Chiral cobalt-catalyzed enantiomer-differentiating oxidation of racemic benzoins by using molecular oxygen as stoichiometric oxidant

Article abstract of DOI:10.1002/chem.200900387

A study was conducted to demonstrate chiral cobalt-catalyzed enantiomer-differentiating oxidation of racemic benzoins using molecular oxygen as stoichiometric oxidant. The cobalt-catalyzed asymmetric oxidation was performed with racemic benzoins due to th

Full text of DOI:10.1002/chem.200900387

DOI: 10.1002/chem.200900387
Chiral Cobalt-Catalyzed Enantiomer-Differentiating Oxidation of Racemic
Benzoins by Using Molecular Oxygen as Stoichiometric Oxidant
Santosh Kumar Alamsetti, Pandi Muthupandi, and Govindasamy Sekar*[a]
Dedicated to Professor Hisao Nishiyama
Enantiopure secondary alcohols are useful key intermedi-
ates in asymmetric synthesis, pharmaceutical, agrochemical
and fine chemical industries.[1] The kinetic resolution of rac-
emic alcohol is an attractive method to obtain optically
active alcohol[2,3] especially in cases where other methods
are not possible or provides poor enantioselectivity. Al-
though excellent catalytic enantioselective methods are
available for a variety of oxidations such as epoxidation,[4]
dihydroxylation[5] and aziridination,[6] there are only very
few methods available for enantioselective alcohol oxidation
[Eq. (1)].[7] The pioneering work by Rychnovsky using chiral
nitroxyl catalyst[8] followed by independent report of Stoltz[9]
and Sigman[10] using chiral palladium complex made signifi-
cant progress in oxidative kinetic resolution (OKR). Very
recently, chiral vanadium catalyst developed by Toste[11] for
the resolution of racemic a-hydroxy esters, chiral iridium
catalyst developed by Ikariya,[12] chiral manganese catalyst[13]
and chiral ruthenium catalysts[14] added strength to the field
of asymmetric oxidation of secondary alcohols.
we are investigating a more efficient and new chiral metal
catalyst to achieve very high selectivity for the synthesis of
enantiopure alcohols through oxidative kinetic resolution
under mild conditions. In this communication for the first
time we report our initial finding regarding chiral cobalt-cat-
alyzed oxidative kinetic resolution of racemic benzoins (a-
hydroxy ketones) using molecular oxygen as ultimate stoi-
chiometric oxidant. Clearly, the usage of molecular oxygen
as a stoichiometric oxidant has extraordinary practical ad-
vantage being water as only the by-product (Scheme 1).
Scheme 1. Chiral cobalt-catalyzed OKR of (Æ)-benzoins using O2.
We started our cobalt-catalyzed[17] asymmetric oxidation
with racemic benzoins because of their importance in phar-
maceutical industry[18] and difficulty in synthesizing them in
enantiomerically pure form.[19] We began our investigation
with (Æ)-4-methoxy benzoin as model substrate for oxida-
tive kinetic resolution. When (Æ)-4-methoxy benzoin was
reacted with 5 mol% of TEMPO and 5 mol% of enantio-
As part of our ongoing research towards the synthesis of
enantiopure secondary alcohols by halogenating kinetic res-
olution using stoichiometric chiral halogenating agent ((R)-
BINAP/NCS)[15] and copper-catalyzed alcohol oxidation,[16]
pure (l)-proline–CoACTHNGUTERNNU(G OAc)2 complex in the presence of mo-
lecular oxygen at room temperature, the oxidation took 7 d
for 44% conversion (C)[20] and provided 41% of 4-methoxy
benzil. In this asymmetric oxidation reaction 52% of 4-me-
thoxy benzoin was recovered with 4% enantiomeric excess
and selectivity (s)[21] = 1.2 at C=44% (Table 1, entry 1).
(R)-BINOL–Co complex failed to catalyze the oxidation re-
action (entry 2) and (À)-sparteine–Co and (R)-BINAM–Co
complexes failed to provide any selectivity for this asymmet-
ric oxidation (entries 3 and 4). Interestingly, the Schiff base
[a] S. Kumar Alamsetti, P. Muthupandi, Dr. G. Sekar
Department of Chemistry
Indian Institute of Technology Madras
Chennai, Tamil Nadu 600036 (India)
Fax : (+91)44-2257-4202
E-mail: gsekar@iitm.ac.in
type ligand L5 along with CoACHTNUTRGENNG(U OAc)2 catalyzed the asymmet-
ric oxidation of (Æ)-4-methoxy benzoin to give 16.5 selectiv-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900387.
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Chem. Eur. J. 2009, 15, 5424 – 5427

COMMUNICATION
Table 1. Effect of ligands and cobalt salts on OKR of (Æ)-4-methoxy
tions, a 1:1 ratio of ligand and cobalt acetate provides better
selectivity than a 1:2 ratio. Among the 1:1 ratio catalyst,
benzoin.[a]
5 mol% of ligand L5 and 5 mol% of CoACTHNUTRGNEUNG(OAc)2 gave a maxi-
mum of 47 selectivity. The selectivity (s) is drastically de-
creased by either increasing or decreasing the catalytic load
(Figure 1).
Entry Ligand Co salt
t
Conversion ee benzoins [%][c] s[d]
(C [%])[b]
1
2
3
4
5
6
7
8
9
L1
L2
L3
L4
L5
L5
L5
L5
–
Co
Co(OAc)2 7 d
Co(OAc)2 4 d
Co(OAc)2 4 d
Co(OAc)2 5h
Co
Co(NO3)2 7 d
G
44
–
49
56
57
4
–
0
0
91
52
–
44
–
1.2
–
0
0
16.5
5.2[e]
–
–
46
–
CoCl2
–
6 d
7 d
4.8
[f]
–
[a] Conditions: 5 mol% Co salt, 5 mol% ligand, 2 mL CH3CN and O2,
[b] Conversion was determined by 1H NMR analysis of crude reaction
mixture, see Supporting Information for details. [c] % ee was determined
by HPLC using Daicel chiralPAK AS-H column. [d] s = krel(fast/slow)
ln[(1ÀC) (1Àee)]/[ln(1ÀC) (1+ee)]. [e] Reaction was carried out without
TEMPO. [f] Reaction with only TEMPO without Co complex.
=
ACHTUNGTRENNUNG
ity at room temperature for oxidation at 57% conversion
with 91% ee for the recovered benzoin (entry 5). When the
reaction was carried out without TEMPO, the selectivity
was drastically reduced to 5.2 (entry 6). Replacing Co-
Figure 1. Effect of different ratios of chiral cobalt complex in OKR.
Table 2. Effect of solvents in the optimization of OKR of (Æ)-4-methoxy
benzoin.[a]
ACHTUNGTRENNUNG(OAc)2 with other cobalt salts such as CoAHCTUNGTREN(NUGN NO3)2 or CoCl2
did not catalyze the reaction or reduced the selectivity. The
reaction with only TEMPO without Co complex failed to
give any oxidized product (entry 9). In this oxidative kinetic
resolution, the (R)-enantiomer of racemate benzoin is oxi-
dized to corresponding benzil and the slow reacting (S)-en-
antiomer is recovered in an optically active form.
Entry
Solvent
t
(C [%])[b]
ee benzoins [%][c]
s
1
2
3
4
5
6
7
8
9
CH3CN
benzene
THF
dioxane
CH3NO2
EtOAc
CH2Cl2
CHCl3
DMF
5 h
57
24
50
41
40
54
49
56
45
45
91
8
16.5
1.8
17.7
8.7
5.5 d
17 h
66 h
66 h
13 h
21 h
40h
17 h
12 h
77
48
43
90
80
99.5
30
30
7.0
22.9
26.7
47.0
2.9
10
DMSO
2.9
[a] Conditions: 5 mol% CoACHTUNRGTNEUNG(OAc)2, 5 mol% ligand L5, O2, [b] Conversion
was determined by 1H NMR analysis of crude reaction mixture, see Sup-
porting Information for details. [c] % ee was determined by HPLC using
Daicel chiralPAK AS-H column.
To probe the scope of the chiral cobalt catalyst, several
racemic benzoins are oxidized under optimized reaction
conditions and the results are summarized in Table 3. The
asymmetric oxidation of simple racemic benzoin proceeded
to 57% conversion after 42 h at ambient temperature, pro-
viding (S)-benzoin in 40% isolated yield and 92% ee
(Table 3, entry 1). Importantly, benzoin derivatives bearing
electron-donating groups at the para (entries 2 and 6) and
meta positions (entries 3 and 8) and electron-withdrawing
constituents at para positions are well tolerated (entries 5
and 7). All benzoins could be oxidized at room temperature
The screening of a wide range of solvents showed that the
enantioselectivity (s) of the OKR of (Æ)-4-methoxy benzoin
is highly dependent on the solvent (Table 2). Although we
have not yet been able to correlate the enantioselectivity
with any single solvent parameter, it is clear that CHCl3 is
the solvent of choice as it gave highest selectivity (entry 8).
We then examined the effect of ratio of ligand L5 and Co-
ACHTUNGTRENNUNG
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G. Sekar et al.
Table 3. OKR of (Æ)-benzoins catalyzed by chiral cobalt complex using stoichiometric O2.[a]
lytic cycle and to expand the
scope and synthetic utility of
the enantioselective oxidation.
Entry
1
Benzoins
t [h]
C (%)[b]
Yield [%][c]
40 (93)
ee [%][d]
s[e]
Experimental Section
42
57
92
18Æ4
Typical experimental procedure for
OKR:
0.05 mmol) and CoAHCTUNGTRENNUNG
A
mixture of L5 (24.7 mg,
(OAc)2 (12.5 mg,
2
40
56
40 (92)
99.5
47Æ12
0.05 mmol) in chloroform (2 mL) was
stirred at room temperature for
10 min, TEMPO (7.8 mg, 0.05 mmol)
was then added to the reaction mix-
ture. After stirring for 5 min, p-me-
thoxy benzoin (272 mg, 1 mmol) was
added and the reaction mixture stirred
under an O2 atmosphere (balloon) and
the progress of the reaction was moni-
tored by 1H NMR spectroscopy. After
40 h, the reaction mixture was concen-
trated and the resulting residue was
purified by silica gel column chroma-
tography (hexanes/ethyl acetate) to
give the p-methoxy benzil (140 mg,
52%) and recovered p-methoxy ben-
zoin (109 mg, 40%).
3
4
55
55
62
57
35 (93)
40 (95)
92
90
11.1Æ1.5
16Æ3
5
6
30
67
55.5
55.5
43 (96)
41 (94)
75
93
8.8Æ4
23Æ5
(S)-p-Methoxybenzoin: Rf =0.44 (hex-
anes/ethyl acetate 70:30); [a]2D5 = 82.7
7
8
9
30
70
60
69
58
55
29 (96)
38 (93)
43 (96)
95
90
92
8.3Æ0.9
14Æ2
(c=1
in
methanol);
1H NMR
(400 MHz, CDCl3): d=7.88–7.92 (m,
2H), 7.23–7.27 (m, 2H), 6.83–6.89 (m,
4H) 5.85 (d, J=6 Hz, 1H), 4.57 (d, J=
6 Hz, 1H), 3.82 (s, 3H), 3.76 ppm (s,
3H); 13C NMR (100 MHz, CDCl3): d=
197.5, 164.1, 159.8, 132.0, 131.7, 129.2,
126.5, 114.7, 114.1, 75.4, 55.6,
55.4 ppm; IR (neat): n˜ = 3446, 2935,
1669, 1253, 1029 cmÀ1; HRMS: m/z:
calcd for C16H16O4Na: 295.0946;
found: 295.0945 [M+Na]+. The enan-
tiomeric excess (ee) was determined to
be 99.5% by HPLC using ChiralPAK
AS-H column (40% iPrOH/hexanes,
23Æ5
[a] 5 mol% CoACHTUNGTRENNUNG(OAc)2, 5 mol% L5, O2, in 2 mL CHCl3 at room temperature. [b] Conversion was determined
1
by H NMR analysis of crude reaction mixture. See the Supporting Information for details. [c] Isolated yield of
enantiomerically enriched benzoins after silica gel column chromatography. Numbers in parantheses is the
total combined yield of the benzoin and benzil. [d] The % ee was determined by HPLC using Daicel chiral-
PAK AS-H column, see Supporting Information for full details. [e] Using an error in the conversion of Æ2.
1 mLminÀ1
,
220 nm): tR (major,
with good to excellent selectivities (s=8.3–47). In all exam-
ples, the R enantiomer of the racemic benzoins are oxidized
to the corresponding benzils and the slow-reacting S enan-
tiomers are recovered in highly enantiomerically enriched
form.[22] The enantiomeric excess (ee) of recovered benzoins
was determined by HPLC on a chiral stationary phase (see
Supporting Information for full details).
8.7 min), tR (minor, 13.3 min).
p-Methoxybenzil: Rf =0.63 (hexanes/ethyl acetate 70:30); 1H NMR
(400 MHz, CDCl3): d=7.92–7.97 (m, 4H), 6.94–6.99 (m, 4H), 3.88 ppm
(s, 6H); 13C NMR (100 MHz, CDCl3): d=193.6, 165.0, 132.5, 126.5, 114.4,
55.8 ppm; IR (neat): n˜ =2917, 1655, 1259, 1259, 1013 cmÀ1; HRMS: m/z:
calcd for C16H14O4Na: 293.0790; found,:293.0794 [M+Na]+.
In summary, we have developed an efficient asymmetric
oxidative reaction catalyzed by chiral cobalt complex using
molecular oxygen as the stoichiometric oxidant. The mild
reaction conditions of the catalytic system provide access to
a wide range of benzoins (a-hydroxy ketones) in high yield
and excellent enantioselectivity (s up to 47). This method is
very versatile in that the sole by-product of our oxidation
process is water, which makes our system eco-friendly and
green. To the best of our knowledge this is the first report in
the literature for chiral cobalt-catalyzed oxidative kinetic
resolution of secondary alcohols. Efforts are currently un-
derway to provide detailed mechanistic insight into the cata-
Acknowledgements
This work was supported by the DST, New Delhi, India. S.K.A. thanks
CSIR, India and P.M. thanks UGC, India for research fellowship.
Keywords: benzoins · cobalt · enantioselectivity · kinetic
resolution · oxidation
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Chem. Eur. J. 2009, 15, 5424 – 5427

Oxidation of Racemic Benzoins
COMMUNICATION
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[21] The selectivity factor s was determined using the equation s
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[(1ÀC)
sion; see Supporting Information for full details.
[22] The absolute configuration of benzoins is determined from sign of
specific rotations in comparison with the literature values. See the
Supporting Information for further details.
=
=
G
E
N
ACHTUNGTRENNUNG
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Received: February 11, 2009
Published online: April 25, 2009
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ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5427