Asymmetric intramolecular Cannizzaro reaction of anhydrous phenylglyoxal

Article abstract of DOI:10.1016/j.jfluchem.2008.04.008

The use of anhydrous phenylglyoxal provides a solution to the problem of low reactivity in the asymmetric intramolecular Cannizzaro reaction with alcohols. Double asymmetric induction was achieved in the reaction of anhydrous phenylglyoxal with d-(+)-menthol promoted by a (S,S)-t-BuBox·copper(II) hexafluoroantimonate complex.

Full text of DOI:10.1016/j.jfluchem.2008.04.008

Journal of Fluorine Chemistry 129 (2008) 994–997
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Journal of Fluorine Chemistry
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Short communication
Asymmetric intramolecular Cannizzaro reaction of anhydrous phenylglyoxal
*
Kazuaki Ishihara , Takayuki Yano, Makoto Fushimi
Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8603, Japan
A R T I C L E I N F O
A B S T R A C T
Article history:
The use of anhydrous phenylglyoxal provides a solution to the problem of low reactivity in the
asymmetric intramolecular Cannizzaro reaction with alcohols. Double asymmetric induction was
Received 16 March 2008
Received in revised form 24 April 2008
Accepted 25 April 2008
Available online 2 May 2008
achieved in the reaction of anhydrous phenylglyoxal with
D-(+)-menthol promoted by a (S,S)-t-
BuBoxꢀcopper(II) hexafluoroantimonate complex.
ß 2008 Elsevier B.V. All rights reserved.
Keywords:
Copper(II) hexafluoroantimonate
Intramolecular Cannizzaro reaction
Phenylglyoxal
Double asymmetric induction
Anhydrous
Bis(oxazoline)
1. Introduction
reaction, probably because water decreases the Lewis acidity of
Cu(OTf)2. Thus, we were interested in whether anhydrous
arylglyoxals could be used for the Lewis acid-catalyzed Cannizzaro
reaction. Furthermore, we expected that more cationic and bulky
Lewis acids such as Cu(NTf2)2 and Cu(SbF6)2 might be more
efficient catalysts for the enantioselective reaction because of the
strong electronegativity of fluorine substituents.
We have recently achieved a highly efficient synthesis of
carboxamides by lithium N,N-diisopropylamide (LDA)-catalyzed
Haller–Bauer and Cannizzaro-type reactions of ketones and
aldehydes with lithium N-alkylamides and lithium N,N-dialkyla-
mides [1]. Phenylglyoxal (1) is
a typical substrate for the
intramolecular Cannizzaro-type reaction. However, commercial
phenylglyoxal monohydrate [1ꢀH2O] is not suitable for the LDA-
catalyzed intramolecular Cannizzaro-type reaction with lithium
pyrrolidinide because of the presence of water. Anhydrous 1 is
unstable at high concentration, and readily oligomerizes. This
problem has been overcome by the use of a ca. 1 M solution of
anhydrous 1 in toluene, which is prepared from its hydrate by the
removal of water under azeotropic reflux conditions in toluene. We
have confirmed that a solution of anhydrous 1 in toluene can be
preserved for more than several months in the refrigerator
(Scheme 1).
Earlier, Morken et al. reported the catalytic enantioselective
Cannizzaro reaction of arylglyoxal hydrates in a 2:1 mixed solvent
of 2-propanol–1,2-dichloroethane [2]. For instance, in the presence
of 10 mol% each of (S,S)-2,20-isopropylidenebis(4-phenyl-2-oxazo-
line) [(S,S)-PhBox (3a)] and Cu(OTf)2, 1ꢀH2O is converted to (R)-
isopropyl mandelate (2a) in 57% yield with 28% ee (Scheme 2).
Large excess amounts of alcohols are required in the above
We report here the asymmetric intramolecular Cannizzaro
reaction of anhydrous phenylglyoxal with alcohols to give optically
active alkyl
a-hydroxyphenylacetates induced by chiral bis(ox-
azoline)ꢀCuX2 catalysts.
2. Results and discussion
Based on Morken’s paper [2], we examined the intramolecular
Cannizzaro reaction of anhydrous phenylglyoxal 1 with just two
equivalents of isopropanol in the presence of 10 mol% of (R,R)-
3aꢀCu(OTf)2 in 1,2-dichloroethane at room temperature (entry 1,
Table 1). As expected, the reaction proceeded more smoothly to
give (S)-isopropyl mandelate 2a in 89% yield. However, the
enantioselectivity was quite low (23% ee), as in Morken’s report
[2]. Although (R,R)-3aꢀCu(SbF6)2 was also examined, the reaction
did not proceed due to the decomposition of (R,R)-PhBox ligand
(entry 2). Evans et al. previously reported that (R,R)-3aꢀCu(SbF6)2 is
very unstable due to the strong Lewis acidity of Cu(SbF6)2 [3a].
Fortunately, the enantioselectivity was improved to 42% ee with
the use of tert-butanol instead of isopropanol in the presence of
10 mol% of (R,R)-3aꢀCu(OTf)2, although the chemical yield of (S)-2b
was reduced to 18% (entry 3).
* Corresponding author. Tel.: +81 52 789 3331; fax: +81 52 789 3222.
E-mail address: ishihara@cc.nagoya-u.ac.jp (K. Ishihara).
0022-1139/$ – see front matter ß 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2008.04.008

K. Ishihara et al. / Journal of Fluorine Chemistry 129 (2008) 994–997
995
presence of 10 mol% of (S,S)-3bꢀCu(OTf)2 also increased the
enantioselectivity to 53% ee (entry 7). The chemical yield of 2b
increased from 11% to 42% with the use of 53 equiv of tert-butanol
(entry 8). Thus, 2b was obtained in 71% yield with 54% ee under
optimized conditions with the use of 53 equiv of tert-butanol in the
presence of 10 mol% of (S,S)-3bꢀCu(SbF6)2 (entry 9).
To develop a highly enantioselective intramolecular Cannizzaro
reaction, we examined double asymmetric induction in the
3ꢀCuX2-catalyzed reaction of anhydrous phenylglyoxal 1 with
(+)- or (ꢁ)-menthol. As shown in Table 2, the reaction of 1 with
D-
(+)-menthol (2 equiv.) in the presence of 10 mol% of (R,R)-
3aꢀCu(OTf)2 gave -(+)-menthyl (S)-mandelate (2c) in 72% yield
with 77% de (entry 1). On the other hand, the reaction of 1 with
(ꢁ)-menthol (2 equiv.) in the presence of 10 mol% of (R,R)-
3aꢀCu(OTf)2 gave -(ꢁ)-menthyl (R)-mandelate (2c) in 81% yield
with 35% de (entry 2). As expected, double asymmetric induction
was observed when -(+)-menthol and (R,R)-3a were used for the
D
Scheme 1.
L-
L
D
reaction of 1. This result was much better than that using tert-
butanol and (R,R)-3a (see Table 1, entry 2). Furthermore, the
chemical yield and diastereoselectivity of 2c were increased to 81%
and 90% de with the use of
(entry 3).
D-(+)-menthol and (S,S)-3bꢀCu(SbF6)2
Based on the stereochemical outcome of these reactions, we
propose a plausible mechanism (Scheme 3) to rationalize the
observed absolute configuration of the products. According to the
mechanism proposed by Morken and co-workers [2], the initial
reaction of 1 with tert-butanol provides hemiacetal. Subsequent
coordination of the hemiacetal to chiral 3ꢀCuX2 followed by
intramolecular hydride transfer, presumably by a three-center
transition state, might then provide the observed reaction product
2b. Enantioselective transformation would result from dynamic
resolution whereby the chiral 3ꢀCuX2 selectively chelates and
catalyzes the rearrangement of one enantiomer of a racemic
equilibrating mixture of the hemiacetal. However, neither we nor
Morken et al. can rule out the enantioselective addition of tert-
butanol to Cu(II)-coordinated 1 as a mechanism for enantioselec-
tive transformation. Steric interactions that would govern this
Scheme 2.
Next,
(S,S)-2,20-isopropylidenebis(4-tert-butyl-2-oxazoline)
[(S,S)-t-BuBox (3b)] was examined instead of (R,R)-3a because of
strong tolerance of 3b to Cu(NTf2)2 and Cu(SbF6)2. Surprisingly, the
(S,S)-3bꢀCu(OTf)2-catalyzed reaction of 1 with isopropanol gave
(S)-2a as a major enantiomer. However, the enantioselectivity was
low (15% ee) (entry 4). The use of Cu(SbF6)2 gave slightly better
reactivity and enantioselectivity than with Cu(OTf)2 and Cu(NTf2)2
(entries 4–6). The use of tert-butanol instead of isopropanol in the
Table 1
3ꢀCuX2-catalyzed enantioselective intramolecular Cannizzaro reaction of anhydrous phenylglyoxal 1a
Entry
3 [R2]
CuX2
R1OH (equiv)
2
Yield (%)
ee (%) [configuration]
1
2
3
4
5
6
7
8
9b
(R,R)-3a [Ph]
(R,R)-3a [Ph]
(R,R)-3a [Ph]
(S,S)-3b [t-Bu]
(S,S)-3b [t-Bu]
(S,S)-3b [t-Bu]
(S,S)-3b [t-Bu]
(S,S)-3b [t-Bu]
(S,S)-3b [t-Bu]
Cu(OTf)2
Cu(SbF6)2
Cu(OTf)2
Cu(OTf)2
Cu(NTf2)2
Cu(SbF6)2
Cu(OTf)2
Cu(OTf)2
Cu(SbF6)2
i-PrOH, 2
i-PrOH, 2
t-BuOH, 2
i-PrOH, 2
i-PrOH, 2
i-PrOH, 2
t-BuOH, 2
t-BuOH, 53
t-BuOH, 53
2a, 89
2a, trace
2b, 18
2b, 85
2b, 80
2b, 87
2b, 11
2b, 42
2b, 71
23 [S]
0
42 [S]
15 [S]
17 [S]
20 [S]
53 [S]
53 [S]
54 [S]
a
Unless otherwise noted, the Cannizzaro reaction of 1 (1 equiv.) with R1OH (2 or 53 equiv.) was conducted in 1,2-dichloroethane in the presence of 3ꢀCuX2 (10 mol%) at
room temperature.
b
Dichloromethane was used instead of 1,2-dichloroethane.

996
K. Ishihara et al. / Journal of Fluorine Chemistry 129 (2008) 994–997
Table 2
Double asymmetric induction in the 3ꢀCuX2-catalyzed intramolecular Cannizzaro reaction of anhydrous phenylglyoxal 1 with (+ or ꢁ)-menthola
Entry
3 [R2]
CuX2
R1OH
2c
Yield (%)
de (%) [configuration]b
1
(R,R)-3a [Ph]
(R,R)-3a [Ph]
(S,S)-3b [t-Bu]
Cu(OTf)2
Cu(OTf)2
Cu(SbF6)2
D
-(+)-menthol
-(ꢁ)-menthol
D-(+)-menthol
72
81
81
77 [S]
35 [R]
90 [S]
2
3c
L
a
Unless otherwise noted, the Cannizzaro reaction of 1 with
L
- or
D
-menthol (2 equiv.) was conducted in 1,2-dichloroethane in the presence of 3ꢀCuX2 (10 mol%) at room
temperature.
b
The absolute configuration of the mandelic moiety of 2c is shown in brackets.
c
Dichloromethane was used instead of 1,2-dichloroethane.
addition process should be similar to those proposed for binding of
the chiral metal complex to hemiacetal. Thus, the nature of the
observed preference for the (S) abolute configuration in product 2b
can be understood through TS-4 and TS-5, which are proposed for
the Cannizzaro reactions of 1 with tert-butanol catalyzed by (R,R)-
3aꢀCuX2 and (S,S)-3bꢀCuX2, respectively. TS-4 is a square planar
complex in which the t-BuO group is directed away from the steric
bulk of the Ph group (shown in bold in Scheme 3) [3a,b]. On the
other hand, TS-5 is a twisted square planar (pseudo-tetrahedral)
complex in which the t-BuO group is directed away from the steric
bulkiness of the t-Bu group (shown in bold in Scheme 3) [3a,b].
The most thermodynamically stable Cu(II)-chelated complex 6
with hemiacetal derived from 1 and D-(+)-menthol can also be
predicted due to the minimized steric hindrance between the i-Pr
group and the Ph group, as shown in Fig. 1. The absolute
configuration of the anomeric carbon of 6 is the same as those of
TS-4 and TS-5. Therefore, double asymmetric induction would be
observed in the reactions of 1 with
(R,R)-3aꢀCuX2 and (S,S)-3bꢀCuX2.
D-(+)-menthol catalyzed by
Scheme 3.
3. Conclusion
Chiral Lewis acid-catalyzed intramolecular Cannizzaro reaction
of 1 with alcohols proceeded more smoothly under anhydrous
conditions. 3bꢀCu(SbF6)2 was a more active and selective chiral
Lewis acid catalyst than 3aꢀCu(OTf)2 for the Cannizzaro reaction.
Thus, the enantioselectivity and chemical yield of product 2 were
improved to 54% ee and 71% under our optimized conditions (for
the previous results, see Scheme 2). Furthermore, we succeeded in
the double asymmetric induction of the Cannizzaro reaction of 1
with
D
-(+)-menthol catalyzed by (S,S)-3bꢀCu(SbF6)2 to give (S)-2c
in 81% yield with 90% de. (S)-2c can be hydrolyzed to (S)-mandelic
acid and D-(+)-menthol. The extremely steric bulkiness and the
delocalized electronagativity of SbF6ꢁ were important as a counter
anion of 3bꢀcopper(II).
4. Experimental
1H NMR spectra were measured on Varian Gemini-2000
(300 MHz) spectrometer at ambient temperature. Data were
Fig. 1. Predicted most thermodynamically stable Cu(II)-chelated complex 6 with a
hemiacetal derived from 1 and -(+)-menthol.
D

K. Ishihara et al. / Journal of Fluorine Chemistry 129 (2008) 994–997
997
recorded as follows: chemical shift in ppm from internal tetrame-
thylsilane on the d scale, multiplicity (s = singlet; d = doublet;
t = triplet; q = quartet, m = multiplet), coupling constant (Hz),
integration, and assignment. High-performance liquid chromato-
graphy (HPLC) analysis was conducted using Shimadzu LC-10 AD
coupled diode array-detector SPD-MA-10A-VP and chiral column
of Daicel CHIRALCEL OD-H (4.6 mm ꢂ 25 cm). For thin-layer
chromatography (TLC) analysis throughout this work, Merck
precoated TLC plates (silica gel 60 GF254 0.25 mm) were used.
The products were purified by column chromatography on silica
gel (E. Merck Art. 9385). Acetonitrile was dried over molecular
4.4. General procedure for the enantioselective intramolecular
Cannizzaro reaction of anhydrous 1 with alcohol induced by 3ꢀCuX2
catalyst
To a solution of 3ꢀCuX2 (0.10 mmol) were added anhydrous 1
(1 mmol, 1 M in toluene) and alcohol. The mixture was stirred at
room temperature for 24 h. The reaction was quenched with 1 M
HCl aqueous solution at room temperature. The products were
extracted with EtOAc, dried over anhydrous MgSO4, filtered and
concentrated in vacuo. Purification by column chromatography on
silica gel (hexane–EtOAc) afforded desired product 2.
˚
sieves 3 A. 1,2-Dichloroethane and dichloromethane were freshly
distilled from calcium hydride. Isopropanol and tert-butanol were
distilled from calcium hydride and stored over molecular sieves
ꢃ
ꢃ
ꢃ
Isopropyl (S)-2-hydroxy-2-phenylacetate (2a) [2]: The ee was
determined by HPLC analysis (Daicel Chiralcel OD-H column,
hexane–i-PrOH = 80:1 for elution, flow rate = 1.0 mL/min;
˚
3 A. Other simple chemicals were analytical-grade and obtained
commercially.
l = 205 nm) tR = 10.6 min for (S)-2a, 20.1 min for (R)-2a.
tert-Butyl (S)-2-hydroxy-2-phenylacetate (2b) [4]: The ee was
determined by HPLC analysis (Daicel Chiralcel OD-H column,
hexane–i-PrOH = 20:1 for elution, flow rate = 1.0 mL/min;
4.1. Preparation of anhydrous phenylglyoxal 1 in toluene [1]
A 10-mL, single-necked, pear-shaped-flask equipped with a
Teflon-coated magnetic stirring bar and a Dean–Stark apparatus
surmounted by a reflux condenser was charged with commercially
available phenylglyoxal hydrate (152 mg, 1 mmol) and toluene
(2.5 mL). The mixture was heated to azeotropic reflux with the
removal of water. After being stirred for 1 h, the resulting mixture
was cooled to ambient temperature.
l = 206 nm) tR = 5.8 min for (S)-2b, 9.9 min for (R)-2a.
D
-Menthyl (S)-2-hydroxy-2-phenylacetate (2c) [5]: The de was
determined by 1H NMR analysis (CDCl3, 300 MHz): d 4.65 (dt,
J = 4.5, 10.8 Hz, 1H, (S)-2c) and 4.77(dt, J = 4.5, 10.8 Hz, 1H, (R)-2c).
Acknowledgements
Financial support for this project was provided by the Toray
Science Foundation and the G-COE in Chemistry, Nagoya. We thank
Ms. Sayaka Tanahara for her help with the experiments.
4.2. Preparation of a Cu(OTf)2ꢀ3 catalyst solution
To a flame-dried flask were added 3 (0.11 mmol), Cu(OTf)2
(36.2 mg, 0.10 mmol) and 1,2-dichloromethane (2 mL). The
mixture was stirred at room temperature for 3 h.
References
[1] K. Ishihara, T. Yano, Org. Lett. 6 (2004) 1983–1986.
[2] A.E. Russell, S.P. Miller, J.P. Morken, J. Org. Chem. 65 (2000) 8381–8383.
[3] For reviews of Cu–bis(oxazoline) complexes in the asymmetric activation of
carbonyls, see:
4.3. Preparation of a Cu(SbF6)2ꢀ3b catalyst solution
(a) J.S. Johnson, D.A. Evans, Acc. Chem. Res. 33 (2000) 325–335;
(b) K.A. Jørgensen, M. Johannsen, S. Yao, H. Audrain, J. Thorhauge, Acc. Chem. Res.
32 (1999) 605–613.
To
a flame-dried flask were added (S,S)-3b (32.4 mg,
0.11 mmol), CuBr2 (22.3 mg, 0.10 mmol), AgSbF6 (37.8 mg,
0.11 mmol) and dichloromethane (4 mL). The mixture was filtered
through a syringe filter.
[4] J.W. Yang, B. List, Org. Lett. 8 (2006) 5633–5655.
[5] E. Aller, D.S. Brown, G.G. Cox, D.J. Miller, C.J. Moody, J. Org. Chem. 60 (1995) 4449–
4460.