The Mn(Salen)-catalyzed oxidative kinetic resolution of secondary alcohols: reaction development and scope

Article abstract of DOI:10.1016/j.tetasy.2008.10.008

A series of chiral Mn(Salen) complexes have been synthesized and submitted to the kinetic resolution of secondary alcohols bearing a large hindrance in the biphasic system, which is composed of water and CH₂Cl₂. After evaluating the appropriate complex, additive, and other conditions, chiral secondary alcohols were obtained with enantiomeric excesses of up to 98.6% in 6 min.

Full text of DOI:10.1016/j.tetasy.2008.10.008

Tetrahedron: Asymmetry 19 (2008) 2359–2362
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The Mn(Salen)-catalyzed oxidative kinetic resolution of secondary alcohols:
reaction development and scope
a,
Qigan Cheng a,b, Fanguo Deng a,b, Chungu Xia a, , Wei Sun
*
*
a State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, PR China
b Graduate School of the Chinese Academy of Sciences, Beijing 100039, PR 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 chiral Mn(Salen) complexes have been synthesized and submitted to the kinetic resolution of
secondary alcohols bearing a large hindrance in the biphasic system, which is composed of water and
CH2Cl2. After evaluating the appropriate complex, additive, and other conditions, chiral secondary alco-
hols were obtained with enantiomeric excesses of up to 98.6% in 6 min.
Received 2 August 2008
Accepted 1 October 2008
Available online 5 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
from methyl to ethyl or other large groups (Fig. 1), the enantio-
meric excesses value decreased sharply.5a As a result, we envi-
Enantiomerically pure secondary alcohols are pivotal com-
pounds in organic synthesis, and are represented in many impor-
tant target molecules, intermediates, and reagents.1 They have
been prepared by many methods, including asymmetric hydroge-
nation of prochiral ketones catalyzed by metal complexes;2 how-
ever, the oxidative kinetic resolution (OKR) of racemic alcohols to
obtain optically active alcohols is also an attractive and practical
method.3,4
sioned that the substituents on the Mn(salen) catalysts may play
a crucial role in this change. Therefore, we synthesized a series of
chiral Mn(salen) complexes with diverse substituents and different
diamine backbones, and evaluated their abilities in the OKR of
racemic secondary alcohols.
2. Results and discussion
Recently, we have reported a convenient OKR of racemic sec-
ondary alcohols catalyzed by chiral Mn(salen) catalysts together
with the cooxidant diacetoxyiodobenzene (PhI(OAc)2) in water or
biphasic system.5,6 Although we have successfully built a system
for the oxidative kinetic resolution, and the values of enantiomeric
excess for a great deal of secondary alcohols can reach >99.9%, the
substrate scope remains to be extended. We found that when the
small substituents in secondary alcohols were made to change
2.1. Synthesis of the chiral Mn(Salen) complexes
As shown in Figure 2, a variety of chiral Mn(salen) complexes
with different substitutes on the aromatic rings and diamine back-
bones were prepared by the procedure reported in the
literature.5a,7
2.2. OKR reaction of secondary alcohols
These chiral Mn(salen) complexes, based on different chiral dia-
mine backbones and bearing various groups on the aromatic rings,
were then evaluated for the OKR with racemic 1-phenyl-1-propa-
nol as a representative substrate. In a typical experiment, as we
reported previously,5 the reactions were carried out in a 1 equiv
of 1-phenyl-1propanol and 0.7 equiv of PhI(OAc)2 with 2 mol % of
chiral Mn(salen) complexes and 8 mol % of N(C4H9)4Br at room
temperature for 0.5 h (Table 1). Among all the tested Mn(salen)
complexes, complex 1c showed the highest enantioselectivity,
and only 24.2% ee was observed (Table 1, entry 3).8 From the re-
sults summarized in Table 1, we can conclude that the tert-butyl
groups on the 5,50-positions of salicylaldehyde parts are very
important for OKR. At the same time, the chiral diamine backbone
also plays a critical role in the OKR of the secondary alcohol. When
OH
L
S
L=large substituent, S=small substituent
Figure 1. Structure of the secondary alcohol.
* Corresponding authors. Tel.: +86 931 496 8278; fax: +86 931 827 7088 (W.S.).
E-mail addresses: wsun@lzb.ac.cn, weisun76@gmail.com (W. Sun).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.10.008

2360
Q. Cheng et al. / Tetrahedron: Asymmetry 19 (2008) 2359–2362
Ph
N
Ph
N
N
O
N
O
N
O
N
O
Mn
Cl
Mn
Cl
Mn
Cl
R1
R1 R1
O
O
R1
R1
R1
R2
R2
R2
R2
R2
R2
1a R1=R2=t-Bu;
2a R1=R2=t-Bu;
3a R1=R2=t-Bu;
3b R1=t-Bu, R2=H
1b R1=t-Bu, R2=CH3
1c R1=t-Bu, R2=H
2b R1=t-Bu, R2=CH3
2c R1=t-Bu, R2=H
2d R1=H, R2=t-Bu
1d R1=H, R2=t-Bu
1e R1=CH3,R2=Adamantyl
Figure 2. The various chiral Mn(Salen) complexes.
Table 1
Table 2
Screening of Mn(salen) complex for the OKR of racemic 1-phenyl-1-propanola
Evaluation of the kinetic resolution of 1-phenyl-1-propanol under different reaction
conditionsa
OH
OH
O
OH
O
OH
2mol%salen-Mn
∗
1c, additive
∗
8mol%N(C4H9)4Br,RT,0.5h
RT, 6 min.
d
Entry
Catalyst
1a
Conversionb (%)
eec (%)
krel
Entry Additive Additive loading
(mol %)
CH2Cl2
(ml)
H2O
(ml)
Conv.b
(%)
eec
(%)
krel
g
1
2
3
4
5
6
7
8
9
61.1
12.2
11.2
24.2
3.4
0
11.5
0
1.7
2.9
3.5
12.9
1.30
1.33
1.73
<1.1
1.44
<1.1
1b
1c
1d
1e
2a
2b
2c
2d
3a
3b
54.1
59.0
54.3
51.6
46.9
48.6
63.2
44.0
53.3
62.3
1
2
3
4
5
6
7
8
9
4d,e
4e
5
5
5
5
5
6
7
8
8
4
6
8
10
12
8
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
0.5
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
1
59.0
60.5
44.4
60.7
63.8
63.8
66.0
68.6
68.2
68.0
64.6
67.6
68.3
65.0
64.4
73.7
77.7
24.2
8.4
1.73
1.20
1.47
2.83
3.28
3.28
3.02
3.26
3.36
3.67
3.58
3.24
3.58
1.87
2.00
3.43
3.88
11.3
46.5
56.8
56.6
56.4
63.6
64.4
68.0
61.6
61.7
67.3
32.3
35.1
74.0
85.4
<1.1
<1.1
1.30
10
11
8
10
11
12
13
14
15
16
17
8
9
8
8
8
8
8
8
8
8
a
Reaction was carried out at room temperature for 0.5 h with catalyst (2 mol %),
N(C4H9)4Br (8 mol %), 1-phenyl-1propanol (0.25 mmol), PhI(OAc)2(0.175 mmol),
and H2O(1 ml), CH2Cl2 (0.5 ml).
10
11
12
13
8f
8f
b
Determined by GC using an internal standard.
Determined by GC on a CP-Chirasil-Dex CB Capillary column.
krel = ln[(1 ꢀ C)(1 ꢀ ee)]/ln[(1 ꢀ C)(1 + ee)].
c
d
a
Reaction conditions: 0.5 mmol of substrate, 0.35 mmol of PhI(OAc)2, 1 mol % of
(1R,2R)-(+)-1,2-diphenyl-1,2-ethanediamine was used as the dia-
mine backbone, although tert-butyl groups were at the 5,50-posi-
tions of the salicylaldehyde regions, only 1.7% ee was observed
(Table 1, entry 8).
1c as catalyst, CH2Cl2 and H2O as solvent, room temperature for 6 min.
b
Determined by GC using an internal standard.
Determined by GC on a CP-Chirasil-Dex CB Capillary column.
2 mol % of 1c as catalyst was used.
The reaction time was 30 min, when N(n-Bu)4Br was selected as an additive.
0.4 mmol of PhI(OAc)2 was used.
krel = ln[(1 ꢀ C)(1 ꢀ ee)]/ln[(1 ꢀ C)(1 + ee)].
c
d
e
Based on these results, we decided to choose complex 1c as the
catalyst for OKR of racemic 1-phenyl-1-propanol to evaluate other
reaction conditions (Table 2). Initially, we evaluated the influence
of the additive (Fig. 3). Replacing N(C4H9)4Br 4 by KBr 5 as an
additive, the reaction time was reduced from 30 min to <10 min
to attain about 50% conversion. It was observed that the molar
ratio of KBr 5 and that of the catalyst were promoted from 4 to
8, the enantiomeric excess value rose from 11.3% to 56.8% (Table
2, entries 3–5). No increase in the enantiomeric excesses value
was detected, when we continued to enhance the loading of KBr
5 (Table 2, entries 6 and 7). The same result did not occur when
using 8 mol % of additive 4 and 1 mol % of 1c (Table 2, entry 2).
We next attempted different quaternary ammoniums with a
bromonium ion. We found that most of the quaternary ammo-
niums tested could enhance the enantiomeric excess values, and
the largest increase occurred with additive 8 with up to 68.0% ee
(Table 2, entry 10). This phenomenon illustrates that the positive
ion of the additive influences the reaction results.
f
g
N
N
Br
N(n-Bu)4Br
KBr
Br
6
5
4
7
N
N
N
Br
Br
Br
10
9
8
Br
Br
As can be seen in Table 2 (entry 16), an increase in the amount
of the PhI(OAc)2 from 0.35 mmol to 0.4 mmol improved the
enantiomeric excess from 68.0% to 74.0%, and also improved the
conversion. An increase in the concentration of the substrate and
catalyst resulted in an improvement of the enantiomeric excess
from 74.0% to 85.4% (Table 2, entry 17). Based on these results,
n-C8H17
N
N
N
n-C8H17
N
Br
12
Figure 3. The additives used in the reaction.
13
11

Q. Cheng et al. / Tetrahedron: Asymmetry 19 (2008) 2359–2362
2361
Table 3
established an improved edition of the OKR of secondary alcohols
catalyzed by chiral Mn(salen) complexes, which is more effective
for many secondary alcohols bearing large groups. Under the opti-
mal conditions, the OKR of 1-phenyl-1-propanol and 1-cyclohexyl-
1-propanol can attain 85.4% ee and 98.6% ee, respectively. Efforts to
further enhance reactivity and selectivity in these oxidations are
currently ongoing.
OKR of secondary alcoholsa
Conversionb (%)
77.7
eec (%)
85.4
krel
g
Entry
1
Substrate
OH
14a
3.88
3.90
OH
OH
OH
2
3
4
14b
77.1
76.3
72.1
84.8
82.6
72.5
4. Experimental
4.1. General
14c
3.80
3.51
Solvents were of analytical grade and used as received.
PhI(OAc)2, tetrabutylammonium bromide, KBr, racemic trans-1,2-
diaminocyclohexane, (1R,2R)-(+)-1,2-diphenyl-1,2-ethanediamine,
and (R)-(ꢀ)-propylenediamine dihyrochloride were purchased from
commercial sources and were used as received. Quaternary ammo-
niums were synthesized from the corresponding pyridine or N-
methyl-imidazole and bromoalkanes. Secondary alcohols which
were used in the present study were prepared by the reduction of
the corresponding ketones with NaBH4. (1R,2R)-Jacobsen’s catalyst
was purchased from ACROS, and other chiral Mn(salen) complexes
were prepared as the procedures reported in the literature.5a,7 GC
analyses were performed on a HP6890 instrument with a CP-Chira-
sil-Dex CB Capillary column to determine the enantiomeric ex-
14d
14e
OH
5
77.8
69.5
59.3
98.6
92.4
72.7
7.05
7.05
6.23
6d
7e
OH
OH
8
77.8
69.6
57.7
98.4
95.3
70.9
7.05
8.15
6.46
14f
9d
cesses. NMR spectra were recorded on
a Bruker Avance III
10e
(400 MHz) operating at 400 MHz (1H NMR) and 100 MHz (13C NMR).
4.2. General procedure for the kinetic resolution of racemic
secondary alcohols
11
14g
Ph
55.0f
11.0
1.32
A mixture of the substrate (0.5 mmol), catalyst (0.005 mmol),
KBr (0.04 mmol), water (1 ml), and CH2Cl2 (0.5 ml) was stirred in
a 5 ml tube for a few minutes at room temperature. The cooxidant
PhI(OAc)2 (0.4 mmol) was then added, and the reaction mixture
was stirred for a further 6 min. The products were extracted with
diethyl ether, when the reaction was complete. The conversion
and enantiomeric excesses were determined by GC. ESI-MS spectra
were recorded on a Waters ZQ4000 mass spectrometer. The HPLC
chiral column used was a Chiralcel OD-H for determination of
the enantiomeric excesses.
a
Reaction conditions: 1 mol % catalyst 1c, 8 mol % 8, 0.5 mmol substrate,
0.4 mmol PhI(OAc)2, 0.5 ml CH2Cl2, 1 ml H2O, room temperature for 6 min.
b
Conversion determined by GC using an internal standard.
Determined by GC on a CP-Chirasil-Dex CB Capillary column or by HPLC on a
c
Daicel Chiral OD column.
d
0.35 mmol PhI(OAc)2 was used.
Reaction condition: 1 mol % Jacobsen’s catalyst 1a, 8 mol % 5, 0.5 mmol sub-
e
strate, 0.35 mmol PhI(OAc)2, 1 ml CH2Cl2, 2 ml H2O, room temperature for 6 min.
f
Isolated conversion.
krel = ln[(1 ꢀ C)(1 ꢀ ee)]/ln[(1 ꢀ C)(1 + ee)].
g
the optimal conditions for OKR of 1-phenyl-1-propanol were as fol-
lows: 0.5 mmol substrate was dissolved in 0.5 ml CH2Cl2 and 1 ml
H2O in the presence of 1 mol % catalyst 1c and 8 mol % of additive 8
with 0.4 mmol PhI(OAc)2 as cooxidant.
4.3. GC and HPLC analysis for determination of the
enantiomeric excesses
The enantiomeric excess of 14a shown in Table 3 was analyzed
by GC/FID in a chiral capillary column (CP-Chirasil-Dex CB Capil-
lary column). GC conditions: Injector 250 °C; detector: 250 °C;
pressure: 6.9 MPa. Column temperature: 80 °C, 10 °C/min up to
170 °C.
Retention times for 14a: [t14a1 = 19.075 min, t14a2
19.314 min].
GC conditions of 14b, 14c, and 14d: Injector 250 °C; detector:
250 °C; pressure: 6.9 MPa. Column temperature: 120 °C.
Retention times for 14b: [t14b1 = 25.978 min, t14b2
26.476 min].
Retention times for 14c: [t14c1 = 42.036 min, t14c2 = 43.887 min].
Retention times for 14d: [t14d1 = 25.182 min, t14d2
25.708 min].
After the optimal conditions for OKR of 1-phenyl-1-propanol
were established, this methodology was employed to other
secondary alcohols. The OKR results are shown in Table 3. The
OKR of 14a, 14b, and 14c was mediated by complex 1c to afford
the corresponding chiral secondary alcohols with 85.4%, 84.8%,
and 82.6% enantiomeric excesses, respectively (Table 3, entries
1–3). Although the ee values of 14e and 14f exceeded 70%, when
Jacobsen’s catalyst 1a was employed as the catalyst, it could attain
>90% ee when 1c was selected as the catalyst with 0.35 mmol
PhI(OAc)2 as the cooxidant. When the amount of the PhI(OAc)2
was 0.4 mmol, the ee values of the residues reached up to >98%.
Unfortunately, the system for OKR of secondary alcohols was still
not suitable for substrates such as 14g, with only 11.0% ee being
detected.
=
=
=
GC conditions for 14e and 14f: Injector 250 °C; detector: 250 °C;
pressure: 6.9 MPa. Column temperature: 60 °C, 2 °C/min up to
120 °C, final time: 10 min. Then 10 °C/min up to 150 °C, final time:
2 min.
3. Conclusion
OKR with chiral Mn(salen) complexes is a powerful tool for the
preparation of enantioenriched secondary alcohols. We have
Retention times for 14e: [t14e1 = 34.485, t14e2 = 34.811].
Retention times for 14f: [t14f1 = 45.995, t14f2 = 46.252].

2362
Q. Cheng et al. / Tetrahedron: Asymmetry 19 (2008) 2359–2362
Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 3522; (h) Pawar, V. D.; Bettigeri, S.; Weng, S.
The ee value of 14g was determined by HPLC on a Daicel Chiral
S.; Kao, J. Q.; Chen, C. T. J. Am. Chem. Soc. 2006, 128, 6308; (i) Li, Y. Y.; Zhang, X.
Q.; Dong, Z. R.; Shen, W. Y.; Chen, G.; Gao, J. X. Org. Lett. 2006, 8, 5565; (j) Chen,
T.; Jiang, J. J.; Xu, Q.; Shi, M. Org. Lett. 2007, 9, 865; (k) Nakamura, Y.; Egami, H.;
Matsumoto, K.; Uchida, T.; Katsuki, T. Tetrahedron 2007, 63, 6383; (l) Arita, S.;
Koike, T.; Kayaki, Y.; Ikariya, T. Angew. Chem., Int. Ed. 2008, 47, 2447.
5. (a) Sun, W.; Wang, H.; Xia, C. G.; Li, J. W.; Zhao, P. Q. Angew. Chem., Int. Ed. 2003,
42, 1042; (b) Li, Z.; Tang, Z. H.; Hu, X. X.; Xia, C. G. Chem. Eur. J. 2005, 11, 1210; (c)
Sun, W.; Wu, X. M.; Xia, C. G. Helv. Chim. Acta 2007, 90, 623.
6. Subsequent to our initial report on the OKR catalyzed by Mn(salen) complexes,
several further studies were reported, see: (a) Kantam, M. L.; Ramani, T.;
Chakrapani, L.; Choudary, B. M. J. Mol. Catal. A: Chem. 2007, 274, 11; (b) Kureshy,
R. I.; Ahmad, I.; Pathak, K.; Khan, N.-u. H.; Abdi, S. H. R.; Prathap, J. K.; Jasra, R. V.
Chirality 2007, 19, 352; (c) Pathak, K.; Ahmad, I.; Abdi, S. H. R.; Kureshy, R. I.;
Khan, N.-u. H.; Jasra, R. V. J. Mol. Catal. A: Chem. 2007, 274, 120; (d) Han, F. R.;
Zhao, J. Q.; Zhang, Y. C.; Wang, W. Y.; Zuo, Y. Y.; An, J. W. Carbohydr. Res. 2008,
343, 1407.
OD column. Hexane/i-PrOH = 95:5, 0.8 ml/min, 254 nm, 2 °C.
Acknowledgments
The authors would like to thank the NSFC (20643008,
20625308) and the Chinese Academy of Sciences for financial
support.
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8. Ligand 1c, (R,R)-N,N0-bis(5-tert-butyl-salicylidene)-1,2-cyclohexanediamine:
½
a 2D0
ꢁ
¼ ꢀ206 (c 0.0142, CH2Cl2); 1H NMR (CDCl3) d 13.10 (s, 2H), 8.19 (s, 2H),
7.21–7.17 (m, 2H), 7.05 (s, 2H), 6.77 (d, J = 8.4 Hz, 2H), 3.24–3.20 (m, 2H), 1.84–
1.78 (m, 4H), 1.64–1.62 (m, 2H), 1.41–1.36 (m, 2H) 1.16 (s, 18H); 13C NMR:
163.9, 157.5, 140.2, 128.4, 126.9, 117.2, 115.2, 71.8, 33.0, 32.2, 30.5, 23.2;
Complex 1c: ESI-MS: m/z 487.6 [MꢀCl]+.