Oxidative kinetic resolution of racemic secondary alcohols in water with chiral PNNP/Ir catalyst

Article abstract of DOI:10.1039/c2gc00028h

Using water as solvent, the oxidative kinetic resolution of a wide range of racemic secondary alcohols with a chiral PNNP/Ir catalyst was investigated. The catalytic reaction proceeded smoothly with excellent enantioselectivity (up to 97% ee) under mild conditions, providing an environmentally benign process to achieve optically active alcohols.

Full text of DOI:10.1039/c2gc00028h

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COMMUNICATION
Oxidative kinetic resolution of racemic secondary alcohols in water with
chiral PNNP/Ir catalyst†
Juanni Zhang, Xiangren Yang, Han Zhou, Yanyun Li,* Zhenrong Dong and Jingxing Gao*
Received 7th January 2012, Accepted 8th March 2012
DOI: 10.1039/c2gc00028h
variety and abundance of racemic alcohols even make the OKR
method more efficient, and thus, more important than the
reduction of ketones for the production of chiral alcohols.
Recently, several effective non-enzymatic catalysts for the OKR
of racemic alcohols have been developed. Sigman’s and Stoltz’s
groups intensively studied aerobic OKR of secondary alcohols
catalyzed by (−)-sparteine/Pd(II) to conveniently access enantio-
merically enriched secondary alcohols.4,5 Katsuki et al. investi-
gated iron-catalyzed aerobic OKR of secondary alcohols with
good to high enantioselectivity.6 Xia et al. reported chiral Mn
(salen)-complex catalyzed kinetic resolution of secondary alco-
hols with excellent enantioselectivity (up to 98% ee) in water.7
In view of sustainable development, green chemistry has
attracted more and more attention. Compared with other organic
solvents, water is abundant and ubiquitous on the earth as well
as being a clean, safe, and easy-to-handle solvent. However,
most organic reactions are carried out in organic solvents, which
results in about 80% of chemical pollution.8 In the past few
years, chemists have devoted themselves to investigating organic
reactions using water as a solvent.9 Compared with the extensive
research being achieved in asymmetric transfer hydrogenation
using water as solvent,9b there are fewer examples on the OKR
method carried out in water.7,8 To our delight, superior to most
transition metal catalysts which are sensitive to moisture, the
PNNP/Ir catalyst shows good water tolerance.9d Therefore, fol-
lowing our previous research on OKR,3f herein we report for the
first time the OKR of racemic secondary alcohols with PNNP/Ir
catalyst in water, which gives chiral alcohols with excellent
enantioselectivity under mild conditions.
Using water as solvent, the oxidative kinetic resolution of a
wide range of racemic secondary alcohols with a chiral
PNNP/Ir catalyst was investigated. The catalytic reaction pro-
ceeded smoothly with excellent enantioselectivity (up to 97%
ee) under mild conditions, providing an environmentally
benign process to achieve optically active alcohols.
Introduction
Optically active alcohols are important for pharmaceutical and
agrochemical industries. In past decades, the highly efficient
asymmetric reduction of prochiral ketones catalyzed by transition
metal complexes to attain chiral alcohols has made great pro-
gress.1 In 1996, we firstly synthesized a series of C2-symmetric
chiral diimino- and diaminodiphosphine ligands (PNNP-type,
Scheme 1). Since then, a new class of chiral Ru, Rh, Fe and Ir
complexes with PNNP-type ligands have been synthesized and
successfully used as catalysts in the asymmetric transfer hydro-
genation of aromatic ketones, leading to corresponding chiral
alcohols with up to 99% ee and the molar ratio of substrate :
catalyst up to 10 000 : 1.2 Among the successful methods used to
obtain chiral alcohols, oxidative kinetic resolution (OKR) of
racemic alcohols—a process where the two enantiomers of a
racemate are transformed to products at different reaction rates—
is another classical and efficient method.3 In some cases, the
Results and discussion
In the initial experiment, the racemic 1-phenylpropanol was
chosen as a model substrate. The enantioselective oxidation was
carried out in water, using catalyst prepared in situ from the
chiral ligand (S,S)-PNNP and metal precursors. We examined the
OKR of racemic 1-phenylpropanol catalyzed by the chiral PNNP
ligand coupled with various Ru(II), Rh(I), or Ir(I) complexes and
the results are summarized in Table 1. It can be seen that both
the Ru- and Rh-based catalysts were almost inert to the enantio-
selective oxidation of 1-phenylpropanol. Under the same reac-
tion conditions, the Ir-based catalysts exhibited high catalytic
activity and enantioselectivity. With the (S,S)-PNNP/Ir catalyst,
(R)-1-phenylpropanol is fast transferred to propiophenone while
Scheme 1 Chiral diaminodiphosphine ligand.
National Engineering Laboratory for Green Chemical Productions of
Alcohols, Ethers and Esters, State Key Laboratory of Physical
Chemistry of Solid Surfaces, College of Chemistry and Chemical
Engineering, Xiamen University, Xiamen 361005, P.R. China. E-mail:
yanyunli@xmu.edu.cn, jxgao@xmu.edu.cn
†Electronic supplementary information (ESI) available: Typical pro-
cedures for OKR of racemic secondary alcohols and GC analytical data
for chiral aromatic alcohols. See DOI: 10.1039/c2gc00028h
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Table 1 OKR of racemic 1-phenylpropanol catalyzed by the chiral
PNNP ligand and various metal complexes in watera
Entry
Metal complexes
Conv.b [%]
eeb [%]
1
2
3
4
5
6
7
8
9
RuCl2(PPh3)3
Ru(DMSO)4Cl2
RuH2(PPh3)4
—
—
—
2
—
0.3
62
53
1
—
—
—
—
—
—
93
90
—
RhCl(PPh3)3
RhH(CO)(PPh3)3
IrH(CO)(PPh3)3
[IrCl(COD)]2
[IrHCl2(COD)]2
IrCl(CO)(PPh3)2
Fig. 1 Effect of time on the OKR of racemic 1-phenylpropanol with
chiral PNNP/Ir catalyst. Reaction conditions: racemic 1-phenylpropanol
(1 mmol); catalyst (0.005 mmol); solvent: water (8 mL); oxidant:
acetone (2.2 mL); additive: PPNCl (0.05 mmol); sub.–cat.–KOH =
200 : 1 : 2; temperature: 28 °C.
a Reaction conditions: racemic 1-phenylpropanol (1 mmol); catalyst
(0.005 mmol); solvent: water (8 mL); oxidant: acetone (2.2 mL);
additive: PPNCl (0.05 mmol); sub.–cat.–KOH = 200 : 1 : 2; room
temperature; time: 21 h. b Conversions and enantiomeric excesses were
determined by GC analysis using a CP-Chirasil-Dex CB column.
Table 2 Effect of PTC on the OKR of racemic 1-phenylpropanol with
chiral PNNP/Ir catalysta
Entry Additive
Conv.b [%] eeb [%]
(S)-1-phenylpropanol—reacting slowly—is left. The ketone and
the final chiral alcohol are key building blocks in organic syn-
thesis; no waste is produced. Notably, the catalyst generated in
situ from chiral PNNP ligand and [IrCl(COD)]2 gave 62% con-
version and 93% ee at room temperature (Table 1, entry 7).
Therefore, [IrCl(COD)]2 was used as the metal precursor for
further study.
1
2
3
4
5
6
7
Hexadecyltrimethylammonium bromide 45 79
Sodium dodecylbenzenesulfonate
Tetramethylammonium bromide
Benzyltriethylammonium chloride
Sodium dodecyl sulfate
Tetrabutylammonium bromide
Bis(triphenylphosphoranylidene)
ammonium chloride
3
43
46
11
40
61
—
77
84
22
62
97
In kinetic resolutions, enantiomers of a racemic substrate react
at different rates to form a product. If the kinetic resolution is
efficient, one of the enantiomers of the racemic mixture is trans-
formed into the product while the other is recovered unchan-
ged.3a,l Thus, conversion around 50% based on racemic starting
material is a preferred result, which means a maximum yield of
enantiopure compound. To obtain the best resolution efficiency,
the optimal reaction time is a vital factor. The influence of reac-
tion time on the OKR of racemic 1-phenylpropanol with chiral
PNNP/Ir catalyst was examined and the results are shown in
Fig. 1. It indicates that the reaction proceeds rapidly at the begin-
ning and then slows down. The highest ee value was obtained
after 16 h at 28 °C, and the corresponding conversion was 61%.
As the substrate and catalyst are insoluble in water, the
addition of a phase transfer catalyst (PTC) is necessary. The
effects of different PTCs, such as sodium dodecyl sulfate (SDS),
tetrabutyl ammonium bromide (TBAB), and bis(triphenylpho-
sphoranylidene)ammonium chloride (PPNCl) on the OKR of
racemic 1-phenylpropanol were investigated (Table 2). When
PPNCl was introduced to the OKR of racemic 1-phenylpropanol,
the catalytic reaction proceeded smoothly with excellent enan-
tioselectivity (97% ee, Table 2, entry 7).
8
Tetrabutylammonium iodide
1
—
a Reaction conditions: racemic 1-phenylpropanol (1 mmol); catalyst
(0.005 mmol); PTC: (0.05 mmol); solvent: water (8 mL); oxidant:
acetone (2.2 mL); sub.–cat.–KOH = 200 : 1 : 2; temperature: 28 °C; time
16 h. b Conversions and enantiomeric excesses were determined as
shown in Table 1.
Table 3 Effect of the amount of base on the OKR of racemic 1-
phenylpropanol with chiral PNNP/Ir catalysta
Entry
Sub.–cat.–KOH
Conv.b [%]
eeb [%]
1
2
3
4
5
200 : 1 : 0
200 : 1 : 1
200 : 1 : 2
200 : 1 : 4
200 : 1 : 8
—
45
62
75
85
—
66
93
87
66
a Reaction conditions: racemic 1-phenylpropanol (1 mmol); catalyst
(0.005 mmol); solvent: water (8 mL); oxidant: acetone (2.2 mL);
additive: PPNCl (0.05 mmol); room temperature; time: 21 h.
b Conversions and enantiomeric excesses were determined as shown in
Table 1.
Adding a base is known to be crucial to the OKR of racemic
alcohols on reactivity and enantioselectivity.3f Table 3 presents
the effect of bases on the OKR of racemic 1-phenylpropanol. It
shows that no reaction occurred if the base was absent. Both the
reaction rate and ee increased dramatically with the addition of
KOH. With 2 eq. (related to catalyst) of KOH, the OKR afforded
the best ee (Table 3, entry 3). However, excess base decreased
1290 | Green Chem., 2012, 14, 1289–1292
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Table 4 The OKR of various racemic secondary alcohols with chiral
PNNP/Ir catalyst in watera
Entry Substrate
1
Temp. [°C] Time [h] Conv.b [%] eeb [%]
28
28
28
28
40
45
10
16
24
24
44
32
65
61
56
58
51
45
90
97
97
97
89
80
2
3
4
5
6
Fig. 2 Effect of temperature on the OKR of racemic 1-phenylpropanol
with chiral PNNP/Ir catalyst. Reaction conditions: racemic 1-phenylpro-
panol (1 mmol); catalyst (0.005 mmol); solvent: water (8 mL); oxidant:
acetone (2.2 mL); additive: PPNCl (0.05 mmol); sub.–cat.–KOH =
200 : 1 : 2; time: 15 h.
7
28
28
28
28
18
18
15
5
65
61
53
—
54
54
80
84
97
—
64
62
the enantioselectivity although the conversion increased
(Table 3, entries 4, 5). The role of the base is considered to be
increasing the concentration of the 2-propoxide ion, which coor-
dinates with M and then β-eliminates, forming a reducing M–H
species and acetone.1l In our previous study, we observed that
excess base initiated the aldol condensation of acetone, which
could hamper the catalytic cycle.3f These results are also in
accordance with Noyori’s study of OKR with chiral Ru–
TsDPEN complexes in acetone.3n
Moreover, we also investigated the correlation between con-
version, enantioselectivity and temperature of the OKR on
racemic 1-phenylpropanol. As shown in Fig. 2, the reaction rate
accelerated when the reaction temperature increased. However, at
higher temperatures, the ee dropped quickly. Therefore, it is vital
to carry out the OKR reaction under proper temperature.
With the optimized conditions in hand, we next screened the
OKR of various racemic secondary alcohols in water with the
catalyst generated in situ from chiral PNNP ligand and
[IrCl(COD)]2. As shown in Table 4, using water as solvent, the
catalytic reactions of racemic 1-phenylethanol and its derivatives
proceeded smoothly with up to 97% ee under mild conditions.
However, when the alkyl substituent of the substrate was substi-
tuted with a bulkier group, the reaction proceeded slowly with
decreased enantioselectivity (Table 4, entry 5). The decrease in
reactivity and enantioselectivity may be due to the steric repul-
sion between alcohol and catalyst. An unexpected example is 1-
cyclohexyl-1-phenyl-methanol, which has bulkier substituents
but affords excellent enantioselectivity (Table 4, entry 9). Fur-
thermore, enantioselective oxidation of substituted phenylethanol
in water was also investigated. Introduction of a substituent
group to the ortho position of the aromatic ring dramatically
decreases the reactivity and enantioselectivity of the reaction
(Table 4, entries 10, 13, and 16). Xia et al. also observed that in
the OKR of secondary alcohols catalyzed by chiral Mn(salen)-
complex, 2′-chloro-1-phenylethanol gave the lowest conversion
and enantioselectivity.7a The decrease in conversion may be
8
9
33
24
6
10
11
12
6
13
14
15
16
17
28
28
28
28
28
5
1
59
68
1
—
94
97
—
91
4.5
5
22
6.5
59
18
28
5.5
63
93
a Reaction conditions: racemic secondary alcohol (1 mmol); catalyst
(0.005 mmol); solvent: water (8 mL); oxidant: acetone (2.2 mL);
additive: PPNCl (0.05 mmol); sub.–cat.–KOH
=
200 : 1 : 2.
b Conversions were determined by GC analysis and enantiomeric
excesses were determined by GC analysis using a CP-Chirasil-Dex CB
column or HPLC analysis using a Daicel Chiralcel OD column.
caused by the steric hindrance of the substituent. When the
chloro substituent is on the meta or para position of the aromatic
ring, the activity was greatly increased, although the enantios-
electivity decreased (Table 4, entries 11 and 12). However, with
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Y. T. Jiang and X. M. Zhang, Chem. Commun., 2010, 46, 3979;
(d) F. Naud, F. Spindler, C. J. Rueggeberg, A. T. Schmidt and H.
U. Blaser, Org. Process Res. Dev., 2007, 11, 519; (e) S. Diez-Gondlez and
S. P. Nolan, Org. Prep. Proced. Int., 2007, 39, 523; (f) T. Ikariya and A.
J. Blacker, Acc. Chem. Res., 2007, 40, 1300; (g) S. Gladiali and
E. Alberico, Chem. Soc. Rev., 2006, 35, 226; (h) J. S. M. Samec, J.
E. Bäckvall, P. G. Andersson and P. Brandt, Chem. Soc. Rev., 2006, 35,
237; (i) K. Muñiz, Angew. Chem., Int. Ed., 2005, 44, 6622; ( j) R. Noyori,
Angew. Chem., Int. Ed., 2002, 41, 2008; (k) R. Noyori and T. Ohkuma,
Angew. Chem., Int. Ed., 2001, 40, 40; (l) R. Noyori, M. Yamakawa and
S. Hashiguchi, J. Org. Chem., 2001, 66, 7931.
electron donating groups, such as a methyl- or methoxy-substitu-
ent on the meta or para position of the aromatic ring, the OKR
leads to excellent results in terms of both conversion and enan-
tioselectivity (Table 4, entries 14, 15, 17 and 18). These results
show that the catalyst is highly active and enantioselective for
the OKR of a wide range of racemic alcohols in water.
Conclusions
2 (a) Z. R. Dong, Y. Y. Li, J. S. Chen, B. Z. Li, Y. Xing and J. X. Gao, Org.
Lett., 2005, 7, 1043; (b) J. S. Chen, L. L. Chen, Y. Xing, G. Chen, W.
Y. Shen, Z. R. Dong, Y. Y. Li and J. X. Gao, Acta Chim. Sin., 2004, 62,
1745; (c) Y. Y. Li, H. Zhang, J. S. Chen, X. L. Liao, Z. R. Dong and J.
X. Gao, J. Mol. Catal. A: Chem., 2004, 218, 153; (d) J. S. Chen, Y. Y. Li,
Z. R. Dong, B. Z. Li and J. X. Gao, Tetrahedron Lett., 2004, 45, 8415;
(e) H. Zhang, C. B. Yang, Y. Y. Li, Z. R. Dong, J. X. Gao, H. Nakamura,
K. Murata and T. Ikariya, Chem. Commun., 2003, 142; (f) J. X. Gao,
X. D. Yi, P. P. Xu, C. L. Tang, H. Zhang, H. L. Wan and T. Ikariya, J. Mol.
Catal. A: Chem., 2000, 159, 3; (g) J. X. Gao, X. D. Yi, P. P. Xu,
C. L. Tang, H. L. Wan and T. Ikariya, J. Organomet. Chem., 1999, 592,
290; (h) J. X. Gao, T. Ikariya and R. Noyori, Organometallics, 1996, 15,
1087.
In summary, when using water as solvent, the OKR of various
racemic secondary alcohols with chiral PNNP/Ir catalyst pro-
ceeded smoothly with up to 97% ee under mild conditions.
Being highly efficient as well as greatly reducing the need for an
organic solvent, this method presents an environmentally benign
process to achieve optically active alcohols. Further studies on
the mechanism are now being investigated in our laboratory.
Experimental section
3 (a) H. Pellissier, Adv. Synth. Catal., 2011, 353, 1613; (b) M. Tomizawa,
M. Shibuya and Y. Iwabuchi, Org. Lett., 2009, 11, 1829; (c) M. Wills,
Angew. Chem., Int. Ed., 2008, 47, 4264; (d) S. Arita, T. Koike, Y. Kayaki
and T. Ikariya, Angew. Chem., Int. Ed., 2008, 47, 2447; (e) O. Onomura,
H. Arimoto, Y. Matsumura and Y. Demizu, Tetrahedron Lett., 2007, 48,
8668; (f) Y. Y. Li, X. Q. Zhang, Z. R. Dong, W. Y. Shen, G. Chen and J.
X. Gao, Org. Lett., 2006, 8, 5565; (g) V. D. Pawar, S. Bettigeri, S.
S. Weng, J. Q. Kao and C. T. Chen, J. Am. Chem. Soc., 2006, 128, 6308;
(h) A. T. Radosevich, C. Musich and F. D. Toste, J. Am. Chem. Soc., 2005,
127, 1090; (i) Y. Nishibayashi, A. Yamauchi, G. Onodera and S. Uemura,
J. Org. Chem., 2003, 68, 5875; ( j) D. E. J. E. Robinson and S. D. Bull,
Tetrahedron: Asymmetry, 2003, 14, 1407; (k) J. W. Faller and A.
R. Lavoie, Org. Lett., 2001, 3, 3703; (l) J. M. Keith, J. F. Larrow and E.
N. Jacobsen, Adv. Synth. Catal., 2001, 343, 5; (m) K. Masutani, T. Uchida,
R. Irie and T. Katsuki, Tetrahedron Lett., 2000, 41, 5119;
(n) S. Hashiguchi, A. Fujii, K. J. Haack, K. Matsumura, T. Ikariya and
R. Noyori, Angew. Chem., Int. Ed. Engl., 1997, 36, 288; (o) Y. Kashiwagi,
Y. Yanagisawa, F. Kurashima, J. Anzai, T. Osa and J. M. Bobbitt, Chem.
Commun., 1996, 2745.
4 (a) M. S. Sigman and D. R. Jensen, Acc. Chem. Res., 2006, 39, 221;
(b) D. R. Jensen, J. S. Pugsley and M. S. Sigman, J. Am. Chem. Soc.,
2001, 123, 7475.
5 (a) B. M. Stoltz, Chem. Lett., 2004, 33, 362; (b) E. M. Ferreira and B.
M. Stoltz, J. Am. Chem. Soc., 2001, 123, 7725.
6 T. Kunisu, T. Oguma and T. Katsuki, J. Am. Chem. Soc., 2011, 133,
12937.
7 (a) W. Sun, H. W. Wang, C. G. Xia, J. W. Li and P. Q. Zhao, Angew.
Chem., Int. Ed., 2003, 42, 1042; (b) Z. Li, Z. H. Tang, X. X. Hu and C.
G. Xia, Chem.–Eur. J., 2005, 11, 1210.
General procedure for the catalytic reaction
Under a nitrogen atmosphere, the metal complex and chiral
PNNP ligand were placed in a Schlenk tube equipped with a
Teflon-coated magnetic stirring bar. Dichloromethane (0.5 mL)
was then added and the mixture was stirred for a few minutes to
generate catalyst in situ. Subsequently, acetone, PPNCl, and
water were successively introduced. After the mixture was stirred
for 1 h, an appropriate amount of KOH/iPrOH solution was
added. After 0.5 h, the substrate was added and the mixture was
continually stirred at the desired temperature for the required
reaction time. At the end of the reaction, the product was
extracted with ethyl acetate and then passed through a short
silica gel column. The conversion of the alcohol was determined
by GC and the ee was determined by GC or HPLC.
Acknowledgements
We would like to thank the National Natural Science Foundation
of China (No. 20423002; 20923004; 21173176), NFFTBS (No.
J1030415), Program for Changjiang Scholars and Innovative
Research Team in University (No. IRT1036), and State Key Lab-
oratory of Physical Chemistry of Solid Surfaces for financial
support.
8 K. H. Shaughnessy and R. B. DeVasher, Curr. Org. Chem., 2005, 9, 585.
9 (a) R. N. Butler and A. G. Coyne, Chem. Rev., 2010, 110, 6302;
(b) X. F. Wu, C. Wang and J. L. Xiao, Platinum Met. Rev., 2010, 54, 3;
(c) C. F. Pan and Z. Y. Wang, Coord. Chem. Rev., 2008, 252, 736;
(d) Y. Xing, J. S. Chen, Z. R. Dong, Y. Y. Li and J. X. Gao, Tetrahedron
Lett., 2006, 47, 4501; (e) U. M. Lindström, Chem. Rev., 2002, 102, 2751;
(f) C. J. Li, in Green Chemistry: Frontiers in Benign Chemical Syntheses
and Processes, ed. P. T. Anastas and T. C. Williamson, Oxford University
Press, New York, 1998, ch. 14, p. 234.
Notes and references
1 (a) T. Irrgang, D. Friedrich and R. Kempe, Angew. Chem., Int. Ed., 2011,
50, 2183; (b) J. H. Xie, X. Y. Liu, J. B. Xie, L. X. Wang and Q. L. Zhou,
Angew. Chem., Int. Ed., 2011, 50, 7329; (c) W. Li, G. H. Hou, C. J. Wang,
1292 | Green Chem., 2012, 14, 1289–1292
This journal is © The Royal Society of Chemistry 2012