Zinc-catalyzed aerobic oxidation of benzoins and its extension to enantioselective oxidation

Article abstract of DOI:10.1016/j.tetlet.2010.12.004

Zn(II)-DABCO complex is used as an efficient catalyst for the aerobic oxidation of benzoins to benzils in the presence of molecular oxygen. Usage of chiral zinc complex as catalyst resulted in enantioselective oxidative kinetic resolution of racemic benzoin to yield enantiomerically enriched benzoins.

Full text of DOI:10.1016/j.tetlet.2010.12.004

Tetrahedron Letters 52 (2011) 692–695
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Zinc-catalyzed aerobic oxidation of benzoins and its extension
to enantioselective oxidation
⇑
Pandi Muthupandi, Govindasamy Sekar
Department of Chemistry, Indian Institute of Technology Madras, Chennai, Tamil Nadu 600 036, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Zn(II)–DABCO complex is used as an efficient catalyst for the aerobic oxidation of benzoins to benzils in
the presence of molecular oxygen. Usage of chiral zinc complex as catalyst resulted in enantioselective
oxidative kinetic resolution of racemic benzoin to yield enantiomerically enriched benzoins.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 1 November 2010
Revised 29 November 2010
Accepted 1 December 2010
Available online 7 December 2010
Keywords:
Aerobic oxidation
Zinc catalyst
Molecular oxygen
Kinetic resolution
Enantioselective oxidation
Transition metal complex catalyzed organic transformations
have been an area of intensive study over the past several dec-
ades.1 In contrast to the wide use of metal complexes, which are
derived from heavy, rare, and expensive metals, zinc has enjoyed
relatively less popularity despite being the second-most abundant
transition metal after iron in biology, the potentially low cost, low
toxicity, and environmental impact.2
O
O
Zinc-catalyst
O2
Ar
Ar
Ar
Ar
Oxidation
O
O
OH
Ar
Ar
OH
*
Chiral zinc-catalyst
O2
O
( )
Ar
Benzils are utilized as intermediates in the synthesis of chiral li-
gands3a,b and biologically active compounds.3c Moreover, benzils
are found in selective inhibitors of carboxylesterases,3d acid corro-
sion of mild steel inhibitors,3e and in photocurable coating as pho-
tosensitive agents.3f Many investigations, such as reaction of oxalyl
chloride with organostannanes,4a oxidation of alkynes,4b aldehyde
condensation,4c and oxidation of alcohols,4d,e on the preparation of
benzils have been documented. In view of significant drawbacks,
such as the use of toxic and expensive reagents,4a high tempera-
ture,4b stoichiometric amount of reagents,4d,e and low yield4c of
these methods, more efficient catalytic system is in high demand.
The synthesis of enantiopure hydroxy ketones (benzoins) is an
important task in pharmaceutical and chemical industries. For
example, chiral hydroxy ketones are found in antidepressants,
antitumor, and antibiotics and are used in the treatment of Alzhei-
mer’s disease.5 Moreover, chiral hydroxy ketones can also be used
in preparing many other important chiral molecules, such as amino
alcohols and diols.5 Though enantioselective benzoin condensation
reaction using chiral catalyst or biocatalyst is well documented for
+ Ar
Oxidative Kinetic
Resolution ~50%
O
Scheme 1.
the synthesis of chiral benzoins,6 aerobic oxidative kinetic resolu-
tion is the most convenient method as it uses molecular oxygen
as terminal oxidant.
As part of our continuing interest in the synthesis of enantio-
pure secondary alcohols and benzoins by chiral copper complex
(galactose oxidase model), cobalt and Fe complex,7 we have been
in the hunt for developing synthetic routes to convince the goal
of modern organic chemistry to maximize the usage of readily
available materials and minimize the generation of waste.8 Herein
we report the transformation of benzoins to benzils catalyzed by
zinc complex, further extended to enantioselective oxidative ki-
netic resolution (OKR) of racemic benzoin using molecular oxygen
as the ultimate oxidant (Scheme 1). To the best of our knowledge,
this is the first report that uses Zn complex as a catalyst for benzo-
ins oxidation and chiral zinc complex as catalyst for oxidative ki-
netic resolution of alcohols.
⇑
Corresponding author. Tel.: +91 44 2257 4229; fax: +91 44 2257 4202.
E-mail address: gsekar@iitm.ac.in (G. Sekar).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.004

P. Muthupandi, G. Sekar / Tetrahedron Letters 52 (2011) 692–695
693
Table 1
Optimization of oxidation reaction with ligands, zinc salts, and solvents
O
ligand (10 mol%)
zinc salt (5 mol%)
O
Ph
Ph
Ph
Ph
K2CO3 (1 equiv.)
solvent, 60 °C, O2
OH
O
2
( )-1
Entry
Ligand
Zinc salt
Solvent
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
—
ZnSO4ꢀ7H2O
ZnSO4ꢀ7H2O
ZnSO4ꢀ7H2O
ZnSO4ꢀ7H2O
ZnSO4ꢀ7H2O
ZnSO4ꢀ7H2O
ZnSO4ꢀ7H2O
Zn(acac)2ꢀ7H2O
Zn(OTf)2
ZnCl2
ZnO
ZnO
ZnO
ZnO
ZnO
ZnO
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
DMF
72
72
12
72
73
62
9
17
24
9
44
87
96
82
68
87
99
84
61
98
99
61
89
97
74
67
L1
L2
L3
L4
L5
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
9
10
11
12
13
14
15
16
NH2
8
13
10
10
10
48
EtOH
EtOAc
THF
CHCl3
N
NH2
N
NH2
NH2
N
N
NH2
NH2
N
N
L1
L2
L6
L3
L5
L4
a
Isolated yield.
Table 2
Study of oxidation reaction with different combination of reagents
Table 3
ZnO–DABCO catalyzed aerobic oxidation of benzoins to benzils
O
O
ligand (10 mol%)
zinc salt (5 mol%)
Ph
Ph
Ph
( )-1
Ph
K2CO3 (1equiv.)
PhMe, 60 °C, O2
OH
O
ZnO (5 mol%)
2
OH
O
L6 (10 mol%)
Ar
Ar
Ar
Ar
K2CO3 (1 equiv.)
Entry
Zinc salt
Ligand
Base
Time (h)
Yielda (%)
O
O
º
PhMe, O2, 60 C
( )
1
2
3
4
5
6
7
8
—
ZnO
—
—
ZnO
—
—
—
—
—
—
K2CO3
—
K2CO3
K2CO3
K2CO3
44
44
44
44
44
34
44
8
Trace
12 (7)
58 (27)
44 (13)
72 (54)
80 (60)
53 (16)
99
Entry
1
Benzils
Time (h)
8
Yielda (%)
99
L6
—
L6
L6
—
O
ZnO
ZnO
O
O
L6
a
Isolated yield, yield in parenthesis corresponds to 8 h.
2
3
4
17
13
15
96
92
94
O
O
Our investigation started with 5 mol % zinc sulfate and benzoin
( )-1 as model substrate with 1 equiv of potassium carbonate in
5 mL toluene at 60 °C under oxygen atmosphere (using O2 balloon)
and the oxidation reaction provided 44% of benzil after 72 h
(Table 1, entry 1). We were pleased to find that the yield is in-
creased to 87% upon the addition of 10 mol % ethylenediamine L1
to the reaction mixture, as zinc is an element of borderline hardness
and nitrogen ligands can all be accommodated9 (entry 2). This
result clearly reveals that the ligand is crucial for this oxidation
reaction. To increase the efficiency of the reaction, several nitrogen
based readily available ligands were screened with zinc sulfate.
Diazobicyclo [2.2.2]octane (DABCO) L6 was found to be a better ligand
as it provided quantitative yield for benzil in just 9 h (entry 7).
Upon further optimization, a range of zinc salts were screened
with DABCO. Although most of the zinc salts gave very good
MeO
OMe
O
O
O
Et
O
5
68
96
O
Et
(continued on next page)

694
P. Muthupandi, G. Sekar / Tetrahedron Letters 52 (2011) 692–695
tive yield with similar reaction times. Milder basic nature, low cost,
Table 3 (continued)
and less hygroscopic nature of K2CO3 than Cs2CO3 made us to go
with K2CO3. Furthermore, temperature and catalytic ratio study
of this oxidation reaction unveiled that 5 mol % of ZnO with
10 mol % DABCO in toluene at 60 °C provided the best result.
The oxidation reaction provided only trace amount of benzil
without any ZnO, DABCO, and K2CO3 after 44 h (Table 2, entry 1).
When we used only ZnO or DABCO or K2CO3, the reaction took
longer time for completion and provided only 12–58% yield (en-
tries 2–4). The yield, however, was increased to 53–80%, when
the combination of any two reagents of ZnO, DABCO, and K2CO3
was used but the time factor remained intact (entries 5–7). Usage
of all the three reagents in the oxidation of benzoin furnished
quantitative yield for the benzil in just 8 h (entry 8). Intriguingly,
it suggests that the combination of all three ZnO, DABCO, and
K2CO3 is important for quantitative yield of the oxidized product.
After optimizing the reaction conditions for aerobic oxidation of
Entry
Benzils
Time (h)
10
Yielda (%)
Br
O
O
6
83
O
O
Br
Cl
7
8
9
6
95
91
Cl
O
O
Cl
O
benzoin, we initiated detailed investigation into substrates scope
10
with other benzoins and the results are summarized in Table 3
.
9
18
10
97
93
The optimized conditions worked well with different types of
benzoins such as electron-withdrawing substitution and elec-
tron-releasing substitution on benzoins. Likewise, both the para-
and meta-substituted benzoins afforded good yield for the aerobic
oxidation reaction. It is worth mentioning that sterically hindered
ortho-substituted benzoin also yielded quantitatively for the oxida-
tion reaction (entry 9). The oxidation reaction took slightly more
time for completion when the benzoin had electron-releasing
methyl or methoxy groups (entries 2, 3, 4, and 9). The p-ethylbenz-
oin took maximum of 68 h for completion (entry 5). The reaction
was found to be fast when benzoin has electron-withdrawing
chloro atom in both the phenyl rings at para-position (entry 8).
After successfully developing zinc catalyzed oxidation method-
ology for the benzoins to benzils, we focused our primary
investigation on enantioselective oxidative kinetic resolution
O
O
10
O
a
Isolated yield.
results, the ZnO provided a maximum of 99% yield in 8 h (entry
11). Similarly, the reaction was conducted in various solvents
and toluene remained as the best solvent (Table 1, entries 11–16).
The aerobic oxidation of benzoin was then screened with sev-
eral bases such as K2CO3, Na2CO3, Cs2CO3, KOH, NaOH, NaOMe,
K3PO4, and tert-BuONa but only K2CO3 and Cs2CO3 gave quantita-
Table 4
Oxidative kinetic resolution of ( )-benzoin using chiral zinc catalyst
OH
O
OH
*
zinc salt (5 mol%)
ligand (5 mol%)
Ph
Ph
Ph
Ph
+ Ph
Ph
TEMPO (5 mol%)
PhMe, O2, 90 °C
(
)
O
O
O
Entry
Zinc salt
Ligand
Time
Ca (%)
Yieldb (%)
eec
s
1
2
3
4
5
ZnO
ZnO
ZnSO4ꢀ7H2O
ZnSO4ꢀ7H2O
ZnSO4ꢀ7H2O
L7
L7
L7
L8
L9
2 d
5 d
9 d
6 d
6 d
62
75
54
67
64
34(97)d
20(90)
38(89)
30(91)
34(94)
0
0
8
12
43
—
—
1.3
1.2
2.4
NH2
NH2
N
N
OH
OH
N
N
OH
OH
L7
L8
L9
a
Conversion was determined by 1H NMR analysis of crude reaction mixture.
Isolated yield of enantiomerically enriched benzoins after silica gel column chromatography. Numbers in parenthesis are the total combined yield of the benzoin and
b
benzil.
c
% ee was determined by HPLC using Daicel chiral PAK AS-H column.
1 equiv K2CO3 used instead of TEMPO.
d

P. Muthupandi, G. Sekar / Tetrahedron Letters 52 (2011) 692–695
695
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6. For asymmetric benzoin condensations and enzymatic kinetic resolutions of
racemic benzions: (a) Dünkelmann, P. D.; Nitsche, K. A.; Demir, A. S.; Siegert, P.;
Baumann, L. B. M.; Pohl, M.; Müller, M. J. Am. Chem. Soc. 2002, 124, 12084; (b)
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(OKR) of racemic benzoins using chiral zinc catalyst to obtain opti-
cally active benzoins. Achiral ligand DABCO L6 was replaced with
chiral ligands L7–L9 and the results are summarized in Table 4.
When the DABCO was replaced by 5 mol % of (R)-BINAM L7 with
5 mol % of ZnO in the presence of K2CO3, the oxidative kinetic res-
olution of racemic benzoin in toluene at 90 °C provided 0% ee for
the unreacted benzoin at 62% conversion (Table 4, entry 1). Simi-
larly, the recovered benzoin was found to be racemic mixture
when 5 mol % TEMPO was used instead of K2CO3 (entry 2). How-
ever, replacement of ZnO with 5 mol % of ZnSO4ꢀ7H2O in the pres-
ence of 5 mol % of TEMPO provided 8% ee for unreacted benzoin at
54% conversion and the selectivity (s) is 1.3. Then we replaced the
chiral ligand L7 with other chiral ligands L8 and L9. Interestingly,
when L97c was used as ligand, the unreacted benzoin was
11
obtained
with 43% ee at 64% conversion and the selectivity (s)
is 2.4 (entry 5). However, without TEMPO, the same reaction pro-
vides poor selectivity with longer reaction time. In this reaction,
R enantiomer of the racemate was oxidized faster to the corre-
sponding benzil and the slow reacting S enantiomer of benzoin
was recovered in an enantiomerically enriched form.
In conclusion, we have developed a very simple and efficient
aerobic oxidation reaction for the conversion of benzoins to benzils
using ZnO–DABCO as a catalyst. This methodology is successfully
extended to enantioselective oxidation using chiral zinc complex
as catalyst for the oxidative kinetic resolution. A detailed optimiza-
tion, mechanistic studies and substrates scope of the OKR are un-
der progress.
7. (a) Alamsetti, S. K.; Mannam, S.; Muthupandi, P.; Sekar, G. Chem. Eur. J. 2009, 15,
1086; (b) Alamsetti, S. K.; Muthupandi, P.; Sekar, G. Chem. Eur. J. 2009, 15, 5424;
(c) Muthupandi, P.; Alamsetti, S. K.; Sekar, G. Chem. Commun. 2009, 3288.
8. (a) Trost, B. M. Science 1991, 254, 1471; (b) Trost, B. M. Acc. Chem. Res. 2002, 35,
695.
9. Parkin, G. Chem. Rev. 2004, 104, 699.
10. General experimental procedure for oxidation of benzoins. A mixture of ZnO
(4.0 mg, 0.05 mmol) and 1,4-diazabicyclo[2.2.2]octane (11.2 mg, 0.1 mmol) in
5 mL of toluene was taken in a reaction tube and stirred at room temperature
for 10 min; benzoin (212 mg, 1 mmol) and K2CO3 (138 mg, 1 mmol) were then
added to the reaction mixture. The reaction was stirred under an O2
atmosphere (using O2 balloon) at 60 °C for 8 h. The reaction mixture was
concentrated and the resulting residue was purified by silica gel column
chromatography (eluents: hexanes/ethyl acetate, 95:5 v/v) to give the benzil
(208 mg, yield 99%). Yellow solid, mp: 95–96 °C (lit.1 94–95 °C). Rf 0.43;
(hexanes/ethyl acetate, 90:10 v/v): 1H NMR (400 MHz, CDCl3): d 7.95–8.01 (m,
4H), 7.66 (t, J = 7.2 Hz, 2H), 7.51 (t, J = 8.0 Hz, 4H); 13C NMR (100 MHz, CDCl3): d
194.7, 135.0, 133.1, 130.0, 129.1; IR (neat) 3064, 1656 cmꢁ1; HRMS (m/z):
[MNa]+ calcd for C14H10O2Na1, 233.0578; found, 233.0585.
Acknowledgments
We thank DST (Project No.: SR/S1/OC-06/2008), New Delhi, for
the financial support. P.M. thanks UGC, New Delhi, for senior re-
search fellowship. We thank DST, New Delhi, for the funding to-
ward the 400 MHz NMR instrument to the Department of
Chemistry, IIT-Madras, under the IRPHA scheme and ESI-MS facil-
ity under the FIST programme.
11. Typical experimental procedure for OKR. A mixture of L9 (9 mg, 0.0125 mmol)
and zinc(II)sulfate heptahydrate (3.6 mg, 0.0125 mmol) in 5 mL of toluene was
stirred at room temperature for 10 min; TEMPO (2 mg, 0.0125 mmol) was then
added to the reaction mixture. After stirring for 5 min, benzoin (53 mg,
0.25 mmol) was added and then the reaction was stirred under an O2
atmosphere (using O2 balloon) and the reaction was followed by TLC. The
conversion was measured by recording 1H NMR of crude reaction mixture. The
reaction mixture was concentrated after 64% conversion and the resulting
residue was purified by silica gel column chromatography (eluents: hexanes/
ethylacetate, 85:15 v/v) to give benzil (60%) and unreacted benzoin (34%). Rf
Supplementary data
Supplementary data (experimental procedures and character-
ization data, full spectroscopic data for all compounds, 1H NMR
and 13C NMR spectra for all the compounds, 1H NMR spectrum
for conversion calculation and HPLC spectra for % ee determina-
tion) associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2010.12.004.
0.26 (hexanes/ethyl acetate, 90:10 v/v); ½a 2D5
ꢂ
= 37.4 (c = 1 in acetone); 1H NMR
(400 MHz, CDCl3): d 7.89–7.95 (m, 2H), 7.52 (t, J = 7.2 Hz, 1H), 7.40 (t, J = 8.0 Hz,
2H), 7.31–7.36 (m, 4H), 7.24–7.31 (m, 1H), 5.96 (d, J = 6.0 Hz, 1H), 4.55 (m, 1H);
13C NMR (100 MHz, CDCl3): d 199.1, 139.1, 134.1, 133.6, 129.3, 128.8, 128.7,
127.9, 76.3; IR (neat) 3418, 1679, 1261, 1068 cmꢁ1; HRMS (m/z): [MNa]+ calcd
for C14H12O2Na1, 235.0735; found, 235.0727; The enantiomeric excess (%ee)
was determined to be 43% in HPLC using Daicel ChiralPAK AS-H column
(10% iPrOH/hexanes, 1 mL/min, 254 nm): tR (major, 10.6 min), tR (minor,
17.0 min).
References and notes
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Transition Metals for Organic Synthesis; Wiley-VCH: Weinheim, 2004; (c)
Yamamoto, H.; Synthesis, Lewis Acids in Organic Wiley-VCH; Weinheim, 2008.