Direct L-proline-catalyzed asymmetric α-amination of ketones

Article abstract of DOI:10.1021/ja026412k

The first direct catalytic asymmetric α-amination of ketones catalyzed by l-proline has been developed. The reactions proceed with various azodicarboxylates as the nitrogen source in high yields and excellent enantioselectivities (up to 99% ee). The scope and potential of the reaction are demonstrated by further transformation of the α-hydrazino ketones formed to both optically active syn and anti-α-amino alcohol derivatives. Copyright

Full text of DOI:10.1021/ja026412k

Published on Web 05/11/2002
Direct L-Proline-Catalyzed Asymmetric r-Amination of Ketones
Nagaswamy Kumaragurubaran, Karsten Juhl, Wei Zhuang, Anders Bøgevig, and
Karl Anker Jørgensen*
Center for Catalysis, Department of Chemistry, Aarhus UniVersity, DK-8000 Aarhus C, Denmark
Received April 4, 2002
The stereoselective formation of C-N bonds from simple and
Table 1. Enantioselective R-Amination of Cyclohexanone 1a and
Butanone 1b by the Azodicarboxylates 2a-c Catalyzed by
easily available starting materials is an important task in organic
chemistry as molecules containing this functionality are chiral key
elements in many important compounds.
L-Proline under Various Reaction Conditions at Room
Temperaturea
cat. load.
(%)
reac.
eec
time (h) product (%)
b
There are several catalytic enantioselective procedures for the
stereoselective formation of R-amino carbonyl compounds of which
entry ketone azodicarboxylate
solvent
3ad
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
2a
2a
2a
2a
2b
2c
2a
2a
2a
2a
2a
2a
20
20
20
20
20
20
20
20
20
10
5
CH
Cl(CH
MeCN
MeCN
MeCN
MeCN
CH
MeCN
Neat
Neat
Neat
2
Cl
2
2
11
44
2.5
66
6
52
76
52
65
65
65
10
79
84
65
82
59
59
91
96
92
93
93
95
1
2
the Strecker and Mannich reactions involve the enantioselective
addition to imines. However, the direct enantioselective addition
of a nitrogen source to a carbon center will be a simple approach
for the formation of a chiral carbon atom bound to a nitrogen atom.3
The first direct metal-catalyzed R-amination of 2-keto esters has
)
2
Cl
3a
3a
3a
e
d
3b
d
3c
2
Cl
2
3d
3d
3d
3d
3d
3d
4
recently been presented, which leads to a simple synthetic approach
f
f
to optically active syn-â-amino-R-hydroxy esters.
10
f
1
1
1
2
In this communication the first catalytic enantioselective direct
R-amination reactions of ketones using azodicarboxylates as the
nitrogen source are presented (eq 1). These reactions are catalyzed
g
10
MeCN
a
See Supporting Information for details. b After full conversion of 2.
5
c
by L-proline and give access to highly valuable optically active
ee determined by chiral GC using Chrompack CP Chiralsil-Dex Câ or
d
Astec G-TA columns. Approximately 10% of the double addition product
R-hydrazino ketones, which by further transformations can give
important optically active compounds such as R-aminated ketones
and alcohols.
e
f
is formed. Reaction performed at -24 °C. Reactions are performed with
equiv of the ketone. g The reaction is performed with 5 equiv of the ketone.
2
latter reaction can also take place as a neat reaction by just adding
a and L-proline to ketone 1b. Under these conditions the
2
R-aminated adduct 3d is obtained with excellent enantioselectivities
in the presence of only 5 mol % of L-proline as the catalyst (entry
9-11). It should be noted that the reactions are very regioselective
as <10% yield of the product obtained from amination of the methyl
group is formed.
The simplicity of the reaction conditions for the L-proline-
catalyzed direct enantioselective R-amination reaction and isolation
procedure should be noted: the reactions are conducted at ambient
conditions, and the R-hydrazino ketones are isolated by addition
of water to the reaction mixture and extraction with diethyl ether
followed by evaporation of the solvent and excess ketone.
The potential and scope of the L-proline (10 mol %)-catalyzed
direct enantioselective R-amination is demonstrated by the reaction
of the ketones 1a-f with DEAD 2a (eq 1). The results are presented
in Table 2.
The results for some of the screening investigations for the
enantioselective direct R-amination of cyclohexanone 1a and
butanone 1b by the azodicarboxylates 2a-c catalyzed by L-proline
(eq 1) under various reaction conditions are presented in Table 1.
The L-proline (20 mol %)-catalyzed direct enantioselective
R-amination of cyclohexanone 1a by diethyl azodicarboxylate
DEAD) 2a proceeds in high yield and the R-hydrazino ketone 3a
The direct R-amination of the various ketones 1a-f by DEAD
(
2
a in the presence of L-proline takes place with excellent enanti-
is obtained in up to 84% ee in the solvents studied with the best
results obtained in 1,2-dichloroethane (Table, 1, entry 1-4). The
reaction also proceeds well using the azodicarboxylates 2b,c;
however, the enantioselectivities of the corresponding R-hydrazino
ketones 3b,c are slightly lower (entry 5,6) compared to those
resulting from the use of 2a. The direct R-amination of butanone
oselectivities, and the reaction is highly regioselective as the
amination takes place at the highest substituted carbon atom. The
R-hydrazino ketone 3a derived from cyclohexanone 1a is formed
in good yield and with 84% ee (Table 2, entry 1). Butanone 1b
reacts with 2a, and adduct 3d is obtained in 80% yield and with
2
9
5% ee (entry 2). Increasing the length of the R substituent from
1b by 2a proceeds also in high yield and with an improvement of
methyl to ethyl and benzyl increases the enantioselectivity of the
R-hydrazino ketones. For 2-pentanone 1c, the product (3e) is formed
with 98% ee (entry 3) and for benzylacetone 1d the enantiomeric
excess of 3f is 98% ee (entry 4). 4-Methyl-2-pentanone 1e is
aminated by 2a in a highly enantioselective reaction and the
the enantioselectivity compared to 1a. In acetonitrile as the solvent,
the R-hydrazino ketone 3d is obtained in 96% ee (entry 8). The
*
To whom correspondence should be addressed. Fax: 45 8619 6199.
Telephone: 45 8942 3910. E-mail: kaj@chem.au.dk.
6
254 J. AM. CHEM. SOC. 2002, 124, 6254-6255
9
10.1021/ja026412k CCC: $22.00 © 2002 American Chemical Society

C O MMU N I C A T I O N S
Table 2. L-Proline (10 mol %)-Catalyzed Enantioselective
R-Amination of Ketones 1a-f with Diethyl Azodicarboxylates 2a in
MeCNa
the R-amination reaction. The enamine-intermediate formed from
the ketone and L-proline has the large R -substituent anti to the
L
carboxylic acid to reduce steric repulsion, and the enamine is formed
to the secondary carbon atom due to its higher stability. The
approach of the azodicarboxylate from the same face as the
carboxylic acid might be directed by interaction of the proton of
the carboxylic acid with the nitrogen atom.
ketone
R1
ratiob
yieldc
eed
react.
entry
R2
time (h) (major: minor)
(%)
(%)
1e
2
3
4
5
1a (CH2)4
1b Me
1c Me
1d Me
1e Me
23
10
20
24
96
60
-
3a - 67
3d - 80
84 (79)
95 (93)
98 (96)
98 (94)
99 (99)
94 (93)
f
Me
Et
Bn
iPr
Me
91:9
81:19
82:18
76:24
-
f
3e - 77
f
3f - 92
3g - 69
f
In summary, we have developed the first organo-catalytic direct
R-amination of ketones applying azodicarboxylates as the nitrogen
fragment and L-proline as the catalyst. The reactions proceed with
excellent enantioselectivity and give an easy access to optically
active R-hydrazino and R-amino ketones, and syn- and anti-R-amino
alcohols.
6
1f
Et
3h - 79
a
See Supporting Information for details. Determined by 1H NMR.
b
c
d
Isolated yield after column chromatography. ee determined after workup
by either chiral GC or HPLC. The values in parentheses are the enantiomeric
excess after column chromatography. 1,2-Dichloroethane was used as
solvent. Isolated total yield of both regioisomers.
e
f
Acknowledgment. Thanks are expressed to The Danish Na-
tional Research Foundation for financial support.
Scheme 1
Supporting Information Available: Complete experimental pro-
cedure and characterization (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
References
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3
f with NaBH
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4
, followed by treatment with NaOH, gives the
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2
2
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23, 4370. (g) Jen, W. S.; Wiener, J. J. M.; MacMillan, D. W. C. J. Am.
6
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4
7
(eq 3). The R-hydrazino ketones formed by the direct R-amination
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(
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(
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JA026412K
J. AM. CHEM. SOC.
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VOL. 124, NO. 22, 2002 6255