmetric ligand structure, which
allows rapid diversification, shown in Figure 1. Variation of the bulkiness of the R substituents at
the backbone allows us to determine the optimal transfer of chirality from the backbone to the
reaction center. The electronic and steric properties of the chelating atoms can also be tuned [5-
7].
Herein we describe a series of chiral C2-symmetric bisphosphine ligands by using
corresponding chiral bromo-substituted hydrobenzoin derivatives which have been reported by
our group [8,9] (Fig. 2). These synthesized ligands have been evaluated and compared in
different types of catalytic reactions. The first one is palladium(0)-catalyzed enantioselective
allylic alkylation which provides a very efficient route for enantioselective C-C and C-
heteroatom bonds formation [10-16]. The second one is ruthenium(II)-catalyzed transfer
hydrogenation reaction that leads secondary alcohols from the reduction of prochiral ketones
which are key compounds for both academic and industrial areas [17-24].
2. Experimental
2.1. Materials and Equipment
All reagents were purchased and used without purification, unless otherwise noted.
Compounds
(1R,2R)-1,2-bis(2′-bromophenyl)-ethane-1,2-diol
10,
(1R,2R)-1,2-bis(3′-
bromophenyl)-ethane-1,2-diol 11 and (1R,2R)-1,2-bis(4′-bromophenyl)-ethane-1,2-diol 12 were
synthesized according to previously described procedures [8,9]. Analytical TLC was performed
2

using Macherey-Nagel SIAL GC-2C5 UEVP25T4EplDatesM. FlaAshNchUromSaCtogRraIpPhyTwas carried out with Rocc
1
13
31
silica gel (0.040–0.063 mm). H, C and P NMR spectra were recorded on a Varian Mercury
400 MHz spectrometer as indicated, with chemical shifts reported in ppm relative to TMS (for
13
31
1H and C), and relative to 85% aqueous phosphoric acid (for P), using the residual solvent
signal as a standard.13C NMR spectra were recorded using the attached proton test. IR-spectra
were recorded on a Perkin-Elmer Spectrum 65 FT-IR spectrometer. Analytical chiral HPLC
separations were performed on a Shimadzu Prominence LC-20A with DAD detection. GC
separations were performed on Shimadzu GC-2010 Plus. Optical rotations were measured with a
Rudolph Autopol-I series polarimeter. Mass spectra were an Agilent LC-MS/MS 6460 Triple
Quadrupole spectrometer. Elemental analyses were obtained with a LECO Elemental Analyzer
(CHNS 0932). Melting points were measured with a Thermo Scientific 9200 melting point
apparatus.
2.2. Synthesis
2.2.1. (1R,2R)-1,2-bis(2′-bromophenyl)-1,2-dimethoxyethane (10)[25]
(1R,2R)-1,2-bis(2′-bromophenyl)-ethane-1,2-diol 7 (2.0 g, 5.3 mmol) in THF was added
dropwise through a dropping funnel to a stirred solution of NaH (1.27 g, 26.5 mmol) in THF (40
mL) at 0 °C over a 0.5 h period. The resulting reaction mixture was stirred at 0 °C for an
additional 10 min. At the end of this period, the mixture was allowed to warm to room
temperature and CH3I (2.62 g, 18.5 mmol) was added. After addition was complete, the reaction
mixture was stirred for another 24 h at room temperature. The reaction was monitored by thin
layer chromatography using hexane - ethyl acetate (8:2) as the solvent system. Next, EtOAc (100
ml) was added and the organic phase was separated, whereupon the aqueous phase was further
3

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extracted with EtOAc (2 x 50 ml). The organic layer was dried over anhydrous Na2SO4 and the
solvent was evaporated under reduced pressure to give the desired product as a white solid (2.14
g, 99%). mp: 66-68 °C. [ꢀ]ꢂꢁꢃ =-59,94 (c= 1 (g/100 ml), CHCl3); retention time 8.47 min, Chiral
ART Amylose-C, 90:10 n-hexane-iPrOH, flow rate of 0.5 ml/min, 254 nm, t = 40 °C; IR (KBr
disc) νmax/cm-1: 3063, 2926, 2856, 2825, 1590, 1465, 1438, 1355, 1204, 1093, 1024, 747, 681. 1H
NMR (400 MHz, CDCl3, ppm) δ: 7.66 (dd J = 8.0 Hz, J = 1.7 Hz, 2H), 7.41 (dd J = 8.0 Hz, J =
1.0 Hz, 2H), 7.32 (dt J = 7.5 Hz, J = 1.0 Hz, 2H), 7.1 (dt J = 7.5 Hz, J = 1.7 Hz, 2H), 4.95 (s,
2H), 3.19 (s, 6H); 13C NMR (101 MHz, CDCl3, ppm) δ: 137.3, 132.4, 130.6, 129.3, 127.2, 124.1,
83.8, 77.3, 76.7, 57.4; MS (ES+) MS calculated [M+Na]+ for C16H16Br2O2Na: 422.1 found: 422.1.
2.2.2. (1R,2R)-1,2-bis(3′-bromophenyl)-1,2-dimethoxyethane (11)
Synthesis of 11 was performed by following the procedure for 10 by using (1R,2R)-1,2-
bis(3′-bromophenyl)-ethane-1,2-diol 8 (2.0 g, 5.3 mmol), NaH (1.27 g, 26.5 mmol) and CH3I
(2.62 g, 18.5 mmol). Yield: 2.11 g, 99%; mp: 59-60 °C. [ꢀ]ꢂꢁꢃ =-119,87 (c= 1 (g/100 ml),
CHCl3); retention time 7.51 min, Chiral ART Amylose-C, 90:10 n-hexane-iPrOH, flow rate of
0.5 ml/min, 254 nm, t = 40 °C; Anal. calcd for C16H16Br2O2: C, 48.03; H, 4.03%. Found: C,
48.12; H, 4.17%. IR (KBr disc) νmax/cm-1: 3062, 2925, 1570, 1468, 1424, 1348, 1187, 1110, 997,
1
787, 747, 692; H NMR (400 MHz, CDCl3, ppm) δ: 7.35 (d, J = 8.0 Hz, 2H), 7.21 (s, 2H), 7.07
13
(t, J = 7.5 Hz, 2H), 6.9 (d, J = 8.0 Hz, 2H), 4.25 (s, 2H), 3.27 (s, 6H); C NMR (101 MHz,
CDCl3, ppm) δ: 140.4, 131.0, 130.7, 129.4, 126.5, 122.2, 86.5, 57.5; MS (ES+) MS calculated
[M+Na]+ for C16H16Br2O2Na: 422.1 found: 422.1.
2.2.3. (1R,2R)-1,2-bis(4′-bromophenyl)-1,2-dimethoxyethane (12) [26]
4

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Synthesis of 12 was performed by following the procedure for 10 by using (1R,2R)-1,2-
bis(4′-bromophenyl)-ethane-1,2-diol 9 (2.0 g, 5.3 mmol), NaH (1.27 g, 26.5 mmol) and CH3I
(2.62 g, 18.5 mmol). Yield: 2.05 g, 99%; mp: 81-82 °C. [ꢀ]ꢂꢁꢃ =+59.92 (c= 1 (g/100 ml),
CHCl3); retention time 9.94 min, Chiral ART Amylose-C, 90:10 n-hexane-iPrOH, flow rate of
0.5 ml/min, 254 nm, t = 40 °C; IR (KBr disc) νmax/cm-1: 3060, 2926, 2858, 2825, 1591, 1485,
1459, 1403, 1188, 1102, 819; 1H NMR (400 MHz, CDCl3, ppm) δ: 7.33 (d, J = 8.5 Hz, 4H), 6.87
13
(d, J = 8.5 Hz, 4H), 4.25 (s, 2H), 3.25 (s, 6H); C NMR (101 MHz, CDCl3, ppm) δ: 136.9,
131.1, 129.5, 121.8, 86.5, 57.3; MS (ES+) MS calculated [M+Na]+ for C16H16Br2O2Na: 422.1
found: 422.1.
2.2.4. (1R,2R)-1,2-bis(2′-(diphenylphosphino)phenyl)-1,2-dimethoxyethane (1)[25]
A mixture of (1R,2R)-1,2-bis(2-bromophenyl)-1,2-dimethoxyethane 10 (0.55 g, 1.25 mmol) and
15 ml of dry THF were placed under a nitrogen atmosphere in a standard Schlenk tube and
cooled to -78 °C. To this solution was added BuLi (2.5 ml, 4.1 mmol) at -78 °C and stirred for 1h
at that temperature. Ph2PCl (0.59 ml, 2.9 mmol) was added dropwise to the resulting mixture.
After addition was complete, the reaction mixture was stirred for another 1 h at room
temperature. The reaction was monitored by thin layer chromatography using hexane - ethyl
acetate (9:1) as the solvent system. Evaporation in vacuo and purification by flash
chromatography over silica gel (hexane/AcOEt, 9:1) resulted in 1 as a pure white solid (0.4 g;
52%). mp: 162-164 °C. [ꢀ]ꢂꢁꢃ =-87.92 (c= 1 (g/100 ml)CHCl3); retention time 9.79 min, Chiral
ART Amylose-C, 90:10 n-hexane-iPrOH, flow rate of 0.5 ml/min, 254 nm, t = 40 °C; IR (KBr
1
disc) νmax/cm-1: 3055, 2922, 2822, 1584, 1473, 1434, 1186, 1092, 744, 697; H NMR (400 MHz,
5

ACCEPTED MANUSCRIPT
CDCl3, ppm) δ: 7.75 (m, 4H, H12,18), 7.14-7.26 (m, 16H, H10,11,13,14,16,17,19,20), 7.02 (m, 2H, H7),
13
6.81-6.87 (m, 6H, H5,6,8), 5.76 (d, J = 6.5 Hz, 2H, H2), 2.91 (s, 6H, H1); C NMR (101 MHz,
CDCl3, ppm) δ: 143.8 (dd, J = 29.3 Hz, 2.9 Hz, C3); 137.0 (dd, J = 13.2 Hz, 6.8 Hz, C9), 137.4
(dd, J = 6.6 Hz, 4.4 Hz, C15), 136.6 (dd, J = 15.4 Hz, 5.1 Hz, C4 ), 129.2 (m, C7,12,18); 128.1-128.5
31
(m, C6,8,11,13,17,19); 127.7-127.8 (m, C5,10,14,16,20), 83.1-83.4 (m, C2), 56.8 (C1); P-NMR: (162
MHz, CDCl3, ppm) δ: -19.2; MS (ES+) MS calculated [M+H]+ for C40H36O2P2: 611.3 found:
611.3.
2.2.5. (1R,2R)-1,2-bis(3′-(diphenylphosphino)phenyl)-1,2-dimethoxyethane (2)
Synthesis of 2 was performed by following the procedure for 1 by using (1R,2R)-1,2-bis(3′-
bromophenyl)-1,2-dimethoxyethane 11 (0.55 g, 1.25 mmol), BuLi (2.5 ml, 4.1 mmol) and Ph2PCl
(0.59 ml, 2.9 mmol). The crude product was purified by silica gel chromatography. The elution
was carried out with hexane-ethyl acetate (9:1). The product was obtained as a white solid. Yield:
0.3 g, 37%; mp: 48-50 °C. [ꢀ]ꢂꢁꢃ =49.95 (c= 1 (g/100 ml), CHCl3); retention time 13.95 min,
Chiral ART Amylose-C, 90:10 n-hexane-iPrOH, flow rate of 0.5 ml/min, 254 nm, t = 40 °C;
Anal. calcd for C40H36O2P2: C, 78.67; H, 5.64%. Found: C, 78.97; H, 5.88%. IR (KBr disc)
νmax/cm-1: 3053, 2982, 2929, 2821, 1584, 1475, 1433, 1186, 1097, 744, 697; 1H NMR (400 MHz,
CDCl3, ppm) δ: 7.44-7.54 (m, 4H, H12,18), 7.29-7.33 (m, 16H, H10,11,13,14,16,17,19,20), 6.92-7.11 (m,
8H, H4,6,7,8), 4.20 (s, 2H, H2), 3.18 (s, 6H, H1); 13C NMR (101 MHz, CDCl3, ppm) δ: 138.3 (d, J
= 7.3 Hz, C3), 136.8 (m, C5,9,15), 133.5-133.8 (m, C8,12,18), 132.9-133.3 (m, C4,6,10,14,16,20) 127.7-
31
128.8 (m, C7,11,13,17,19), 87.4 (C2), 57.1 (C1); P-NMR: (162 MHz, CDCl3, ppm) δ: -5.44; MS
(ES+) MS calculated [M+H]+ for C40H36O2P2: 611.3 found: 611.3.
2.2.6. (1R,2R)-1,2-bis(4′-(diphenylphosphino)phenyl)-1,2-dimethoxyethane (3)
6

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Synthesis of 3 was performed by following the procedure for 1 by using (1R,2R)-1,2-bis(4′-
bromophenyl)-1,2-dimethoxyethane 12 (0.55 g, 1.25 mmol), BuLi (2.5 ml, 4.1 mmol) and Ph2PCl
(0.59 ml, 2.9 mmol). The crude product was purified by silica gel chromatography. The elution
was carried out with hexane-ethyl acetate (9:1). The product was obtained as a white solid. Yield:
0.25 g, 32%; mp: 44-46 °C. [ꢀ]ꢂꢁꢃ =59.94 (c= 1 (g/100 ml), CHCl3); retention time 10.35 min,
Chiral ART Amylose-C, 90:10 n-hexane-iPrOH, flow rate of 0.5 ml/min, 254 nm, t = 40 °C;
Anal. calcd for C40H36O2P2: C, 78.67; H, 5.64%. Found: C, 78.43; H, 5.59%. IR (KBr disc)
νmax/cm-1: 3055, 2982, 2929, 2823, 1479, 1434, 1188, 1098, 1021, 743, 696; 1H NMR (400 MHz,
CDCl3, ppm) δ: 7.40-7.58 (m, 4H, H12,18), 7.28-7.31(m, 8H, H11,13,17,19), 7.10-7.24 (m, 12H,
13
H5,7,10,14,16,20), 6.94 (dd, J = 8.5 Hz, 4H, H4,8), 4.30 (s, 2H, H2), 3.29 (s, 6H, H1); C NMR (101
MHz, CDCl3, ppm) δ: 138.94 (C3), 136.6-137.0 (m, C6,9,15), 133.0-133.8 (m, C12,18), 131.5-132.0
31
(m, C5,7,10,14,16,20), 128.7-127.4 (m, C11,13,17,19), 127.9-128.0 (m, C4,8), 87.5 (C2), 57.3 (C1); P-
NMR: (162 MHz, CDCl3, ppm) δ: -6.44; MS (ES+) MS calculated [M+H]+ for C40H36O2P2: 611.3
found: 611.3.
2.2.7. (1R,2R)-1,2-bis(2′-(dicyclohexylphosphino)phenyl)-1,2-dimethoxyethane (4)
Synthesis of 4 was performed by following the procedure for 1 by using (1R,2R)-1,2-bis(2′-
bromophenyl)-1,2-dimethoxyethane 10 (0.55 g, 1.25 mmol), BuLi (2.5 ml, 4.1 mmol) and
PCy2Cl (0.65 ml, 2.9 mmol). The crude product was purified by silica gel chromatography. The
elution was carried out with hexane-ethyl acetate (9:1). The product was obtained as a white
solid. Yield: 0.41 g, 51%; mp: 120-122 °C. [ꢀ]ꢂꢁꢃ =-23.97 (c= 1 (g/100 ml), CHCl3); retention
time 7.26 min, Chiral ART Amylose-C, 90:10 n-hexane-iPrOH, flow rate of 0.5 ml/min, 254 nm,
t = 40 °C; Anal. calcd for C40H60O2P2: C, 75.68; H, 9.53%. Found: C, 75.54; H, 9.79%. IR (KBr
7

1
-1
ACCEPTED MANUSCRIPT
disc) νmax/cm : 3052, 2923, 2850, 1446, 1092, 746; H NMR (400 MHz, CDCl3, ppm) δ: 7.70
(d, J = 7.3 Hz, 2H, H5), 7.34 (m, 4H, H6,8), 7.20 (t, J = 7.3 Hz, 2H, H7), 5.74 (s, 2H, H2), 3.15 (s,
6H, H1), 1.92-0.98 (m, 44H, H10-14,16-20); 13C NMR (101 MHz, CDCl3, ppm) δ: 145.7 (d, J = 9.5
Hz, C3), 132.4 (m, C8), 130.8 (d, J = 8.1 Hz, C5), 129.5 (C6), 128.5 (d, J = 41 Hz, C4), 126.8 (d, J
= 7.3 Hz, C7), 86.4 (C2), 56.0 (C1), 35.7 (d, J = 33 Hz, C9), 34.7 (d, J = 33 Hz, C15), 26.9-27.8 (m,
C10,11,13,14,16,17,19,20), 25.9-26.0 (m, C12,18); 31P-NMR: (162 MHz, CDCl3, ppm) δ: -18.74; MS
(ES+) MS calculated [M+H]+ for C40H60O2P2: 635.4 found: 635.5.
2.2.8. (1R,2R)-1,2-bis(3′-(dicyclohexylphosphino)phenyl)-1,2-dimethoxyethane (5)
Synthesis of 5 was performed by following the procedure for 1 by using (1R,2R)-1,2-bis(3′-
bromophenyl)-1,2-dimethoxyethane 11 (0.55 g, 1.25 mmol), BuLi (2.5 ml, 4.1 mmol) and
PCy2Cl (0.65 ml, 2.9 mmol). The crude product was purified by silica gel chromatography. The
elution was carried out with hexane-ethyl acetate (9:1). The product was obtained as oil. Yield:
0.27 g, 34%; [ꢀ]ꢂꢁꢃ =9.39 (c= 1 (g/100 ml), CHCl3); retention time 6.97 min, Chiral ART
Amylose-C, 90:10 n-hexane-iPrOH, flow rate of 0.5 ml/min, 254 nm, t = 40 °C; Anal. calcd for
C40H60O2P2: C, 75.68; H, 9.53%. Found: C, 75.33; H, 9.29%. IR (KBr disc) νmax/cm-1: 3049,
1
2925, 2853, 2447, 1416, 1171, 1108, 999, 704; H NMR (400 MHz, CDCl3, ppm) δ: 7.59-7.56
(m, 2H, H7), 7.54 (d, J = 9.8 Hz, 2H, H4), 7.30 (m, 2H, H6), 7.18 (d, J = 7.8 Hz, 2H, H8), 4.44 (s,
13
2H, H2), 3.24 (s, 6H, H1), 2.01-1.14 (m, 44H, H10-14,16-20); C NMR (101 MHz, CDCl3, ppm) δ:
138.3-138.2 (d, J = 10.1 Hz, C3), 134.5-134.8 (m, C7), 131.3-131.4 (m, C4,6), 130.4-130.6 (m,
C8), 128.5-128.6 (d, J = 9.5 Hz, C5), 86.7 (C2), 57.3 (C1), 35.5 (d, J = 22 Hz, C9), 34.8 (d, J = 22
31
Hz, C15), 25.5-26.7 (m, C10,11,13,14,16,17,19,20), 24.6 (m, C12,18); P-NMR: (162 MHz, CDCl3, ppm)
δ: 2.75 MS (ES+) MS calculated [M+H]+ for C40H60O2P2: 635.4 found: 635.5.
8

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2.2.9. (1R,2R)-1,2-bis(4′-(dicyclohexylphosphino)phenyl)-1,2-dimethoxyethane (6)
Synthesis of 6 was performed by following the procedure for 1 by using (1R,2R)-1,2-bis(4′-
bromophenyl)-1,2-dimethoxyethane 12 (0.55 g, 1.25 mmol), BuLi (2.5 ml, 4.1 mmol) and
PCy2Cl (0.65 ml, 2.9 mmol). The crude product was purified by silica gel chromatography. The
elution was carried out with hexane-ethyl acetate (9:1). The product was obtained as a white
solid. Yield: 0.56 g, 71%; mp: 48-50 °C. [ꢀ]ꢂꢁꢃ =27.97 (c= 1 (g/100 ml), CHCl3); retention time
6.79 min, Chiral ART Amylose-C, 90:10 n-hexane-iPrOH, flow rate of 0.5 ml/min, 254 nm, t =
40 °C; Anal. calcd for C40H60O2P2: C, 75.68; H, 9.53%. Found: C, 75.86; H, 9.94%. IR (KBr
1
disc) νmax/cm-1: 3050, 2925, 2851, 1448, 1173, 1105, 821; H NMR (400 MHz, CDCl , ppm) δ:
3
7.44-7.40 (m, 4H, H5,7), 6.81-7.17(m, 4H, H4,8), 4.38 (s, 2H, H2), 3.34 (s, 6H, H1), 1.14-2.00 (m,
44H, H10-14,16-20); 13C NMR (101 MHz, CDCl3, ppm) δ: 141.4-141.5 (d, J = 2.9 Hz, C3), 130.9 (d,
J = 8.1 Hz, C4,8), 129.5 (d, J = 81 Hz, C6), 127.4-127.7 (m, C5,7), 86.9 (C2), 57.7 (C1), 35.4 (d, J
= 37 Hz, C9), 34.7 (d, J = 37 Hz, C15), 25.4-26.5 (m, C10,11,13,14,16,17,19,20 ), 24.6-24.7 (m, C12,18);
31P-NMR: (162 MHz, CDCl3, ppm) δ: 1.92 MS (ES+) MS calculated [M+H]+ for C40H60O2P2:
635.4 found: 635.5.
2.2.10. Ruthenium(II) complex of (1R,2R)-1,2-bis(4′-(diphenylphosphino)phenyl)-1,2-
dimethoxyethane (Ru(II)-3)
Ru(II)-3
complex
was
prepared
by
the
reaction
of
(1R,2R)-1,2-bis(4′-
(diphenylphosphino)phenyl)-1,2-dimethoxyethane 3 (0.2 g, 0.3 mmol) with [Ru(ƞ6-p-cymene)(µ-
Cl)Cl]2 (0.2 g, 0.3 mmol) in 15 ml of toluene at room temperature for 2 hours. The solvent was
evaporated to dryness under reduced pressure and addition of 10 ml of diethtyl ether gave Ru(II)-
3 as an orange solid. The product was collected by filtration and dried in vacuum. Yield: 0.19 g
9

ꢂꢃ
ACCEPTED MANUSCRIPT
(47%); mp: 214-215 °C. [ꢀ]ꢁ = 39.95 (c= 0.5 (g/100 ml), CHCl3); Anal. calcd for
C60H64Cl4O2P2Ru2: C, 58.92; H, 5.27%. Found: C, 58.76; H, 5.14%. IR (KBr disc) νmax/cm-1:
3053, 2982, 2929, 2821, 1637, 1435, 1094, 748, 698; 1H NMR (400 MHz, CDCl3, ppm) δ: 7.72-
7.62 (m, 12H), 7.34-7.29 (m, 12), 6.96 (dd, J = 8.3 Hz, J = 1.5 Hz, 4H), 5.19 (t, J = 5.7 Hz, 4H),
4.94 (d, J = 6.0 Hz, 2H), 4.91 (d, J = 6.0 Hz, 2H), 4.30 (s, 2H), 3.26 (s, 6H), 2.84 (m, 2H), 1,78
13
(s, 6H), 1,10 (m, 12H); C NMR (101 MHz, CDCl3, ppm) δ: 140.1, 134.4-134.3 (m), 133.72-
133.63 (d, J = 9.3 Hz), 133.5, 133.3-133.2 (d, J =7.3 Hz), 130.2, 127.9-128.04 (m), 127.41-
127.31 (d, J = 10.3 Hz), 111.1, 95.9, 89.3, 88.8, 87.48-87.42 (d, J = 5.1 Hz), 87.13-87.08 (d, J =
31
5.9 Hz), 86.6, 57.5, 30.3, 22.1, 21.8, 17.8; P-NMR: (162 MHz, CDCl3, ppm) δ: 24.52; Maldi-
Tof calculated [M]+ for C60H64Cl4O2P2Ru2: 1226.1 found: 1226.4.
2.2.10. General procedure for the asymmetric transfer hydrogenation of aromatic ketones
A mixture of [Ru(p-cymene)Cl2]2 (0.004 mmol) and corresponding chiral bisphosphine ligand
i
(1-6) (0.004 mmol) in PrOH (7 ml) were placed under a nitrogen atmosphere in a standard
Schlenk tube. The reaction mixture was heated and stirred under nitrogen at 82 °C for 2 h. After
cooling to room temperature, the aromatic ketone (1 mmol) was added to this mixture and the
solution was then heated to 82 °C. To initiate the reaction, the solution of tBuOK (0.05 mmol) in
iPrOH was added to the stirring reaction mixture. To monitor the conversions of ketones to
corresponding secondary alcohols, a small volume of reaction mixture was taken from Schlenk
i
tube via micro syringe and diluted with PrOH, and then passed from microfilter. The conversion
and enantiomeric excess were monitored by GC using Agilent HP-Chiral 20B column.
2.2.11. General procedure for Pd(0)-catalyzed enantioselective allylic alkylation
10

3
ACCEPTED MANUSCRIPT
Corresponding bisphosphine ligand (1-6) (0.05 mmol) and [Pd(η -C3H5)Cl]2 (0.02 mmol)
were dissolved in degassed CH2Cl2 under argon atmosphere using Schlenk techniques. The
reaction mixture was stirred for 1h at 50 °C and cooled to room temperature. Then (E)-1,3-
diphenylallyl acetate (13) (1 mmol) in CH2Cl2 was added and stirred at room temperature for 30
min. Finally, a solution of BSA (3 mmol), AcOLi or AcOK (0.1 mmol) and dimethylmalonate (3
mmol) was added to the mixture. The reaction mixture was stirred for 16 h at room temperature.
Next, diethylether was added, washed with saturated NH4Cl, dried on MgSO4 and concentrated in
vacuo. The crude product was purified by flash chromatography on silica gel (Hexane/AcOEt,
90/10) to afford the target compound. All adducts were fully characterized by comparison of their
spectral data with those reported in the literature. The absolute configurations were assigned via
correlation of their optical rotation with literature values [27]. The enantiomeric excess was
determined by chiral HPLC analysis: Chiral OD-H column (250 x 4.6 mm, particle size 10 µm),
solvent: n-hexane/ iPrOH (50/50), flow rate 0.5 ml /min, t = 40 °C, retention times: 10.9 min for
(R)-(-)-14 and 12.9 min for (S)-(+)-14.
3. Result and Discussion
A two-step synthetic route towards chiral C2-symmetric bisphosphine ligands started with the
corresponding enantiomerically pure bromo-substituted diols 7-9 which were earlier described by
our group [8,9]. Chiral bromo-substituted diols are the key structures in our synthesis of
bisphosphine ligands 1-6 (Scheme 1). Bisphosphine ligand 1 has been synthesized by Brunner
[25]. However, moderate chemical yields or needing more purification procedures reported in the
literature prompted us to devise a different route involving more chemical yields and less
purification procedures. Thus, bisphosphine ligand 1 was synthesized in two steps in good overall
yields. The first step was methylated of compound 7 via CH3I in the presence of a base yielded
11

99% [26]. The second steAp gCavCe bEispPhTospEhiDne lMigaAndN1 (U60%S)CbyRrIeaPctTing the compound 10 with
the desired chlorodiphenylphosphine in the presence of a base. Novel bisphosphine ligands 2 and
3 were synthesized from the corresponding diols 11 and 12 according to this procedure,
respectively. Dicyclohexylphosphine substituted ligands 4-6 were synthesized from the
corresponding diols (10-12) by the treatment of chlorodicyclohexylphosphine in the presence of a
base. It should be noted that diphenylphosphine substituted ligands 1-3 are stable in air at room
temperature for a few days, while dicyclohexylphosphine substituted ligands 4-6 are stable for a
couple of hours.
The reaction of [Ru(p-cymene)Cl2]2 with one equivalent of bisphosphine 3 in toluene at room
temperature gave the orange compound Ru(II)-3 (Scheme 2). The reaction between ruthenium
(II) precursor and bisphosphine ligand 3 is not affected by the molar ratio of [Ru(p-cymene)Cl2]2
as well as the steric and electronic properties of the donor atoms. The initial color changed from
orange to orange-red, attributed to the dimer cleavage most probably by the bisphosphine ligand
[28]. Ru(II)-3 was isolated as indicated by singlet in the 31P NMR spectrum at 24.52 ppm.
Transfer hydrogenation reaction was chosen as the first catalytic test reaction in order to
determine the efficiency of the bisphosphine ligands 1-6. This type of reaction is one of the mild
methodologies for reduction of ketones using 2-propanol as a hydrogen source [29-33]. Initial
tests were carried out in order to determine efficient reaction parameters such as amount of base,
i
type of base and substrate/catalyst ratio using acetophenone as a substrate in refluxing PrOH
(Table 1). According to the method, chiral bisphosphine ligand and [Ru(p-cymene)Cl2]2 were
i
dissolved in PrOH and heated to reflux for 2h. Ketone and base were added to the reaction
mixture after cooling to room temperature. Adding all reagents, reaction was heated to reflux for
24h. To find efficient reaction conditions, we investigated catalytic activities of all bisphosphine
ligands in the presence of NaOH (0.05 mmol) with a low substrate/catalyst (1000/1) ratio. We
determined some conversions but any enantioinduction (Table 1, entries 1-6). Bisphosphine
12

ligand 3 gave a slightly AhigCheCr cEonPveTrsEionDamMonAg tNhe UallSliCgaRndsIP(TTable1, entry 3). Next, we
increased the concentration of NaOH in same conditions under the catalysis bisphosphine ligand
3 (Table 1, entries 7-11). It showed that increasing the concentration of the base resulted in high
conversions (up to 98%). Despite the high conversions, we focused our attention on mild
condition in related with using low concentration of the base with slightly higher
substrate/catalyst ratio. When we performed the reaction with 500/1 (substrate/catalyst) ratio in
the presence of 0.05 mmol of NaOH, moderate conversion was detected (Table 1, entry 12).
However, an increase in the concentration of NaOH to 0.4 was resulted in acceptable conversion
(Table1, entry 13). 100/1 (substrate/catalyst) ratio with 0.05 mmol and 0.1 mmol of NaOH gave
excellent conversions (Table 1, entries 14-16, up to 99%). Changing substrate/catalyst ratio as
250/1 using with 0.05 mmol of NaOH gave 98% conversion. In a low concentration of NaOH, all
results showed that the best reactivity was observed using with 250/1 (substrate/catalyst) ratio.
After finding the ratio of substrate-catalyst as 250/1, next study was planned to compare the base
activity in conversion of aromatic ketones to corresponding secondary alcohols. Various bases
t
such as NaOH, KOH and BuOK have been explored under the same reaction conditions. All
three bases gave the same conversion as 98% (Table 1, entries 17-19). Extended study was
applied in order to determine the best base (Table 2). Therefore, conversions were compared for
t
each base every hour till 24h. Conversion obtained with BuOK gave the highest result in 2h
(91%). We examined control experiments for the reactivity data. Performing the control
experiments showed that the base, the pre-catalyst and the ligand were required for the catalysis
(Table 1, entries 20-22).
With the appropriate condition in hand (250/1 substrate/catalyst ratio and 0.05 mmol tBuOK),
a series of ketones were investigated in transfer hydrogenation reaction (Table 3). In general
excellent conversions ranging between 93% and 99% were observed in the reduction of
13

acetophenone derivativesA(TCablCe 3E, ePnTtrieEs D2-10M) eAxceNptiUonSofCpR-chIloProTsubstituted acetophenone
(Table 3, entry 1, 71%)
Bisphosphine ligands 1-6 were further tested in the palladium-catalyzed enantioselective
allylic substitution of 1,3-diphenyl-2-propenyl acetate 13 with dimethylmalonate (DMM), which
is regarded as a standard test substrate for evaluating the catalysts (Table 4). The nucleophile was
generated from DMM (3 equiv) in the presence of N-O-bis(trimethylsilyl)acetamide (BSA) (3
equiv) and 0.1 mol % BSA activator. With bisphosphine ligand 1, we obtained poor results with
both chemical yield and enantioselectivity (Table 4, entry 1). When we used AcOK as a BSA
activator, a slightly higher enantioselectivity was obtained (Table 4, entry 2). When we
performed the reaction with ligands 2 and 3, we observed low catalytic activities (Table 4, entries
3-6). While bisphosphine ligand 4 catalyzed the reaction with moderate enantioselectivity (43%)
and good activity (70%) in the presence of AcOLi, poor results were detected with AcOK (Table
4, entries 7 and 8). We determined almost racemic results under the catalysis of bisphosphine
ligands 5 and 6 (Table 4, entries 9-12).
4. Conclusion
In conclusion, we have synthesized a set of six C2-symmetric bisphosphine ligands as five of
them are novel and one of them is known. As proof of their potential in enantioselective
transition metal catalysis, these ligands were evaluated in ruthenium(II)-catalyzed transfer
hydrogenation reactions and palladium(0)-catalyzed enantioselective allylic substitution
reactions. The best catalytic results were obtained in the presence of diphenylphosphine
substituted ligand 3 in the reduction of acetophenone derivatives (up to >99% conversion).
Remarkably, with bisphosphine ligand 4, good activities were observed in the palladium(0)-
catalyzed enantioselective allylic alkylation reaction (70% chemical yield and 43% ee). Current
14

ACCEPTED MANUSCRIPT
studies are focused upon expanding the scope of these novel ligands backbone by variation of its
steric and electronic properties. These results will be reported in due course.
Acknowledgements
This study was supported by the Scientific & Technological Research Council of Turkey
(TUBITAK) (Project No: KBAG-115Z029).
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
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Figure captions:
Fig. 1. General structure of modular C2-symmetric bisphosphine ligands L*.
Fig. 2. Retrosynthetic analysis of C2-symmetric bisphosphine ligands 1-6.
Scheme 1. Synthesis of C2-symmetric bisphosphine ligands 1-6.
Scheme 2. Reaction of [Ru(p-cymene)Cl2]2 with bisphosphine ligand 3.
Table 1. Reaction optimization for transfer hydrogenation of acetophenone.
Table 2. Screening of the conversion against base and time.
Table 3. Ru-catalyzed asymmetric transfer hydrogenation of ketones with C2-symmetric
bisphosphine ligand 3.
Table 4. Pd-catalyzed enantioselective allylic alkylation of 13 with dimethylmalonate in the
presence of using bisphosphine ligands 1-6.
18

ACCEPTED MANUSCRIPT
A set of six chiral modular C2-symmetric bisphosphine ligands have been synthesized in a
straightforward manner through a two-step reaction from the corresponding diols with
moderate yields. The applicability of these chiral ligands was evaluated in Ru-catalyzed
enantioselective transfer hydrogenation reactions and Pd-catalyzed enantioselective allylic
substitution reactions.

ACCEPTED MANUSCRIPT
Table 1.
Conversion
Entry
Acetophenone
S/C
Ligand
Base
Base mmol
Time (h)
(%)a,b,c
20
20
23
20
20
21
32
64
98
97
94
50
82
92
99
95
98
98
98
5
1 mmol
1 mmol
1 mmol
1 mmol
1 mmol
1 mmol
1 mmol
1 mmol
1 mmol
1 mmol
1 mmol
1 mmol
1 mmol
1 mmol
1 mmol
1 mmol
1 mmol
1 mmol
1 mmol
1 mmol
1 mmol
1 mmol
1000/1
1000/1
1000/1
1000/1
1000/1
1000/1
1000/1
1000/1
1000/1
1000/1
1000/1
500/1
500/1
100/1
100/1
100/1
250/1
250/1
250/1
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
KOH
0.05
0.05
0.05
0.05
0.05
0.05
0.1
0.2
0.4
0.8
1
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22d
1
2
3
4
5
6
3
3
3
3
3
3
3
3
3
3
3
3
3
0.05
0.4
0.05
0.1
0.2
0.05
0.05
0.05
-
tBuOK
-
250/1
250/1
3
-
tBuOK
tBuOK
0.05
50
250/1
3
0.05
8
a
:
Determined by GC (HP-Chiral-20B); b: İPA (7ml), 82°C; c: No significant ee was observed; d: In absence of [Ru(p-cymene)Cl2]2.

ACCEPTED MANUSCRIPT
Table 2.
% Conv. % Conv. % Conv. % Conv. % Conv. % Conv. % Conv.
Base Ligand S/C
(0.5h)
3
(1h)
5
(2h)
45
(4h)
61
(6h)
79
(8h)
91
(24h)a,b, c
NaOH
KOH
3
3
3
250/1
250/1
250/1
98
98
98
18
37
47
62
81
91
93
93
97
95
97
97
tBuOK
a
:
Determined by GC (HP-Chiral-20B); b: İPA (7ml), 82°C; c: No significant ee was observed

ACCEPTED MANUSCRIPT
Table 3.
Time
(h)
Conversion
(%)a,b
Time
(h)
Conversion
(%)a, b, c
Entry
1
Substrate
S/C
Entry
6
Substrate
S/C
250/1
24
24
24
24
24
71
98
97
98
93
250/1
24
24
24
24
24
96
>99
98
250/1
250/1
250/1
250/1
250/1
250/1
250/1
250/1
2
3
4
7
8
96
9
>99
5
10
a
:
Determined by GC (HP-Chiral-20B); b: İPA (7ml), 82°C; c: No significant ee was observed

ACCEPTED MANUSCRIPT
Table 4.
Entry
1
2
3
4
5
6
7
8
9
10
11
12
Ligand
BSA Activator
AcOLi
AcOK
AcOLi
AcOK
AcOLi
AcOK
AcOLi
AcOK
AcOLi
AcOK
AcOLi
AcOK
Yield a) %
ee b)c) %
15 (R)
33 (R)
13 (R)
16 (R)
25 (S)
rac
43 (R)
12 (R)
11 (S)
5 (S)
21 (S)
rac
25
30
16
18
40
15
70
34
12
35
20
15
1
1
2
2
3
3
4
4
5
5
6
6
a) Yield of isolated product. ) Determined by HPLC analysis with a chiral stationary phase (Chiralcel OD-H). c) The absolute configuration was
b
assigned by the sign of the optical rotation.

ACCEPTED MANUSCRIPT
Variable backbone
R
R
O
O
Variable position of PR'2
R'2P
Variable phosphine unit
PR'2
L*
Fig. 1.

ACCEPTED MANUSCRIPT
Fig. 2.

ACCEPTED MANUSCRIPT
Scheme 1.

ACCEPTED MANUSCRIPT
Scheme 2.

ACCEPTED MANUSCRIPT
► A set of six chiral modular C2-symmetric bisphosphine ligands have been synthesized
► C2-symmetric modular ligand structure can be altered easily by using different alkyl or aryl
groups.
► Catalytic activity of the ligands was investigated in enantioselective catalytic reactions.