Asymmetric α-oxyamination of aldehydes by synergistic catalysis of imidazolethiones and metal salts

Article abstract of DOI:10.1039/c4ra08556f

Novel and efficient imidazolethione catalysts combined with metal salts were successfully introduced to the asymmetric α-oxyamination of aldehydes. The desired products with high yields and good to excellent enantioselectivities were obtained via a one-pot oxidation-oxyamination reaction system.

Full text of DOI:10.1039/c4ra08556f

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Asymmetric a-oxyamination of aldehydes by
synergistic catalysis of imidazolethiones and metal
Cite this: RSC Adv., 2014, 4, 44039
salts†
Received 24th July 2014
Accepted 9th September 2014
*
Xianrui Liang, Na Li, Xinlei Chen and Weike Su
DOI: 10.1039/c4ra08556f
www.rsc.org/advances
Novel and efficient imidazolethione catalysts combined with metal reported with using other catalyst systems, such as porous
salts were successfully introduced to the asymmetric a-oxyamination cross-linked polymers (PCPs) photocatalysts,11 TiO2 photo-
of aldehydes. The desired products with high yields and good to catalyst,12 or electrochemical oxidation.13 In 2012, MacMillan
excellent enantioselectivities were obtained via a one-pot oxidation– extended the scope of substrates and gained excellent enan-
oxyamination reaction system.
tioselectivity in low temperature using synergistic catalysis
system of imidazolidinone and metal salts.14 Meanwhile, these
asymmetric a-oxyamination aldehydes can be also obtained by
many related multistep reactions15 and two of them were
applied to the synthesis of oxylipins16 and pentoses17
successfully.
Asymmetric organocatalysis play a pivotal role in the synthesis
of a variety of chiral molecules. Among them, oxygen-bearing
stereocenters, especially the enantioselective a-oxygenated
carbonyl formations are one of the fundamental structural
motifs in natural and synthetic products, such as taxol, bestai,
and zaragozic acid.1 Many traditional methods including ami-
nohydroxylations,2 olen epoxydation3 and dihydroxylation4
exhibited good ability to provide these asymmetric oxygen-
bearing stereocenters. Recently, the newly developed asym-
metric a-oxidation of aldehydes as an important approach to
form the enantioselective oxygen-bearing stereocenters has also
been substantially studied in the presence of different catalytic
systems.
MacMillan5 and Zhong6 reported the rst direct a-oxidation
of aldehydes using natural proline and nitrosobenzene in 2003.
The catalytic enantioselective a-oxyamination of aldehydes
using 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO) as
an electrophilic source of oxygen in the presence of imidazoli-
dinone were reported by Sibi7 and MacMillan8 in their respec-
tive work in 2007 and 2010. In 2010, Kudo's group developed a
bioinspired catalyst and used it to the asymmetric a-oxy-
amination of aldehydes via a tandem system with primary
alcohol's oxidation.9 Maruoka used binaphthyl-based chiral
amine catalysts and an oxoammonium salt instead of metal
reagents to obtain stable a-oxy aldehydes with excellent enan-
tioselectivity.10 Similar a-oxyamination reaction was also
Although many of the reported organocatalysts show effi-
cient in this asymmetric a-oxyamination of aldehydes, not all
the substrates can be obtained with good enantioselectivity, and
the yield still need to be improved via the one-pot reaction
system. So new organocatalysts aimed to provide better yields
and enantioselectivity with expanded substrate scopes are still
worthwhile to investigate. In previous works,18 we had reported
the successful application of newly developed chiral imidazo-
lethiones catalysts (Fig. 1) in the enantioselective Friedel–Cras
reactions. The structure of thioamide was used to increase the
rigidity of catalyst18 and the more ‘stiffer’ imidazolethiones were
anticipated to help improve the stereoselectivity in reactions.
Base on the good catalytic activity and applications of imida-
zolethiones, the synergistic catalysis of imidazolethiones and
metal salts were introduced to the reactions of a-oxyamination
of aldehydes in this work to provide another useful choice for
asymmetric C–O bond formation. The possible synergistic
catalytic mechanism was also discussed.
To evaluate the efficiency of catalysts, the reaction of
3-phenylpropanal 3a and TEMPO was used as a model reaction
Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals,
College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou
310014, China. E-mail: pharmlab@zjut.edu.cn; Tel: +86 57188320899
† Electronic supplementary information (ESI) available: Experimental details and
characterization data. See DOI: 10.1039/c4ra08556f
Fig. 1 Chiral imidazolethione catalysts.
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Table 2 Optimization of the reaction conditionsa
based on the reaction conditions reported in literature.7 The 3a
and TEMPO in DMF were treated with a stoichiometric amount
of ferric chloride and a catalytic amount of different imidazo-
lethione catalysts, respectively. Reduction of product a-aminoxy
aldehyde 4a to the primary alcohol 5a was performed to aid
analysis and the results were presented in Table 1. Compared
with imidizolidinone 1a (Table 1, entry 1), a better stereo-
selectivity were obtained in the presence of imidazolethione 2a
(Table 1, entry 2). The imidazolethione catalyst 2b with a larger
cyclohexyl group was also evaluated for its catalytic activity,
however, nearly no product was observed (Table 1, entry 3). The
preliminary experiment results indicate that catalyst imidazo-
lethione 2a has a better catalytic efficiency against 1a and 2b.
The (S)-congurations were the main products according to the
HPLC data reported in the literature.7
Entry Solvent (v/v)
Acid Metal T (ꢀC) Yieldb (%) eec (%)
1
2
3
4
5
6
7
8
DMF
TFA
TFA
TFA
TFA
TFA
FeCl3 25
FeCl3 25
FeCl3 25
FeCl3 25
FeCl3 25
FeCl3 25
FeCl3 25
FeCl3 25
FeCl3 25
FeCl3 25
78
Trace
23
15
85
85
53
8
83
73
80
57
80
76
83
77
89
77
83
74
65
83
80
76
CH2Cl2
Acetone
i-PrOH
H2O
H2O–CH2Cl2 (4 : 1) TFA
H2O–CH2Cl2 (1 : 1) TFA
H2O–CH2Cl2 (1 : 4) TFA
H2O–acetone (4 : 1) TFA
n.d.
n.d.
n.d.
75
74
65
n.d.
70
67
73
64
79
82
72
72
80
73
85
78
With the optimized catalyst imidazolethione 2a in hand, the
reaction conditions including solvents, additives acids and
synergistic metal salts were further examined with results
summarized in Table 2. Among DMF, CH2Cl2, acetone, i-PrOH,
H2O (Table 2, entries 1–5) and a series of mixed solvents (Table
2, entries 6–10), the proportion of H2O affecting the yield of the
reaction signicantly and higher yield and good selectivity were
obtained in H2O at room temperature (Table 2, entry 5). Then
additive acids that help to activate the substrates were evaluated
and results showed that imidazolethione 2a with triuoroacetic
acid gave the product in high yield and enantioselectivity
(Table 2, entries 5, 11, 12). To further improve the enantio-
9
10
11
12
13d
14e
15
16
17
18
19
20e
21f
22f
23g
H2O–DMF (4 : 1)
TFA
H2O
H2O
H2O
HBF4 FeCl3 25
p-TSA FeCl3 25
TFA
FeCl3
0
H2O–acetone (4 : 1) TFA
FeCl3 ꢁ10
FeCl2 25
FeSO4 25
CuCl2 25
CuSO4 25
CuCl 25
H2O
H2O
H2O
H2O
H2O
TFA
TFA
TFA
TFA
TFA
H2O–acetone (4 : 1) TFA
H2O–acetone (2 : 1) TFA
H2O–acetone (2 : 1) TFA
H2O–acetone (2 : 1) TFA
CuCl
CuCl
ꢁ10
ꢀ
ꢀ
ꢁ20
72
89
90
selectivity, the reaction was performed at 0 C and ꢁ10 C by
adding a certain amount of acetone to H2O to lower its freezing
point, but the ee value was still unsatisfactory (Table 2, entries
13 and 14). The synergistic metal salts, including FeCl3, FeCl2,
CuCl2, CuSO4 and CuCl were chosen to facilitate the catalytic
CuCl2 ꢁ20
CuCl2 ꢁ20
a
Reaction condition: 3a (1 mmol), TEMPO (2 mmol), 2a (20 mol%), HX
(20 mol%), metal (1 equiv.), solvent (2 mL), NaBH4 (2 equiv.). b Isolated
c
d
yield. Enantiomeric excess determined by HPLC analysis. 12 h.
e
24 h. f 48 h. g CuCl2 (10 mol%), TEMPO (1.5 equiv.), 48 h.
Table 1 a-Oxyamination of 3a using different catalystsa
system. And better enantioselectivity was obtained when
10 mol% CuCl2 was used at ꢁ20 ꢀC (Table 2, entry 23). At room
temperature, both CuCl2 and CuCl gave good yields and ee
values (Table 2, entries 17 and 19) with reaction time at 3 h.
Lower reaction temperatures were also investigated to obtain
even better enantioselectivity albeit with somewhat longer
reaction time. Curiously, differences were observed between the
synergistic metal salts of Cu(I) and Cu(II). The ee value decreased
from 85% to 72% when the temperature was down to ꢁ20 ꢀC in
the presence of CuCl (Table 2, entry 21). However, the good ee
value was obtained with CuCl2 at ꢁ20 ꢀC (Table 2, entry 22).
High yield and enantioselectivity could also be observed when
the amount of CuCl2 and TEMPO were decreased to 10 mol%
and 1.5 equiv. (Table 2, entry 23).
Entry
Catalyst
Time (h)
Yieldb (%)
eec (%)
Allowed for the unstable properties of aldehydes and
observed good yield and ee value in H2O–CH2Cl2 (Table 2, entry
6). We developed a one-pot reaction system under the optimal
reaction conditions (Table 2, entry 23) including oxidation of
primary alcohols, followed by the asymmetric a-oxyamination
of aldehydes, and then the NaBH4 reduction of aldehydes to
corresponding alcohols as shown in Table 3. The TEMPO and
1
2
3
1a
2a
2b
3
3
3
80
75
Trace
68
73
n.d.d
a
Reaction condition: 3a (1 mmol), TEMPO (2 mmol), catalyst (20
mol%), HBF4 (20 mol%), FeCl3 (1 equiv.), DMF (2 mL), NaBH4 (2
equiv.). Isolated yield. Enantiomeric excess determined by HPLC
analysis. d Not determined.
b
c
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Table 3 One-pot oxidation–oxyamination of various alcoholsa
but showed very low enantioselectivity with 4% ee, which might
have resulted from the rapid racemization of phenyl-
acetaldehyde. Both aromatic and aliphatic alcohols were
applied in these sequential reaction systems. When 4-phenyl-
1-butanol 3c was used as substrate, the product 5c can be
obtained in good yield and enantioselectivity. This was the case
with several long-chain and short-chain aliphatic alcohols 3d,
3e and 3f. It was worth noting that the yields of product 5g and
5h were decreased when the g-position substituted alcohols
were used. It might be due to the presence of the steric groups
hinder the attack of TEMPO. Olen, cyclohexyl, ester containing
alcohols 3h, 3i and 3j were also conrmed to be the competent
substrates, which yielded the corresponding products in good
yields and excellent enantioselectivity. Overall, the above results
demonstrate that this one-pot sequential reaction system with
optimized reaction conditions catalyzed by imidazolethione 2a
can be applied to a broad substrate scope.
There existed two mainly differential opinions about the
mechanism of asymmetric a-oxyamination of aldehydes. In
2007, Sibi7 proposed a singly occupied molecular orbital
(SOMO) activation mechanism. In 2010, MacMillan and his co-
workers8 revealed the reaction proceeded via a more traditional
enamine addition pathway. Based on the enamine addition
mechanism8,19 and experimental results in this work, we
proposed a synergistic catalysis mechanism (Scheme 1). The
catalyst imidazolethione coupled with Cu(II) activated alde-
hydes and TEMPO in their own catalytic cycles, respectively. The
two activated intermediates narrowed the energy gap and
facilitated reaction. Firstly, aldehyde was activated by chiral
imidazolidinone catalysts and formed the enamine interme-
diate I. Simultaneously, TEMPO as another substrate was acti-
vated by Cu(II) and formed the Cu(II)–TEMPO complex II. Then,
the complex as electrophile attacked enamine intermediate to
produce the iminium ion III. The hydrolysis of intermediate III
released imidazolethiones and Cu(I). The Cu(I) was reoxidized
by ambient oxygen to regenerate the Cu(II) salt and worked in
the cycle again.
a
Reaction condition: 3 (1 mmol), TEMPO (1.5 mmol), CH2Cl2 (1 mL), 2a
(20 mol%), TFA (20 mol%), CuCl2 (10 mol%), H2O–acetone (v/v ¼ 2 : 1),
NaBH4 (2 equiv.). b Isolated yield. c Enantiomeric excess determined by
HPLC analysis.
NaClO system was chosen as oxidizing agent in the rst step due
to its mild reaction condition and high conversion rates. The
oxidation–oxyamination and reduction reactions of alcohols 3
provided products 5 in good yields and with high to excellent
enantioselectivities except 3b. It was observed that the reaction
of 2-phenylethanol 3b provided the product in very high yield
Scheme 1 The possible synergistic catalytic mechanism.
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8 J. F. Van Humbeck, S. P. Simonovich, R. R. Knowles and
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Conclusions
In summary, the imidazolethione catalyst 2a is successfully
applied to the asymmetric a-oxyamination of aldehydes via the
efficient one-pot sequential reaction system. The corresponding
products are obtained in good yields and high to excellent
enantioselectivities. Applications of this synergistic catalysis
system to a-functionalization of carbonyl compounds are
underway in our laboratory.
10 T. Kano, H. Mii and K. Maruoka, Angew. Chem., Int. Ed., 2010,
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11 Z. Xie, C. Wang, K. E. deKra and W. Lin, J. Am. Chem. Soc.,
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Acknowledgements
This work was supported by National Natural Science Founda-
tion of China (Grant no. 21206148).
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