Thermodynamic Resolution and Enantioselective Synthesis of C2-Symmetric Bis-sulfoxides Based on Chiral Iridium(III) Complexes

Article abstract of DOI:10.1021/acs.inorgchem.9b01682

Enantiopure λ-[Ir(dfppy)₂(MeCN)₂](PF₆) and Δ-[Ir(dfppy)₂(MeCN)₂](PF₆) (where dfppy is (4,6-difluoropheny)pyridine) were demonstrated to preferentially react with (S,S)-1,2-bis(arylsulfinyl)

Full text of DOI:10.1021/acs.inorgchem.9b01682

Article
pubs.acs.org/IC
Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX
Thermodynamic Resolution and Enantioselective Synthesis of
C2‑Symmetric Bis-sulfoxides Based on Chiral Iridium(III) Complexes
Li-Ping Li, He-Long Peng, and Bao-Hui Ye*
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-sen University, Guangzhou 510275,
China
S
* Supporting Information
ABSTRACT: Enantiopure Λ-[Ir(dfppy)2(MeCN)2](PF6) and Δ-[Ir-
(dfppy)2(MeCN)2](PF6) (where dfppy is (4,6-difluoropheny)pyridine) were
demonstrated to preferentially react with (S,S)-1,2-bis(arylsulfinyl)ethane and
(R,R)-1,2-bis(arylsulfinyl)ethane, respectively, under thermodynamic equili-
brium. Sequential treatment of Λ-[Ir(dfppy)2(MeCN)2](PF6) and Δ-[Ir-
(dfppy)2(MeCN)2](PF6) with C2-symmetric bis-sulfoxides led to diaster-
eoselective formation of the corresponding diastereomers Λ-[Ir(dfppy)2(R,R)-
bis-sulfoxide)](PF6) in 90−92% and Δ-[Ir(dfppy)2(S,S)-bis-sulfoxide)](PF6)
in 88−90%, respectively. The uncoordinated (R,S)-bis-sulfoxides were
afforded in 45% with >97% de values. Enantiopure (S,S)-bis-sulfoxides and
(R,R)-bis-sulfoxides were respectively obtained by the release of sulfoxide
ligands from the corresponding complexes in the presence of glycine in yields
of 20−21% with 97−99% ee values. The enantioreceptors Λ-[Ir-
(dfppy)2(MeCN)2](PF6) and Δ-[Ir(dfppy)2(MeCN)2](PF6) can be recycled and reused in the next reaction cycle. Moreover,
a protocol for asymmetric oxidation of prochiral bis-sulfide into enantiopure C2 symmetric bis-sulfoxide was also developed in a
high enantioselectivity. The absolute configurations at the metal centers and sulfur atoms were determined by X-ray
crystallography.
Ru(II) complexes in the presence of chiral sulfoxides.22,23 They
found the diastereoselectivities are different between (S)-
methyl p-tolyl sulfoxide (monodentate) and (S)-ortho-
INTRODUCTION
■
Chiral sulfoxides are important compounds that are widely
applied in organic synthesis1−6 and pharmaceutical chem-
phenolsulfoxide (bidentate) toward Ru(II) complex: The
istry.7−9 Although many methodologies have been developed
former led to formation of Λ-Ru-R-sulfoxide diastereomer,22
for the synthesis of chiral sulfoxides,10−15 they still suffer from
while the latter generation of Δ-Ru-R-sulfoxide diaster-
a lack of generality and functional group tolerance. Andersen’s
method has often been employed to synthesize enantiopure
sulfoxides because it is a relatively straightforward to generate
eomer.23,24 Inspired by these findings, our group has developed
a new protocol for resolution of sulfoxides up to 99% ee value
on the basis of a chiral-at-Ir(III) complex.25 Moreover, a new
either enantiomer, whereas the experimental procedures are
approach for the asymmetrical generation of chiral sulfoxides
tedious and require the use of an organometallic reagent.
by means of in situ oxidation of sulfide complexes has also
Moreover, C2-symmetric bis-sulfoxides have been applied
been developed based on a chiral-at-metal strategy,26 where
the stereochemistry of the sulfoxide is mediated by the
configuration of Ru(II) complex. Although the oxidation of
sulfide complexes into sulfoxide complexes is well-docu-
mented,27,28 the enantioselective oxidation in situ to generate
chiral sulfoxide complex is still rare.26,29 The aforementioned
observations for chiral resolution and asymmetric oxidation of
sulfoxides are limited in one chiral sulfur center. What will
happen in the C2-symmetric bis-sulfoxides, where there are
three stereogenic centers, one from metal center and two from
two sulfur atoms? Theoretically, six isomers (Δ-M-(R,R)-
sulfoxide, Δ-M-(S,S)-sulfoxide, Δ-M-(R,S)-sulfoxide, Λ-M-
(R,R)-sulfoxide, Λ-Μ-(S,S)-sulfoxide, and Λ-M-(R,S)-sulfox-
widely in organic synthesis;16−19 new development of these
chiral ligands much relies in their generally straightforward
preparation in enantiopure form.20 Therefore, the enantiose-
lective synthesis and chiral resolution of bis-sulfoxides are
attracting great attention. However, this is a challenging task
because there are two chiral centers and three stereoisomers:
meso (R,S) and racemates (R,R) and (S,S) in the C2-
symmetric bis-sulfoxides. Khiar and co-workers have developed
an approach for the synthesis of enantiomerically C2-symmetric
bis-sulfoxides via dynamic kinetic transformation of sulfinyl
chlorides.21 However, although the sulfinyl chloride is hard to
control, the yields and enantiomeric excess (ee) values are
moderate.
Inoue and Meggers have independently demonstrated that
chiral sulfoxide would induce the configuration of metal
centers and further used it to asymmetrically synthesize chiral
Received: June 6, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.inorgchem.9b01682
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
159.77, 148.24, 140.61, 134.03, 132.96, 129.62, 129.50, 129.48,
125.34, 124.48, 124.20, 114.30, 101.16, 51.67. The de value is >98%
(as determined by NMR). CD (Δε/M−1 cm−1, CH2Cl2): 302 (+63),
325 (+15), 353 (−58), 424 nm (−4). For Δ-[Ir(dfppy)2{(S,S)-
1}](PF6) (Δ-Ir-(S,S)-1): Yield, 88%. CD (Δε/M−1 cm−1, CH2Cl2):
302 (−62), 325 (−13), 353 (+63), 424 nm (+5). For (R,S)-1, yield,
ide) would be generated, leading to more complicated
products. Herein, we observe the chiral recognition and
resolution of bis-sulfoxides using enantiopure Λ-[Ir-
(dfppy)2(MeCN)2](PF6) or Δ-[Ir(dfppy)2(MeCN)2](PF6)
(where dfppy is (4,6-difluoropheny)pyridine) complex as a
chiral receptor. We find that the discriminations are highly
stereoselective: (R,R)-Sulfoxide preferentially coordinates with
Δ-[Ir(dfppy)2(MeCN)2](PF6) to generate Δ-[Ir-
(dfppy)2{(S,S)-sulfoxide}](PF6) diastereomer, whereas (S,S)-
sulfoxide binds to Λ-[Ir-(dfppy)2(MeCN)2](PF6) to produce
Λ-[Ir(dfppy)2{(R,R)-sulfoxide}](PF6) diastereomer under the
thermodynamic equilibrium. Therefore, the bis-sulfoxide
enantiomers (R,R)-sulfoxide and (S,S)-sulfoxide are separated.
Furthermore, a protocol for asymmetric oxidation of bis-sulfide
into C2-symmetric bis-sulfoxide is also developed in high
enantioselectivity.
1
45% (on the basis of 1); de, 97.1%. H NMR (400 MHz, CDCl3) δ
7.59−7.49 (m, 10H), 3.05 (s, 4H). 13C NMR (101 MHz, CDCl3) δ
142.28, 131.56, 129.64, 129.64, 124.11, 124.11, 47.11. Single crystals
of Λ-Ir-(R,R)-1 and Δ-Ir-(S,S)-1 suitable for X-ray analysis were
obtained by slow diffusion of Et2O into the concentrated DCM
solution of the complexes, respectively.
For Λ-[Ir(dfppy)2{(R,R)-2}](PF6) (Λ-Ir-(R,R)-2): Yield, 92%.
Anal. Calcd for C38H30F10IrN2O4PS2: C 43.22, H 2.86, N 2.65, S
6.07%. Found: C 43.50, H 3.17, N 2.76, S 6.25%. ESI-MS: m/z =
1
911.1 [M − PF6]+. H NMR (400 MHz, CDCl3) δ 9.82 (d, J = 5.8
Hz, 2H), 7.92−7.79 (m, 4H), 7.60 (t, J = 5.8 Hz, 2H), 6.74 (d, J = 8.9
Hz, 4H), 6.61 (d, J = 8.9 Hz, 4H), 6.55−6.46 (m, 2H), 5.50 (d, J =
8.1 Hz, 2H), 4.31 (d, J = 9.7 Hz, 2H), 4.13 (d, J = 9.8 Hz, 2H), 3.80
(s, 6H). 13C NMR (101 MHz, CDCl3) δ 164.20, 163.61, 163.10,
161.71, 159.59, 152.24, 148.65, 140.48, 126.23, 126.20, 125.34,
124.38, 123.82, 114.71, 114.70, 114.41, 100.89, 56.04, 51.14. CD
(Δε/M−1 cm−1, CH2Cl2): 306 (+78), 324 (+30), 353 (−38), 420 nm
(−5). For Δ-[Ir(dfppy)2{(S,S)-2}](PF6) (Δ-Ir-(S,S)-2), yield, 90%;
CD (Δε/M−1 cm−1, CH2Cl2): 305 (−76), 324 (−31), 354 (+36),
420 nm (+5). For (R,S)-2, yield, 46% (on the basis of 2); de, 97.1%.
1H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 8.8 Hz, 4H), 7.02 (d, J =
8.8 Hz, 4H), 3.86 (s, 6H), 3.00 (s, 4H). 13C NMR (101 MHz,
CDCl3) δ 162.37, 133.12, 125.97, 125.97, 115.16, 115.16, 55.73,
47.65.
EXPERIMENTAL SECTION
■
Materials and Methods. All chemicals were commercially
available and used as purchased unless otherwise noted. The
enantiopure Λ-[Ir(dfppy)2 (MeCN) 2 ](PF6 ), Δ-[Ir-
(dfppy)2(MeCN)2](PF6), 1,2-bis(phenylthio)ethane (L1), 1,2-bis-
((4-methoxyphenylthio)ethane (L2), l,2-bis(p-tolylthio)ethane (L3),
1,2-bis(phenylsulfinyl)ethane (1), 1,2-bis(4-methoxyphenylsulfinyl)-
ethane (2), and l,2-bis(p-tolylsulfinyl)ethane (3) were synthesized
according to the literature.30,31 The complex rac-[Ir(dfppy)2(L1)]-
(PF6) and rac-[Ir(dfppy)2(1)](PF6) were synthesized according to
the literature.32 Elemental (C, H, N, and S) analyses were carried out
on an Elementar Vario EL analyzer. Electrospray ionization mass
spectra (ESI-MS) were recorded on a Thermo LCQ DECA XP mass
For Λ-[Ir(dfppy)2{(R,R)-3}](PF6) (Λ-Ir-(R,R)-3): yield, 91%.
Anal. Calcd for C38H30F10IrN2O2PS2: C 43.57, H 2.95, N 2.74, S
6.26%. Found: C 43.80, H 2.64, N 2.96, S 6.55%. ESI-MS: m/z =
1
spectrometer. H and 13C NMR spectra were recorded on a Bruker
1
879.1 [M − PF6]+. H NMR (400 MHz, CDCl3) δ 9.83 (d, J = 5.1
AV-400 spectrometer using CDCl3 as solvent, and chemical shifts (in
ppm) were referenced to a residual solvent proton peak. Circular
dichroism (CD) spectra were recorded on a JASCO J-810 CD
spectropolarimeter (1 s response, 3.41 nm bandwidth, scanning speed
of 200 nm/min, accumulation of 3 scans). The ee and diastereomeric
excess (de) values of sulfoxides were measured by chiral high-
performance liquid chromatography (HPLC) analyses on a Shimadzu
LC 20AT with UV detector SPD-20A (Daicel Chiralpak AD-H
column, 250 mm × 4.6 mm, flow rate = 1 mL/min, column
temperature = 30 °C, 254 nm).
General Procedure for Resolution of C2-Symmetric Bis-
sulfoxide Isomers. Λ-[Ir(dfppy)2(MeCN)2](PF6) (40.0 mg, 0.05
mmol), bis-sulfoxide (0.20 mmol), and MeOH (10 mL) were added
to a flask. The mixture was stirred at 50 °C under argon for 3 h. The
solvent was removed, and the resulting material was dissolved in 4 mL
of CHCl3. Next, 40 mL of hexane was added to the above solution to
produce a precipitate. The solid product was filtrated and recrystal-
lized from CHCl3 and hexane to yield a pale yellow powder, Λ-
[Ir(dfppy)2{(R,R)-sulfoxide}](PF6). The filtrate was concentrated
under reduced pressure. Then, Δ-[Ir(dfppy)2(MeCN)2](PF6) (0.05
mmol) and MeOH (10 mL) were added to the residue. The mixture
was further stirred at 50 °C under argon for 3 h. Upon removal of the
solvent, 4 mL of CHCl3 was used to dissolve the residue, and 40 mL
of hexane was added to yield a precipitate. The solid was filtrated to
obtain Δ-[Ir(dfppy)2{(S,S)-sulfoxide}](PF6). The filtrate was further
concentrated and further purified by a silica gel chromatography with
hexane/EtOAc (1:1 to 1:3 v/v) as eluent to afford pure (R,S)-
sulfoxide.
Hz, 2H), 7.87 (dd, J = 11.6, 4.3 Hz, 2H), 7.79 (d, J = 10.0 Hz, 2H),
7.65−7.58 (m, 2H), 6.94 (d, J = 8.2 Hz, 4H), 6.72 (d, J = 8.5 Hz,
4H), 6.49 (ddd, J = 12.3, 8.7, 2.3 Hz, 2H), 5.48 (dd, J = 8.1, 2.2 Hz,
2H), 4.36 (d, J = 10.0 Hz, 2H), 4.16 (d, J = 9.9 Hz, 2H), 2.33 (s, 6H).
13C NMR (101 MHz, CDCl3) δ 164.30, 163.50, 162.20, 161.71,
159.71, 152.22, 148.38, 144.14, 140.49, 130.75, 130.04, 129.91,
125.24, 124.30, 124.08, 114.37, 101.02, 51.40, 21.40. CD (Δε/M−1
cm−1, CH2Cl2): 306 (+63), 323 (+27), 353 (−46), 420 nm (−5). For
Δ-[Ir(dfppy)2{(S,S)-3}](PF6) (Δ-Ir-(S,S)-3), yield, 88%. CD (Δε/
M
−1 cm−1, CH2Cl2): 306 (−76), 323 (+32), 354 (+57), 419 nm (+5).
For (R, S)-3, yield, 45% (on the basis of 3); de, 98.1%. 1H NMR (400
MHz, CDCl3) δ 7.43 (d, J = 8.2 Hz, 4H), 7.33 (d, J = 8.0 Hz, 4H),
3.01 (s, 4H), 2.41 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 142.06,
139.00, 130.28, 130.28, 124.10, 124.10, 47.13, 21.64. Single crystals of
(R,S)-3 suitable for X-ray analysis were obtained by slow diffusion of
hexane into the ethyl acetate solution of the compound.
General Procedures for Release of Chiral Bis-Sulfoxides and
Recovery of Chiral Ir(III) Complexes. A suspension of bis-sulfoxide
complex Λ-[Ir(dfppy)2{(R,R)-sulfoxide}](PF6) (0.02 mmol), glycine
(gly, 0.1 mmol), and MeONa (0.16 mmol) in MeOH (5 mL) was
stirred at 50 °C under argon for 2 h. The solvent was removed, and
the resulting material was dissolved in water (15 mL) and extracted
with CH2Cl2 (3 × 10 mL). The organic layer was dried over Na2SO4,
and the solvent was removed under reduced pressure. The crude
product was purified by a silica gel column chromatography with
hexane/EtOAc (1:3 v/v) as an eluent to afford the target pure
sulfoxide (S,S)-sulfoxide and Λ-[Ir(dfppy)2(gly)] (yield in 95%).
Furthermore, Λ-[Ir(dfppy)2(gly)] (0.02 mmol) and NH4PF6 (0.15
mmol) were added to an acetonitrile (5 mL). The solution was stirred
under argon at 55 °C for 5 min, then TFA (0.36 mmol) was added to
the solution and further stirred for 1 h. Upon removal of the solvent,
the solid product was collected and washed with Et2O-hexane (1:5)
and a KPF6 solution to afford Λ-[Ir(dfppy)2(MeCN)2](PF6) in yield
of 91%. When Δ-[Ir(dfppy)2{(S,S)-sulfoxide}](PF6) was used instead
of Λ-[Ir(dfppy)2{(R,R)-sulfoxide}](PF6), (R,R)-sulfoxide and Δ-
[Ir(dfppy)2(MeCN)2](PF6) were obtained.
For Λ-[Ir(dfppy)2{(R,R)-1}](PF6) (Λ-Ir-(R,R)-1): Yield, 90%.
Anal. Calcd for C36H26F10IrN2O2PS2: C 43.42, H 2.63, N 2.81, S
6.44%. Found: C 43.61, H 2.94, N 3.02, S 6.64%. ESI-MS: m/z =
1
851.1 [M − PF6]+. H NMR (400 MHz, CDCl3) δ 9.82 (d, J = 5.6
Hz, 2H), 7.86 (t, J = 7.9 Hz, 2H), 7.78 (d, J = 8.5 Hz, 2H), 7.62 (t, J =
6.6 Hz, 2H), 7.41 (t, J = 7.5 Hz, 2H), 7.15 (t, J = 7.9 Hz, 4H), 6.85
(d, J = 7.8 Hz, 4H), 6.50 (ddd, J = 11.4, 8.7, 2.3 Hz, 2H), 5.48 (dd, J
= 8.1, 2.1 Hz, 2H), 4.30 (d, J = 10.0 Hz, 2H), 4.10 (d, J = 9.9 Hz,
2H). 13C NMR (101 MHz, CDCl3) δ 164.40, 163.62, 162.29, 161.85,
B
DOI: 10.1021/acs.inorgchem.9b01682
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
For (S,S)-1: yield, 21% (on the basis of 1). Anal. Calcd for
strated that enantiopure Λ/Δ-[Ir(ppy)2(MeCN)2](PF6)
(where ppy is 2-phenypyridine) complexes reacted diaster-
eoselectively with ortho-phenolsulfoxides (HLO-R) to form Λ-
[Ir(ppy)2{(S)-LO-R}] and Δ-[Ir(ppy)2{(R)-LO-R}] com-
plexes.28 What will happen in C2-symmetric bis-sulfoxide
compounds? To address this question, we initially observed the
reaction between bis-sulfoxide 1 and Λ-[Ir(dfppy)2(MeCN)2]-
C14H14O2S2: C 60.40, H 5.07, S 23.03%. Found: C 60.21, H 5.23, S
1
23.25%. ESI-MS: m/z = 301.0 [M + Na]+. ee, 98.6%. H NMR (400
MHz, CDCl3) δ 7.50−7.42 (m, 10H), 3.45−3.31 (m, 2H), 2.77−2.65
(m, 2H). 13C NMR (101 MHz, CDCl3) δ 142.43, 131.36, 129.47,
129.47, 129.93, 129.93, 47.74. CD (Δε/M−1 cm−1, CH2Cl2): 246 nm
(−107). For (R,R)-1, yield, 20% (on the basis of 1). ee, 99.2%. CD
(Δε/M−1 cm−1, CH2Cl2): 246 nm (+108).
1
(PF6) (receptor) by means of H NMR technique. When 1
For (S,S)-2: yield, 20% (on the basis of 2). Anal. Calcd for
C16H18O4S2: C 56.78, H 5.36, S 18.95%. Found: C 56.91, H 5.76, S
equiv of 1 was added to the solution of Λ-[Ir-
(dfppy)2(MeCN)2](PF6) in CDCl3, the characteristic reso-
nance band of the α-H at 9.05 ppm (Figure 1a) for the
1
18.76%. ESI-MS: m/z = 361.1 [M + Na]+. ee, 97.1%. H NMR (400
MHz, CDCl3) δ 7.46 (d, J = 8.8 Hz, 4H), 7.00 (d, J = 8.8 Hz, 4H),
3.85 (s, 6H), 3.33−3.21 (m, 2H), 2.82−2.70 (m, 2H). 13C NMR (101
MHz, CDCl3) δ 162.33, 133.26, 125.96, 125.96, 115.11, 115.11,
55.70, 48.25. CD (Δε/M−1 cm−1, CH2Cl2): 252 nm (−116). For
(R,R)-2, yield, 20% (on the basis of 2). ee, 98.6%. CD (Δε/M−1
cm−1, CH2Cl2): 252 nm (+116).
For (S,S)-3: yield, 21% (on the basis of 3). Anal. Calcd for
C16H18O2S2: C 62.71, H 5.92, S 20.92%. Found: C 62.50, H 5.63, S
1
20.64%. ESI-MS: m/z = 329.0 [M + Na]+. ee, 98.9%. H NMR (400
MHz, CDCl3) δ 7.40 (d, J = 8.0 Hz, 4H), 7.29 (d, J = 7.9 Hz, 4H),
3.37−3.28 (m, 2H), 2.80−2.68 (m, 2H), 2.41 (s, 6H). 13C NMR (101
MHz, CDCl3) δ 142.02, 139.21, 130.25, 130.25, 124.09, 124.09,
48.08, 21.56. CD (Δε/M−1 cm−1, CH2Cl2): 248 nm (−118). For
(R,R)-3, yield, 21% (on the basis of 3). ee, 98.9%. CD (Δε/M−1
cm−1, CH2Cl2): 248 nm (+120). Single crystals of (S,S)-3 suitable for
X-ray analysis were obtained by slow diffusion of hexane into the ethyl
acetate solution of the compound.
General Procedures for Enantioselective Synthesis of C2-
Symmetric Bis-sulfoxide Complexes. Λ-[Ir(dfppy)2(MeCN)2]-
(PF6) or Δ-[Ir(dfppy)2(MeCN)2](PF6) (80.0 mg, 0.1 mmol) and L1
(25 mg, 0.1 mmol) were added to a MeOH (10 mL) solution. The
mixture was stirred at 50 °C under argon for 3 h. Then, the solvent
was removed, and the resulting material was dissolved in 4 mL of
CHCl3. Next, 40 mL of hexane was added to the solution to produce
the corresponding Λ-[Ir(dfppy)2(L1)](PF6) or Δ-[Ir(dfppy)2(L1)]-
(PF6) precipitate. Yield, 95%. Anal. Calcd for C36H26F10IrN2PS2:C
44.86, H 2.72, N 2.91, S 6.65%. Found: C 44.60, H 2.50, N 2.73, S
1
Figure 1. Excerpts of H NMR spectra of Λ-[Ir(dfppy)2(MeCN)2]-
(PF6) (receptor) with 1 in CDCl3 at 50 °C for 3 h: (a) receptor, (b)
receptor and 1.0 equiv of 1, (c) receptor and 2.0 equiv of 1, (d)
receptor and 3.0 equiv of 1, (e) receptor and 4.0 equiv of 1 ( , Λ-Ir-
■
(R,R)-1).
1
6.54%. ESI-MS: m/z = 819.1 [M − PF6]+. H NMR (400 MHz,
receptor disappeared; instead, new peaks at 9.20, 9.82, 9.90,
and 10.32 ppm appeared, as shown in Figure 1b. This
observation indicated that the receptor was completely
converted into Ir(III) sulfoxide complexes and that multiple
products formed. On increasing the amount of 1 to 2.0 equiv,
the peak at 9.82 ppm became more intense. In contrast, the
other peaks became weaker (Figure 1c), indicating that the
reaction reached a new equilibrium and the species with 9.82
ppm peak became predominant. To our delight, on increasing
the amount of 1 to 4 equiv, the NMR spectra became simple
and clear, and only the peak at 9.82 ppm was observed,
indicating that a new thermodynamic equilibrium was
achieved. In this case, only the species with a 9.82 ppm
resonance peak formed; the other unstable complexes were
completely converted into the stable complex, indicating that
the reaction was highly selective. To ascertain the structure and
composition, the stable species was isolated and proved by
single-crystal X-ray diffraction (vide infra) to be Λ-Ir-(R,R)-1.
It should be pointed out that there are three isomers, (S,S)-1,
(R,R)-1, and (R,S)-1, in the ratio of 1:1:2.35 Therefore, a 1:4
ratio of receptor toward 1 indicated that Λ-Ir(III) complex
reacted with (S,S)-1 in equivalent amounts to form the stable
species Λ-Ir-(R,R)-1 by thermodynamically control. During
this processes, the unstable complexes Λ-Ir-(S,S)-1 and Λ-Ir-
(R,S)-1 formed initially were completely converted into stable
Λ-Ir-(R,R)-1 via the ligand-displacement reaction, and no
racemization at the metal center was observed. As expected,
when Δ-[Ir(dfppy)2(MeCN)2](PF6) reacted with 4 equiv of 1
under identical conditions, only Δ-Ir-(S,S)-1 diastereomer was
CDCl3) δ 9.17 (d, J = 5.6 Hz, 2H), 7.79−7.66 (m, 4H), 7.57−7.46
(m, 2H), 7.10 (t, J = 7.4 Hz, 2H), 6.86 (t, J = 7.8 Hz, 4H), 6.45−6.31
(m, 6H), 5.66 (dd, J = 8.1, 1.9 Hz, 2H), 3.83 (dd, J = 16.6, 8.4 Hz,
2H), 3.48 (t, J = 12.5 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ
164.47, 163.63, 162.65, 161.90, 160.05, 152.09, 149.43, 138.99,
129.13, 128.78, 127.79, 127.23, 126.45, 124.61, 123.62, 113.81, 99.73,
32.17.
Meta-chloroperoxybenzoic acid (m-CPBA, 779 mg, 3.5 mmol) was
added to a solution of Λ-[Ir(dfppy)2(L1)](PF6) or Δ-[Ir-
(dfppy)2(L1)](PF6) (0.1 mmol) in MeOH (10 mL). The solution
was stirred at room temperature for 6 h. Then, the solvent was
removed, and the solid product was recrystallized from CH2Cl2/Et2O
to afford Λ-Ir-(R,R)-1 or Δ-Ir-(S,S)-1. Yield, 90%.
Single-Crystal X-ray Crystallography. The diffraction inten-
sities for Λ-Ir-(R,R)-1·CH2Cl2, Δ-Ir-(S,S)-1·CH2Cl2, (S,S)-3, and
(R,S)-3 were collected at 298 K on an Oxford Gemini S Ultra CCD
Area detector diffractometer with graphite-monochromated Cu Kα
radiation (λ = 1.54178 Å). All of the data were corrected for
absorption effect using the multiscan technique. The structures were
solved via direct methods (olex2.solve)33 and refined by iterative cycles
of least-squares refinement on F2 followed by difference Fourier
synthesis.34 All non-hydrogen atoms were refined anisotropically. All
hydrogen atoms were included in the final structure factor calculation
at idealized positions and were allowed to ride on the neighboring
atoms. The crystal data and the details of data collection and
refinement for the complexes are summarized in Table S1.
RESULTS AND DISCUSSION
■
Chiral Recognition of Chiral Ir(III) Complexes and C2-
Symmetric Bis-sulfoxides. Our previous study has demon-
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Figure 2. Crystal structures of Λ-Ir-(R,R)-1 (left) and Δ-Ir-(S,S)-1 (right). Selected bond lengths (Å) and angles (deg) for Λ-Ir-(R,R)-1 and Δ-Ir-
(S,S)-1 (in parentheses): Ir1−N1 = 2.073(6) (2.082(8)), Ir1−N2 = 2.083(6) (2.063(7)), Ir1−C11 = 2.044(8) (2.042(18)), Ir1−C22 = 2.018(7)
(2.023(10)), Ir1−S1 = 2.359(17) (2.360(2)), Ir1−S2 = 2.355(18) (2.358(2)), S1−O1 = 1.473(7) (1.490(9)), S2−O2 = 1.464(8) (1.483(8)) S1−
Ir1−S2 = 84.60(7) (84.49(9)), N1−Ir1−N2 = 169.2(2) (169.6(3)), Ir1−S1−C29−C30 = 54.4(7) (54.1(8)). Perspective drawing with 50%
probability thermal ellipsoids.
Scheme 1. Resolution of C2-Symmetric Bis-sulfoxides on the Basis of Chiral-at-Metal Strategy
obtained. That is to say, the Λ-Ir(III) complex prefers to react
with the (S,S)-configuration of bis-sulfoxide to generate the
stable Λ-(R,R) diastereomer, whereas the Δ-Ir(III) complex
likes to react with the (R,R)-configuration of bis-sulfoxide to
produce the stable Δ-(S,S) diastereomer. The diastereoselec-
tivities observed here are consistent with those of the previous
reports on methyl p-tolyl sulfoxide and Ru(bpy)2Cl2 (bpy is
2,2′-bipyridine), where the stable Λ-Ru-R-sulfoxide and Δ-Ru-
S-sulfoxide diastereomers are predominant.25,26 However, they
are different from those of (S)-ortho-phenolsulfoxides and
[Ru(bpy)2(MeCN)2]2+,27a,c (S)-N-sulfinylcarboximidares and
[Ru(bpy)2Cl2],27b and (R/S)-ortho-phenolsulfoxides and [Ir-
(ppy)2(MeCN)2]+,28 where Λ-M-S-sulfoxide and Δ-M-R-
sulfoxide diastereomers are obtained.
Ir-(R,R)-1 and Δ-Ir-(S,S)-1 were measured by X-ray
crystallography, respectively. They both crystallize in a chiral
space groups P212121. As shown in Figure 2, the Ir(III) center
shows a slightly distorted octahedral geometry with coordina-
tion of two carbon atoms in cis and two nitrogen atoms in
trans from the two dfppy ligands. The Ir−N and Ir−C
distances of the dfppy ligands are around 2.0 Å, which are
consistent with those reports for Ir(III) complexes.36,37 The
Ir1−S1 distances and the S−O bond distances are around 2.35
and 1.48 Å, respectively, in accord with the reported distance
for the Ir(III) sulfoxide complexes.28
The absolute configurations at the metal centers are of Λ
and Δ fashions, and the sulfur atoms are (R,R) and (S,S)
configurations, respectively. The Flack parameters of Λ-Ir-
(R,R)-1 (−0.007(13)) and Δ-Ir-(S,S)-1 (−0.032(17)) are
close to zero, indicating that the assignments of stereo-
To ascertain the structure and have a better understand the
diastereoselectivity, single crystal structures of enantiomers Λ-
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chemistry at the metal and sulfur centers are correct. Further
structural analyses show that the O1 and O2 from the sulfoxide
groups are connected via hydrogen bond to the C1−H and
C12−H of the pyridine ring (C1···O1 = 3.036 Å, H1···O1 =
2.183 Å, ∠C1−H−O1 = 152.3°, C12···O2 = 3.049 Å, H12···
O2= 2.213 Å, ∠C12−H−O2 = 149.2° for Λ-Ir-(R,R)-1; C1···
O1 = 3.027 Å, H1···O1 = 2.189 Å, ∠C1−H−O1 = 149.4°,
C12···O2 = 3.010 Å, H12···O2 = 2.158 Å, ∠C12−H−O2=
152.65° for Δ-Ir-(S,S)-1) to stabilize the diastereomers.
Moreover, the phenyl groups from bis-sulfoxide are intra-
molecular π···π interact (ca. 3.86 Å) with the pyridine rings of
dfppy ligand to further stabilize the diastereomers (see Figure
2). In comparison with the reported crystal structures of
M(L)2-sulfoxide complexes (where M is Ru(II) and Ir(III), L
is bpy- and ppy-like ligand), C−H···O hydrogen bonding
interactions are found in both Δ-M-(R)-sulfoxide and Δ-M-
(S)-sulfoxide diastereomers.22,23,25−27 However, the intra-
molecular π−π interaction is only found in the latter stable
diastereomer.22b Therefore, the intramolecular π−π interaction
may play an important role in the diastereoselectivity between
the configurations of metal center and chirality of bisulfox-
ide.22b,38
Figure 3. CD spectra of Λ-Ir-(R,R)-1 and Δ-Ir-(S,S)-1 in CH2Cl2 (1
× 10−5 M).
Chiral Resolution of C2-Symmetric Bis-sulfoxides
Based on Thermodynamic Control. The aforementioned
observations indicate that the reaction between the receptor
and 4 equiv of bis-sulfoxide 1 is quantitative and highly
diastereoselective. Therefore, these processes could be applied
to resolve C2-symmetric bis-sulfoxide via thermodynamic
control, as shown in Scheme 1. First, 1 equiv of Λ-
[Ir(dfppy)2(MeCN)2](PF6) was added to the solution of 4
equiv of bis-sulfoxide 1 to quantitatively react with (S,S)-1
isomer to produce Λ-Ir-(R,R)-1 diastereomer, which was easily
isolated from the uncoordinated bis-sulfoxide in an excellent
yield of 90%. Then, 1 equiv of Δ-[Ir(dfppy)2(MeCN)2](PF6)
was further added to the uncoordinated bis-sulfoxide solution
to react with (R,R)-1 to yield Δ-Ir-(S,S)-1 complex which was
isolated from the unreacted meso (R,S)-1 in a yield of 88%.
Residual (R,S)-1 was obtained in a yield of 45% (theory in
50%) upon purification by a silica gel chromatography. Its de
value was found to be >97% (as determined by chiral HPLC,
vide infra).
CD spectroscopy was used to characterize optical activity of
the bis-sulfoxide complexes. CD spectra of enantiomers Λ-Ir-
(R,R)-1 and Δ-Ir-(S,S)-1 are mirror images with Cotton bands
at 302, 325, 353, and 424 nm, as shown in Figure 3. NMR
technique was used to evaluate the purity of bis-sulfoxide
complexes. As shown in Figure 4, the resonance peaks at 9.82,
6.85, 4.30, and 4.10 ppm of rac-[Ir(dfppy)2(1)](PF6) are split
into four corresponding pairs of peaks at 9.82 and 9.78 ppm,
6.85 and 6.74 ppm, 4.30 and 4.20 ppm, and 4.10 and 3.95 ppm
in the presence of 30 equiv of (S)-1,1′-binaphthol (S-binol) as
a chiral shift reagent, in accord with those of Λ-Ir-(R,R)-1 and
Δ-Ir-(S,S)-1 enantiomers. These peaks can be used to evaluate
the enantiopurities of Λ-Ir-(R,R)-1 and Δ-Ir-(S,S)-1 enan-
tiomers and show the ee values to be >98% from the ratio of
the integrals of the α-H peaks of the two enantiomers.
Furthermore, the enantiopure C2-symmetric bis-sulfoxide
can be obtained by release of the bis-sulfoxide ligand from
complex Λ-Ir-(R,R)-1 or Δ-Ir-(S,S)-1. First, the acid
dissociation and solvent coordination method was examined.23
When TFA was added to the MeCN solution of bisulfoxide
complex, then the solution was stirred at 50 °C under argon for
2 h. However, only partial bisulfoxide ligand dissociated.
Figure 4. Excerpts of 1H NMR spectra in CDCl3: (a) rac-
[Ir(dfppy)2(1)](PF6), (b) rac-[Ir(dfppy)2(1)](PF6) with 30 equiv
of S-binol, (c) Λ-Ir-(R,R)-1 with 30 equiv of S-binol, and (d) Δ-Ir-
(S,S)-1 with 30 equiv of S-binol.
Extending the reaction time had no significant effect on the
dissociation. Therefore, a chelating ligand with strongly
coordinated ability, such as gly, was used to replace bisulfoxide.
To our delight, when 5 equiv of gly was added to the solution
of bis-sulfoxide complex in the presence of NaOMe, bis-
sulfoxide (S,S)-1 or (R,R)-1 was afforded in yield of 20−21%
(theory in 25%) after a column separation. The sulfoxide
compounds were characterized by NMR spectroscopy and
mass spectrometry. CD spectroscopy was used to examine
their optical activity. As shown in Figure 5, they are optically
active with mirror images, and each have a Cotton band at 246
nm. The enantiopurities of (S,S)-1 and (R,R)-1 were measured
by means of chiral HPLC analyses (see Figure 6), and their ee
values were found to be 98.6 and 99.2%, respectively. To our
knowledge, no resolution approach for C2-symmetric bis-
sulfoxide has been reported. Here, a new resolution protocol is
developed to resolve C2-symmetric bis-sulfoxide in high
enantiopurities. In addition, Δ/Λ-[Ir(dfppy)2(gly)] was
afforded in a yield of 95%, which can be converted into the
corresponding Δ/Λ-[Ir(dfppy)2(MeCN)2](PF6) receptor that
can be reused. In this case, the acid dissociation method was
applied because the coordination strength of gly ligand to
metal would be reduced by protonation of the carboxylate and
amine groups and then displaced by the coordinated solvent
CH3CN. Indeed, when TFA was added to the MeCN solution
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spectroscopies (see the Experimental Section and Figures S1
and S2). Uncoordinated meso (R,S)-2 and (R,S)-3 were also
isolated in yields of 46% with 97.1% de and 45% with 98.1%
de, respectively. Moreover, enantiopure (S,S)-2 and (R,R)-2, as
well as (S,S)-3 and (R,R)-3, were also obtained in a yield of ca.
20% (theory in 25%) by release from the corresponding bis-
sulfoxide complexes in the similar procedure of 1. CD
technique was used to characterize their optical activity (see
Figures S3 and S4). Their enantiopurities were determined by
means of chiral HPLC analyses and found to be 97.1% for
(S,S)-2, 98.6% for (R,R)-2, 98.9% for (S,S)-3, and 98.9% for
(R, R)-3, respectively (see Figures S5 and S6). Furthermore,
the absolute configurations of (S,S)-3 and (R,S)-3 were further
confirmed by single-crystal X-ray diffraction. They crystallize in
Pna21 and Pbca space groups, respectively. The molecular
structures of them are presented in Figure 7. The sulfur atoms
configurations are all in a S fashion in (S,S)-3 compound,
where the Flack parameter −0.03(3) also demonstrates that
the chiral assignment at the sulfur atom is correct. The S−O
distances of 1.476(4)−1.496(4) Å are comparable to those of
previous reports.28
Enantioselective Synthesis of C2-Symmetric Bis-
sulfoxides via a Chiral-at-Metal Strategy. The highly
diastereoselective discrimination between the bis-sulfoxides
and chiral Ir(III) complexes encouraged us to examine the in
situ oxidation of prochiral bis-sulfide complexes into chiral bis-
sulfoxide complexes using a chiral-at-Ir(III) complex as a
structural template. When m-CPBA was used as an oxidant to
oxidize Λ-[Ir(dfppy)2(L1)](PF6) (where L1 is 1,2-bis-
(phenylthio)ethane) in MeOH at room temperature for 6 h
(see Scheme 2), to our delight, NMR spectra showed only Λ-
Ir-(R,R)-1 diastereomer, afforded in a yield of 90%. When Δ-
[Ir(dfppy)2(L1)](PF6) was used as a substrate instead of Λ-
Figure 5. CD spectra of (R,R)-1, (S,S)-1 and (R,S)-1 in DCM (1 ×
10−4 M).
of Λ-[Ir(dfppy)2(gly)] or Δ-[Ir(dfppy)2(gly)] in the presence
of NH4PF6, the corresponding Λ-[Ir(dfppy)2(MeCN)2](PF6)
or Δ-[Ir(dfppy)2(MeCN)2](PF6) was afforded in a yield of
91%. Their enantiopurities were examined by treatment with
enantiopure (S,S)-1 and (R,R)-1 to convert into corresponding
Λ-Ir-(R,R)-1 and Δ-Ir-(S,S)-1 complexes, respectively, and
found to be >98%. These also indicated that the configuration
at metal center is retention.
To examine the generality of this protocol, the resolution
process was applied to C2-symmetric bis-sulfoxides 2 and 3. To
our delight, enantiomers Λ-Ir-(R,R)-2 and Δ-Ir-(S,S)-2, as well
as Λ-Ir-(R,R)-3 and Δ-Ir-(S,S)-3, were isolated in yields of
88−92%. They were characterized by NMR, MS, and CD
Figure 6. HPLC traces of (a) 1, (b) (R,R)-1 with 99.2% ee value, (c) (R,S)-1 with 97.1% de value, and (d) (S,S)-1 with 98.6% ee value. HPLC
conditions: Daicel Chiralpak AD-H column, 250 mm × 4.6 mm, flow rate = 1 mL/min, column temperature = 30 °C, 254 nm, hexane/(EtOH/
MeOH)/TFA= 85/15(1:1)/0.1 as eluent.
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tive synthesis of C2-symmetric bis-sulfoxides via a chiral-at-
metal strategy.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.inorg-
chem.9b01682.
Summary of crystallographic data and Figures for CD
and HPLC for the compounds (PDF)
Accession Codes
CCDC 1920716−1920719 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Figure 7. Crystal structures of (S,S)-3 (left) and (R,S)-3 (right).
Selected bond lengths (Å) and angles (deg) for (S,S)-3 and (R,S)-3
(in parentheses): S1−O1 = 1.496(4) (1.487(2)), S2−O2 = 1.476(4),
C1−S1−O1 = 107.7(2) (106.9(11)), C8−S1−O1 = 105.8(2)
(106.2(11)), C9−S2−O2 = 105.5(2), C10−S2−O2 = 109.0(19),
C1−S1−C8 = 98.10(17) (98.32(9)), C9−S2−C10 = 97.51(18).
Perspective drawing with 50% probability thermal ellipsoids.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail:cesybh@mail.sysu.edu.cn.
ORCID
Scheme 2. Enantioselective Synthesis of C2-symmetric Bis-
sulfoxide Complex
Bao-Hui Ye: 0000-0003-0990-6661
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (21571195).
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