Novel chiral C2-symmetric multidentate aminophosphine ligands for use in catalytic asymmetric reduction of ketones

Article abstract of DOI:10.1016/j.cclet.2013.03.043

A series of novel chiral C₂-symmetric multidentate aminophosphine ligands have been successfully synthesized by Schiff-base condensation of bis(o-formylphenyl)phenylphosphane and easily available monoprotected (1R,2R)-diaminocyclohexane. The ca

Full text of DOI:10.1016/j.cclet.2013.03.043

Chinese Chemical Letters 24 (2013) 527–530
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Chinese Chemical Letters
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Original article
Novel chiral C2-symmetric multidentate aminophosphine ligands for use in
catalytic asymmetric reduction of ketones
*
Ya-Qing Xu, Shen-Luan Yu, Yan-Yun Li , Zhen-Rong Dong, Jing-Xing Gao
State Key Laboratory of Physical Chemistry of Solid Surfaces, National Engineering Laboratory for Green Chemical Productions of Alcohols-Ethers-Esters and Department of Chemistry,
College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A series of novel chiral C2-symmetric multidentate aminophosphine ligands have been successfully
synthesized by Schiff-base condensation of bis(o-formylphenyl)phenylphosphane and easily available
monoprotected (1R,2R)-diaminocyclohexane. The catalytic properties of these ligands were investigated
in Ir-catalyzed asymmetric transfer hydrogenation of various aromatic ketones, giving the correspond-
ing optical active alcohols with up to 98% conversion and good ee under mild reaction conditions.
ß 2013 Yan-Yun Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Received 24 January 2013
Received in revised form 6 March 2013
Accepted 14 March 2013
Available online 19 April 2013
Keywords:
Asymmetric catalysis
Iridium
Aromatic ketones
Aminophosphine ligands
Asymmetric transfer hydrogenation
1. Introduction
our study on chiral aminophosphine ligands and related
asymmetric catalysis, herein we report the synthesis and full
The catalytic synthesis of chiral secondary alcohols, which
are key building blocks in the pharmaceuticals, agrochemicals,
and fragrances industries, continues to be a topic of great
interest in asymmetric catalysis. A particularly useful method
for this transformation is asymmetric transfer hydrogenation
(ATH) catalyzed by metal complexes associated with various
characterization of novel chiral C2-symmetric multidentate
aminophosphine ligands as well as their catalytic evaluation
in the enantioselective transfer hydrogenation of aromatic
ketones.
2. Experimental
chiral ligands using 2-propanol as
a safe, nontoxic, and
environmentally friendly hydrogen source [1–4]. During this
process, a chiral ligand plays a significant role in the catalytic
reaction. Therefore, the design and synthesis of new efficient
chiral ligands is still a challenge in the area of asymmetric
catalysis. For the past two decades, many chiral ligands having
heterodonor atoms with nitrogen and phosphorus functional
moieties have been prepared and their usefulness for metal-
catalyzed ATH of aromatic ketones have been studied [5–9].
Until now, there have been only a few reports on the use of
multidentate aminophosphine ligands as chiral inductors for
ATH of ketones. We recently reported a new and easy method for
the preparation of chiral multidentate ligands containing
nitrogen and phosphorus donors [10–12], which are efficient
ligands in asymmetric reduction of ketones. In continuation of
2.1. General
Unless otherwise stated, all reactions were carried out under an
atmosphere of nitrogen using conventional Schlenk glassware.
Solvents were dried using standard procedures and distilled
immediately prior to use. Bis(o-formylphenyl)phenylphosphane 1
was prepared as previously described [13]. (1R,2R)-1-(N-t-buty-
loxycarbonylamino)-2-aminocyclohexane 2 was prepared accord-
ing to the literature [14]. NMR spectra were recorded on Bruker AV
400 or Bruker AV 500 spectrometer, with
TMS or solvent peaks [chloroform: 7.26 (1H), 77.00
d
referenced to external
13C)],
(
respectively. Mass spectra were obtained on Bruker En Apex ultra
7.0T FT-MS. All melting points were measured using X-4 digital
melting point apparatus and were uncorrected. Optical rotation
values were measured on Perkin-Elmer 341 polarimeter. The
conversion and ee values were determined by a GC-950 instrument
with an FID detector and
a CP-Chiralsil-Dex CB column
* Corresponding author.
E-mail address: yanyunli@xmu.edu.cn (Y.-Y. Li).
(25 m ꢀ 0.25 mm, 0.25 m film).
m
1001-8417/$ – see front matter ß 2013 Yan-Yun Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.03.043

[
Y.-Q. Xu et al. / Chinese Chemical Letters 24 (2013) 527–530
O
N
HN
HN
O
a
PPh
O
N
O
OHC
P
3
+
O
b
H2N HN
O
OHC
2
1
O
NH NH2
NH HN
O
d
c
PPh
PPh
O
NH NH2
NH HN
O
5
4
Scheme 1. Synthesis of novel chiral C2-symmetric multidentate aminophosphine ligands. Reagent and conditions: (a) CH3OH, reflux, 34 h; (b) CH3OH, NaBH4, reflux, 12 h; (c)
(1) CH3OH, reflux; (2) NaBH4; (d) CF3COOH, CH2Cl2, r.t., 12 h.
2.2. Synthesis of chiral C2-symmetric multidentate aminophosphine
ligands
stirred at 40 8C for a certain period of time. At the end of
experiment, the reaction products were analyzed by GC using a
chiral CP-Chiralsil-Dex CB column.
To a mixture of bis(o-formylphenyl)phenylphosphane 1 and
(1R,2R)-1-(N-t-butyloxycarbonylamino)-2-aminocyclohexane
2
3. Results and discussion
was added methanol under nitrogen atmosphere. The reaction
mixture was heated to reflux with vigorous stirring for 34 h.
Reaction monitored by 31P NMR showed full conversion of 1. The
resulting solution was slowly cooled to room temperature under
nitrogen atmosphere. The solvent was evaporated and the residue
was dried under vacuum to afford 3 in 98% yield as a pale yellow
solid (Scheme 1).
A solutionofimine3and NaBH4 inabsolutemethanolwasheated
under reflux for 12 h. The reaction mixture was then allowed to cool
to room temperature and quenched by adding water and the
solvents were removed under reduced pressure. The residue was
extracted with CH2Cl2 and the combined organic phases were
washed withwater. Afterdryingoveranhydrous Na2SO4, the solvent
was removed under reduced pressure and the resulting product was
dried under vacuum to afford 4 in 91% yield as a white solid.
To a stirred solution of 4 in CH2Cl2 at 0 8C was added
trifluoroacetic acid under nitrogen atmosphere. The reaction
mixture was allowed to warm to room temperature and stirred
for 12 h, diluted with CH2Cl2 and poured into saturated NaHCO3
solution. The mixture was extracted with CH2Cl2 and dried over
anhydrous Na2SO4. After the solvent was removed, the product
was dried under vacuum to afford 5 in 96% yield as a white solid.
The chiral ligand 3 was prepared by the condensation of bis(o-
formylphenyl)phenylphosphane 1 and monoprotected diamine 2
in refluxing methanol for 34 h and obtained as a pale yellow solid
in 98% yield. It featured the HRMS signals at 711.4034 [M+H]+ [15].
The 1H NMR spectrum presented two singlets at
the two imino protons. The 31P NMR spectrum exhibited a singlet
at
d 8.79 and 8.76 for
d
ꢁ20.55. Reduction of 3 with excess NaBH4 was carried out in
refluxing methanol, giving the corresponding amine ligand 4 as a
white solid in 91% yield, featuring the HRMS signals at 715.4345
[M+H]+. It can also be synthesized in one pot from bis(o-
formylphenyl)phenylphosphane 1 and monoprotected diamine
2. The appearance of a broad peak in the 1H NMR spectrum of
ligand 4 at
imino groups were reduced to the corresponding amino groups.
The 31P NMR spectrum showed a singlet at
d 4.42–5.05 for the –NH– protons indicated that the two
d
ꢁ25.35. Deprotection
of the Boc group of amine ligand 4 with CF3COOH gave primary
amine ligand 5 in 96% yield as a white solid, featuring the HRMS
signals at 515.3303 [M+H]+. The disappearance of a singlet peak
(18 H) in the 1H NMR spectrum of ligand 4 at
groups indicated that the ligand
deprotected. The 31P NMR spectrum showed a singlet at
d
1.44 for the Boc
had been successfully
ꢁ24.80.
4
d
In order to examine the chiral induction abilities of these C2-
symmetric multidentate aminophosphine ligands, we investigated
the Ir-catalyzed ATH of aromatic ketones using 2-propanol as a
hydrogen source. Typical results were listed in Table 1. Initially, we
chose propiophenone as a model substrate and conducted the
catalytic hydrogenation in the presence of KOH. It could be seen
that when (R,R)-5 was employed as chiral auxiliary, [IrCl(COD)]2 or
[IrHCl2(COD)]2 was used as metallic precursor, good conversions
but low enantioselectivities were obtained (98% conversion,
2.3. ATH of aromatic ketones
To a 50 mL Schlenk tube were added Ir complex (0.005 mmol)
and ligand 5 (0.005 mmol). Under nitrogen atmosphere, freshly
distilled and degassed iPrOH (10 mL) were introduced. After
stirring at 40 8C for 30 min, an appropriate amount of KOH/iPrOH
solution was then added. The mixture was continually stirred for
another 15 min, ketone was then introduced and the mixture was

Y.-Q. Xu et al. / Chinese Chemical Letters 24 (2013) 527–530
529
Table 1
ATH of aromatic ketones catalyzed by chiral multidentate aminophosphine ligand/Ir (I) systems.a
Ir (I) complexes/L*
O
OH
[
.
*
i
R1
R2
R1
R2
KOH/ PrOH
Entry
1
Ketones
Ligand
Metal complex
[IrCl(COD)]2
Time (h)
2
Conv.b (%)
98
eeb (%)
Config.c
(R,R)-5
22
S
S
S
O
[TD$INLINE]
2
3
(R,R)-5
(R,R)-5
[IrHCl2(COD)]2
IrCl(CO)(PPh3)2
2
2
98
80
27
60
O
O
[TD$INLINE]
[TD$INLINE]
4
5
(R,R)-5
(R,R)-5
(R,R)-3
(R,R)-4
(R,R)-5
(R,R)-5
(R,R)-5
IrCl(COD)PPh3
IrH(CO)(PPh3)3
IrH(CO)(PPh3)3
IrH(CO)(PPh3)3
IrH(CO)(PPh3)3
IrH(CO)(PPh3)3
IrH(CO)(PPh3)3
2
5
5
5
5
5
5
98
97
14
12
55
32
97
54
80
64
63
17
35
48
S
S
R
R
S
S
S
O
O
O
O
O
O
O
[TD$INLINE]
[TD$INLINE]
6
[TD$INLINE]
7
[TD$INLINE]
8
[TD$INLINE]
9
[TD$INLINE]
10
[TD$INLINE]
11
12
(R,R)-5
(R,R)-5
IrH(CO)(PPh3)3
IrH(CO)(PPh3)3
5
5
71
98
66
28
S
S
O
[TD$INLINE]
O
[TD$INLINE]
CF3
13
14
(R,R)-5
IrH(CO)(PPh3)3
5
93
20
S
O
[TD$INLINE]
F3C
(R,R)-5
(R,R)-5
IrH(CO)(PPh3)3
IrH(CO)(PPh3)3
5
5
80
90
80
79
S
S
O
O
[TD$INLINE]
15
[TD$INLINE]
a
Reaction conditions: ketone: 0.5 mmol; ligand: 0.005 mmol; Ir(I) complex: 0.005 mmol; 0.2 mol/L KOH/iPrOH: 0.1 mL; 2-propanol: 10 mL; temperature: 40 8C.
Conversions and enantiomeric excesses were determined by GC analysis using a CP-Chiralsil-Dex CB column.
b
c
The configurations were determined by comparison of the retention times of the enantiomers on the GC traces with literature values.

530
Y.-Q. Xu et al. / Chinese Chemical Letters 24 (2013) 527–530
ketones with chiral rhodium-diamine catalyst, Tetrahedron 60 (2004) 7411–
7417.
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22%–27% ee, Table 1, entries 1 and 2). Improved enantioselectivity
was obtained when IrCl(CO)(PPh3)2 or IrCl(COD)PPh3 was used
(54%–60% ee, Table 1, entries 3 and 4). The catalytic system
generated in situ from (R,R)-5 and IrH(CO)(PPh3)3 gave the best
enantioselectivity (80% ee, Table 1, entry 5). Under the same
conditions, C2-symmetric multidentate aminophosphine ligands
(R,R)-3 and (R,R)-4 exhibited low activities, producing (R)-1-
phenylpropan-1-ol with only 12%–14% yield and 63%–64% ee
(Table 1, entries 6 and 7). These results indicated that the structure
of amine groups –NH2 in the ligand 5 is responsible for the good
activity as well as enantioselectivity and the –NH2 linkage can
possibly stabilize a catalytic transition state [5].
With the optimized conditions in hand, we examined the
asymmetric reduction of a wide range of aromatic ketones using
the catalytic system of IrH(CO)(PPh3)3 in combination with (R,R)-5.
For acetophenone and its derivatives, the catalyst system showed
decreased enantioselectivities (17%–66% ee; Table 1, entries 8–13).
In the case of more hindered aromatic ketones, such as
isobutyrophenone and cyclohexyl phenyl ketone, equally good
enantioselectivities were observed with certain decrease in
activity (Table 1, entries 14 and 15). These may imply that the
interaction between substrate and chiral ligands plays an
important role in asymmetric catalysis.
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diphosphine/diamine tetradentate ligand for asymmetric transfer hydrogenation
of aromatic ketones, Organometallics 15 (1996) 1087–1089.
[7] C. Wang, X.F. Wu, J.L. Xiao, Broader, greener, and more efficient: recent advances
in asymmetric transfer hydrogenation, Chem. Asian J. 3 (2008) 1750–1770.
[8] V.A. Pavlov, C2 and C1 symmetry of chiral auxiliaries in catalytic reactions on
metal complexes, Tetrahedron 64 (2008) 1147–1179.
6
ˇ
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´
ˇ
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[9] J. Vaclavık, P. Kacer, M. Kuzma, L. Cerveny, Opportunities offered by chiral h -
arene/N-arylsulfonyldiamine-RuII catalysts in the asymmetric transfer hydro-
genation of ketones and imines, Molecules 16 (2011) 5460–5495.
[10] S.L. Yu, Y.Y. Li, Z.R. Dong, et al., Synthesis of novel chiral N, P-containing multi-
dentate ligands and their applications in asymmetric transfer hydrogenation,
Chin. Chem. Lett. 22 (2011) 1269–1272.
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Lett. 23 (2012) 533–536.
[12] S.L. Yu, W.Y. Shen, Y.Y. Li, et al., Iron-catalyzed highly enantioselective reduction
of aromatic ketones with chiral P2N4-type macrocycles, Adv. Synth. Catal. 354
(2012) 818–822.
4. Conclusion
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for ferromagnetic interactions between aminoxyl units, Eur. J. Org. Chem. (2003)
167–171.
In conclusion, we have developed
a series of novel
[14] P. Lagriffoule, P. Wittung, M. Eriksson, et al., Peptide nucleic acids with a con-
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(1997) 912–919.
C2-symmetric chiral multidentate aminophosphine ligands from
commercially available (1R,2R)-diaminocyclohexane through a
convenient transformation. These ligands have been successfully
employed in the Ir-catalyzed asymmetric reduction of various
aromatic ketones to obtain corresponding optically active alcohols
with up to 98% conversion and 80% ee. The results demonstrated
that the ligand with primary amine tended to give higher
enantioselectivity. Furthermore, in comparison with the chiral
N,P-ligands traditionally used in the catalytic enantioselective
transfer hydrogenation, these multidentate aminophosphine
ligands have more coordination sites, which maybe result in
unique features in asymmetric reaction. Further investigation of
these chiral aminophosphine ligands is in progress.
20
[15] Compound 2: ½aꢂD +32.8 (c 0.4, CH2Cl2); 1H NMR (500 MHz, CDCl3): d 4.65 (d, 1H,
J = 8.0 Hz, NH carbamate), 3.28–3.05 (m, 1H, CHN), 2.36 (dt, 1H, J = 10.0 Hz and
3.5 Hz, CHN), 2.05–1.95 (m, 2H, CH2, cycl), 1.78–1.65 (m, 4H, CH2, cycl and NH2),
1.45 (s, 9H, tBoc), 1.38–1.05 (m, 4H, 2CH2, cycl). Compound 3: mp 114–116 8C;
20
½aꢂD +53.5 (c 0.2, CH2Cl2); 1H NMR (500 MHz, CDCl3): d 8.79 (s, 1H), 8.76 (s, 1H),
8.02 (s, 1H), 7.94 (s, 1H), 7.68–7.56 (m, 1H), 7.40–7.18 (m, 10H), 6.90–6.77 (m,
2H), 3.58–3.42 (m, 2H), 2.94–2.77 (m, 2H), 2.23–2.08 (m, 2H), 2.08–1.95 (m, 2H),
1.75–1.62 (m, 4H), 1.50–1.42 (m, 4H), 1.34 (s, 18H), 1.25–1.16 (m, 4H); 13C NMR
(125 MHz, CDCl3): d 159.0, 158.8, 155.3, 139.8 (d, J = 18.8 Hz), 139.3 (d,
J = 17.5 Hz), 136.4 (d, J = 16.3 Hz), 136.2, 134.4, 134.2, 133.7, 133.4, 130.3,
130.2, 129.1, 128.9, 128.7, 128.6, 128.2, 78.8, 73.9, 54.3, 33.2, 33.0, 31.8, 28.4,
24.9, 24.8, 24.0 (d); 31P NMR (202 MHz, CDCl3): d ꢁ20.55; HRMS (ESI, m/z) Calcd.
for C42H56N4O4P [M+H]+: 711.4034, found: 711.4034. Compound 4: mp 134–
20
136 8C; ½aꢂD ꢁ7.0 (c 0.2, CH2Cl2); 1H NMR (500 MHz, CDCl3): d 7.62–7.45 (m, 2H),
7.43–7.30 (m, 5H), 7.29–7.20 (m, 2H), 7.20–7.18 (m, 2H), 6.87–6.72 (m, 2H), 5.05–
4.42 (br m, 2H), 4.08–3.82 (m, 4H), 3.35–3.11 (m, 2H), 2.26–2.14 (m, 2 H), 2.10–
2.00 (m, 2H), 1.98–1.85 (m, 4H), 1.69–1.56 (m, 4H), 1.44 (s, 18 H), 1.30–1.21 (m, 2
H), 1.13–0.98 (m, 6 H); 13C NMR (125 MHz, CDCl3): d 156.1, 145.0, 135.0, 134.3,
134.1, 133.6, 133.4, 129.1, 129.0, 128.9, 128.7, 128.6, 127.2, 60.6, 60.4, 54.6, 49.3,
49.2, 49.1, 49.0, 32.7, 32.6, 31.6, 28.4, 24.7, 24.5; 31P NMR (202 MHz, CDCl3): d
ꢁ25.35; HRMS (ESI, m/z) Calcd. for C42H60N4O4P [M+H]+: 715.4347, found:
Acknowledgments
We would like to thank the National Natural Science Foundation
of China (No. 21173176), Program for Changjiang Scholars and
Innovative Research Team in University (No. IRT1036) and State Key
Laboratory of Physical Chemistry of Solid Surfaces for financial
support.
20
715.4345. Compound 5: mp 60–62 8C; ½aꢂD ꢁ37.0 (c 0.2, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d 7.58–7.36 (m, 3H), 7.35–7.28 (m, 4H), 7.26–7.13 (m, 4H),
6.92–6.75 (m, 2H), 4.12–3.73 (m, 4H), 3.25 (br s, 6H), 2.46–2.28 (m, 2H), 2.28–2.00
(m, 4H), 1.98–1.84 (m, 2H), 1.75–1.60 (m, 4H), 1.28–1.12 (m, 6H), 1.03–0.82 (m,
2H); 13C NMR (100 MHz, CDCl3): d 144.5 (d, J = 32 Hz), 144.2 (d, J = 31 Hz), 136.4
(d, J = 7 Hz), 135.6 (d, J = 12 Hz), 135.4 (d, J = 11 Hz), 134.4, 134.2, 134.0, 133.8,
129.8 (d, J = 5 Hz), 129.3, 128.9, 128.7 (d, J = 7 Hz), 127.7 (d, J = 12 Hz), 61.9 (d,
J = 17 Hz), 55.1 (d, J = 17 Hz), 50.0, 49.8, 49.4, 49.3, 33.8, 33.4, 31.2, 31.1, 25.1 (d),
24.8 (d). 31P NMR (162 MHz, CDCl3): d ꢁ 24.80; HRMS (ESI, m/z) Calcd. for
C32H44N4P [M+H]+: 515.3298, found: 515.3303.
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