Organocatalysis in radical chemistry. Enantioselective α-oxyamination of aldehydes

Article abstract of DOI:10.1021/ja069245n

We have developed an efficient radical α-oxyamination reaction using chiral organocatalysts. The reaction can be carried out with inexpensive SET reagents, and a reasonably broad substrate scope has been established. Good to high enantioselectivity for th

Full text of DOI:10.1021/ja069245n

Published on Web 03/16/2007
Organocatalysis in Radical Chemistry. Enantioselective r-Oxyamination of
Aldehydes
Mukund P. Sibi* and Masayuki Hasegawa
Department of Chemistry, North Dakota State UniVersity, Fargo, North Dakota 58105
Received December 22, 2006; E-mail: mukund.sibi@ndsu.edu
Scheme 1
Chiral Lewis acids play a critical role in providing substrate
activation and the necessary chirality for enantioselective transfor-
mations.1 Chiral Lewis acid mediated enantioselective radical
reactions have been investigated extensively in many laboratories.2
A complementary technique to chiral Lewis acid mediated processes
is organocatalysis.3 Spectacular advances have been made in recent
years using organocatalysts. However, only a few examples of
radical reactions utilize organocatalysts.4 In this Communication
we report an enantioselective radical-mediated C-O bond-forming
reaction using organocatalysts.5 This new transformation further
Table 1. Identification of Reaction Conditionsa
broadens the utility of organocatalysts in enantioselective trans-
formations.
In general, radical species are produced using tin-mediated chain
reactions. Alternatively, enolates6 and enamines7 can be oxidized
using a single electron transfer (SET) reagent, and the resultant
radical species captured in useful bond-forming processes (Scheme
1). We surmised that enamines prepared from aldehydes and chiral
amines could be oxidized using a SET reagent and the intermediate
radical trapped stereoselectively by TEMPO providing access to
R-oxyaminated aldehydes, an important class of chiral building
entry
catalyst, mol %
time, h
yield, %b
ee, %c
blocks.8 Herein, we describe a catalytic and highly enantioselective
R-oxyamination process using chiral imidazolidinone catalysts.
We began our work to identify reaction conditions for the
R-functionalization process and these results are tabulated in Table
1. Treatment of phenylpropanal 7 with a stoichiometric amount of
ferrocenium terafluoroborate in the presence of TEMPO gave the
R-oxygentated product in good yield (entry 1). This suggested that
the aldehyde could undergo reaction through its enol form efficiently
but at a slow rate. The product R-aminoxy aldehyde was reduced
to the primary alcohol 9 to aid in analysis. An identical reaction as
in entry 1 but using 1 equiv of pyrrolidine gave 9 in high yield in
1 h (entry 2). This experiment indicated that the SET reagent could
readily oxidize the pyrrolidine-derived enamine. Reaction using
chiral imidazolidinone 10a gave the product in good yield and
enantioselectivity (entry 3).9 Reaction with 20 mol % of 10a was
also efficient, indicating catalyst turnover (entry 4). Changing the
catalyst to 10b, a tetrafluoroborate salt, led to an improvement in
selectivity from 64 to 80% ee (entry 5). Proline was an efficient
catalyst for the reaction but the enantioselectivity was very low
(entry 6).
Optimization with respect to the catalyst, SET reagent, and
solvent was investigated next and results from these experiments
are tabulated in Table 2. Reducing the amount of SET reagent from
100 to 50 mol % in reactions using 10b as a catalyst gave lower
chemical efficiency (compare entry 1 with 2). We then explored a
cheaper SET reagent, FeCl3. The oxygenation reaction catalyzed
by 10b did not proceed in the presence of a stoichiometric amount
of FeCl3 with THF as the solvent (entry 3). However, DMF as a
solvent proved to be effective and gave the product in high yield
and ee (entry 4). A catalytic amount of the SET reagent could be
used when a cooxidant (NaNO2/O2)10 was employed without
1
2
3
4
5
6
none
pyrrolidine (100)
10a (100)
10a (20)
10b (20)
24
1
1
1
1
79
61
63
78
87
71
76
64
80
L-proline (20)
1
-3
a For reaction conditions, see Supporting Information. b Isolated yield.
c Determined by chiral HPLC.
compromising yield or selectivity (entries 5 and 6). We then
explored alternative chiral amines with the hope of improving
selectivity (entries 7-10).11 However, these reactions were not very
rewarding.
Having identified a reasonable set of conditions, we then
investigated reactions with a variety of aldehydes and these results
are presented in Table 3. The reactions were carried out at two
different temperatures (room temp and -10 °C) using 10b as the
catalyst and FeCl3 as the SET reagent. Reaction with phenyl-
acetaldehyde provided modest selectivity owing to relatively rapid
background reaction and partial racemization of the product (entry
1). In contrast, compound 7 gave good yield and selectivity at room
temperature (entry 2). The selectivity could be improved by
conducting the reaction at -10 °C (compare entry 2 with 3).
However the reaction was less efficient and took longer to complete.
Reaction with phenylbutanal 12 was efficient and selectivity could
be improved by cooling the reaction to -10 °C (entries 4 and 5).
A variety of aryl substituted aldehydes underwent R-oxygenation
with high selectivity (entries 6-11). Heterocycle containing alde-
hydes were also competent substrates in the oxygenation reaction
(entries 12-15). Reaction with 4-pentene-1-al was also successful
with selectivity reaching 90% for reaction at -10 °C (entries 16
9
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J. AM. CHEM. SOC. 2007, 129, 4124-4125
10.1021/ja069245n CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Effect of SET Reagent, Ligand, and Solventa
Figure 1. Stereochemical model.
with models proposed in the literature for reactions of aldehydes
using imidazolidinone catalysts.2,13
In conclusion we have developed an efficient radical R-oxygen-
ation reaction using organocatalysts. The reactions proceed with
good to excellent enantioselectivity. The methodology reported in
this work adds to the repertoire of reactions that can be conducted
using organocatalysts. Work is underway to utilize organocatalysts
in radical-mediated C-C bond-forming processes.
SET reagent
(mol %)
NaNO2
(equiv)
yield
(%)b
ee
entry
ligand
solvent
(%)c
1
2
3
4
Cp2FeBF4 (100)
Cp2FeBF4 (50)
FeCl3 (100)
FeCl3 (100)
FeCl3 (30)
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
10b
10b
10b
10b
10b
10b
10c
10d
10e
10f
0
0
0
0
0.3
0.3
0.3
0.3
0.3
0.3
THF
THF
THF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
87
40
4
74
82
83
75
64
26
33
80
74
ndd
72
75
72
5
46
0
17
5e
6e
7e
8e
9e
10e
Acknowledgment. This work was supported by the National
Institutes of Health (Grant NIGMS-54656).
Supporting Information Available: Characterization data for
compounds 9, 15, 17, and 20-28 and experimental procedures. This
material is available free of charge via the Internet at http://pubs.acs.org.
FeCl3 (10)
a For reaction conditions, see Supporting Information. b Isolated yield.
c Determined by chiral HPLC. d Not determined. e Reaction run using 2
equiv of TEMPO and oxygen as a co-oxidant.
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1
C6H5 11
C6H5CH2 7
room temp
room temp
-10
2
2
24
2
24
2
24
2
24
2
24
2
74
80
68
78
64
77
64
76
68
74
75
65
66
32
71
82
60
84
81
86
72
84
75
82
84
90
2
3d
4
C6H5CH2CH2 12
room temp
-10
5
6
7
8
4-MeOC6H4CH2CH2 13
3,4-(MeO)2C6H3CH2 14
4-NO2C6H4CH2CH2 15
room temp
-10
room temp
-10
9d
10
11
12
13
room temp
-10
room temp
-10
24
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14
15
room temp
-10
2
24
49
50
56
85
16
17
18
allyl 18
room temp
-10
room temp
2
24
24
49
58
74
80
90
0
(CH3)2CH 19
a For reaction conditions, see Supporting Information. b Isolated yield.
c Determined by chiral HPLC. d Reaction run using 4.0 equiv of TEMPO.
and 17). Isovaleraldehyde, a simple aliphatic aldehyde gave the
oxidation product in good yield but with no selectivity (entry 18).
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substrate scope in these R-oxygenation reactions.12
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