Catalytic asymmetric electrophilic α-amination of α-cyanoketones in the presence of chiral palladium complexes

Article abstract of DOI:10.1055/s-2008-1078564

The catalytic enantioselective electrophilic α-amination promoted by chiral palladium complexes is described. Treatment of α-cyanoketones with azodicarboxylates as electrophilic amination reagents under mild reaction conditions afforded the corresponding

Full text of DOI:10.1055/s-2008-1078564

LETTER
1821
Catalytic Asymmetric Electrophilic a-Amination of a-Cyanoketones in the
Presence of Chiral Palladium Complexes
Catalytic
A
u
symmetric Electro
H
philic
a
-Aminatio
e
n
of
a
-Cya
e
noketone
s
Lee, Hyoung Tae Bang, Dae Young Kim*
Department of Chemistry, Soonchunhyang University, Asan, Chungnam 336-745, Korea
Fax +82(41)5301247; E-mail: dyoung@sch.ac.kr
Received 1 May 2008
2+
2+
H
O
Abstract: The catalytic enantioselective electrophilic a-amination
P
P
P
P
P
OH2
promoted by chiral palladium complexes is described. Treatment of
Pd
Pd
2X–
*
2X–
Pd
*
*
a-cyanoketones with azodicarboxylates as electrophilic amination
O
H
NCMe
P
reagents under mild reaction conditions afforded the corresponding
a-amino a-cyanoketones with excellent enantiomeric excesses (81–
95% ee).
2a–c
1a–c
a Ar = Ph: (R)-BINAP
Key words: electrophilic amination, asymmetric catalysis, chiral
palladium catalysts, a-cyanoketones
b Ar = 4-methylphenyl: (R)-Tol-BINAP
c Ar = 3,5-dimethylphenyl: (R)-Xylyl-BINAP
Chiral a-amino nitriles are very useful bifunctional com-
pounds for a large number of synthetic applications.1 The
most popular and wide use of chiral a-amino nitrile in-
volves hydrolysis of the nitrile group to generate chiral a-
amino acids,2 which are often used as key building blocks
in pharmaceuticals. In addition, since the cyano group is
easily converted into other functional groups, chiral a-
substituted a-amino nitriles would be versatile synthetic
intermediates for the synthesis of nitrogen-containing
heterocycles3 and chiral 1,2-diamine derivatives, which
P
PAr2
=
*
PAr2
P
Figure 1
As part of a research program related to the development
of synthetic methods for the enantioselective construction
are employed as medicinal agents or chiral ligands.4 The of stereogenic carbon centers,11 we report the catalytic
catalytic asymmetric cyanation of imines, Strecker reac- enantioselective functionalization of ester derivatives pro-
tion, represents one of the most popular methods for the moted by air- and moisture-stable chiral palladium com-
synthesis of chiral a-amino nitriles and their derivatives. plexes.12e–g In this letter, we report the direct a-amination
Several successful achievements in catalytic asymmetric of cyclic and acyclic a-cyanoketones 3 catalyzed by pal-
Strecker reaction were reported.5 However, most of the ladium complexes 1 and 212 (Figure 1) with azodicarbox-
known asymmetric Strecker reactions rely on the use of ylates 4 as the electrophilic nitrogen source.
toxic and anhydrous cyanide reagents. The catalytic
Our investigation began with the catalytic enantioselec-
asymmetric electrophilic amination of a-substituted ni-
tive electrophilic amination of 2-cyanoindanone 3a with
triles seems to be an alternate method for the synthesis of
azodicarboxylates 4 as the electrophilic aminating reagent
in MeOH at room temperature in the presence of 5 mol%
of catalyst 1a (BF4). We examined the impact of the struc-
ture of azodicarboxylates 4 on enantioselectivity (Table 1,
entries 1–4). The best results were obtained with tert-
butyl ester of azodicarboxylate. Concerning the solvent
chiral a-amino nitrile derivatives. The catalytic, enan-
tioselective, direct C–N bond-formation reaction of active
methine compounds represents an efficient and simplest
procedure to generate stereogenic carbon center attached
to a nitrogen atom.6 Recently, several groups presented
the direct enantioselective amination of active methine
(entries 4–13), the use of acetone gave the best results in
compounds in the presence of chiral metal complexes or
the yield and the enantiomeric excess (entry 10). Catalysts
1a (BF4) and 1a (PF6) were more effective than other cat-
alysts (entries 10 and 15).
organocatalysts.7–9 To the our best knowledge, although
electrophilic amination of active methines such as b-ke-
toester,7 b-ketophosphonates,8 and a-cyanoacetates9 have
To examine the generality of the catalytic enantioselective
been reported, up to now there are no examples of these
reactions with a-cyanoketones.10
amination of a-cyanoketones 3 by using chiral palladium
complexes 1, we studied the amination of various a-
cyanoketones 3a–g.13 As it can be seen by the results sum-
marized in Table 2, the corresponding a-aminated a-cy-
anoketones 5a–g were obtained in excellent yields and
enantioselectivities.
SYNLETT 2008, No. 12, pp 1821–1824
x
x
.x
x
.2
0
0
8
Advanced online publication: 02.07.2008
DOI: 10.1055/s-2008-1078564; Art ID: U04608ST
© Georg Thieme Verlag Stuttgart · New York

1822
J. H. Lee et al.
LETTER
Table 1 Optimization of the Reaction Conditions
O
O
Pd cat.
CO2R
CN
CN
RO2C
N
N
(5 mol%)
*
N
CO2R
CO2R
r.t.
HN
3a
4
5
Entry
1
4, R
Catalyst
1a (BF4)
1a (BF4)
1a (BF4)
1a (BF4)
1a (BF4)
1a (BF4)
1a (BF4)
1a (BF4)
1a (BF4)
1a (BF4)
1a (BF4)
1a (BF4)
1a (BF4)
1a (OTf)
1a (PF6)
1b (PF6)
1c (PF6)
2a (BF4)
2b (BF4)
2c (BF4)
Solvent
MeOH
Time (min)
Yield (%)
93
ee (%)a
4a, Et
5
37
40
60
73
73
81
75
–
2
4b, Bn
MeOH
20
10
10
20
20
15
24 h
6 h
10
40
30
10
15
15
15
15
10
10
10
90
3
4c, i-Pr
4d, t-Bu
4d, t-Bu
4d, t-Bu
4d, t-Bu
4d, t-Bu
4d, t-Bu
4d, t-Bu
4d, t-Bu
4d, t-Bu
4d, t-Bu
4d, t-Bu
4d, t-Bu
4d, t-Bu
4d, t-Bu
4d, t-Bu
4d, t-Bu
4d, t-Bu
MeOH
93
4
MeOH
95
5
EtOH
95
6
t-BuOH
THF
93
7
94
8
MeCN
0
9
CH2Cl2
acetone
acetone–THF
acetone–PhMe
acetone–H2O
acetone
acetone
acetone
acetone
acetone
acetone
acetone
90
60
92
85
83
79
83
92
79
83
85
85
77
10
11b
12c
13d
14
15
16
17
18
19
20
95
93
95
94
95
93
93
90
96
94
95
a Enantiopurity of 5 was determined by HPLC analysis with Chiralpak AD column.
b Acetone–THF, 4:1.
c Acetone–PhMe, 4:1.
d Actone–H2O, 19:1.
The cyclic a-cyanoketones 3a–d reacted with tert-butyl (Scheme 1). The absolute configuration of 7 was deter-
azodicarboxylate (4d) to give the corresponding a-ami- mined to be R by comparing specific rotation and chiral
nated a-cyanoketones 5a–d in 90–95% yields and 83– HPLC data with an authentic sample.9b,c
95% ee (Table 2, entries 1–5). Acyclic a-cyanoketones
In conclusion, we have developed a highly efficient cata-
lytic enantioselective a-amination of cyclic and acyclic a-
cyanoketones using air- and moisture-stable chiral palla-
3e–g reacted with tert-butyl azodicarboxylate (4d) or eth-
yl azodicarboxylate (4a) to afford the a-aminated adducts
5e–g in alcoholic solvents with 81–91% ee in the presence
of catalyst 2c (Table 2, entries 6–8).
CO2t-Bu
CO2t-Bu
HN
N
CN
We examined the catalytic enantioselective electrophilic
amination of a-cyanoacetate 6 with tert-butyl azodicar-
boxylate (4d) using palladium complexes 1 and 2 at room
temperature. In the presence of 5 mol% of catalyst 1a
(X = BF4), the reaction proceeded to afford the a-aminat-
ed product 7 after one hour with 86% yield and 53% ee
N
N
1a (BF4)
CO2t-Bu
NC
Ph
Et2O, r.t., 1 h
86%, 53% ee (R)
Ph
CO2Et
t-BuO2C
CO2Et
6
4d
7
Scheme 1 Catalytic enantioselective amination of a-cyanoacetate 6
Synlett 2008, No. 12, 1821–1824 © Thieme Stuttgart · New York

LETTER
Catalytic Asymmetric Electrophilic a-Amination of a-Cyanoketones
1823
Table 2 Catalytic Enantioselective Amination of a-Cyanoketones
CO2R
CO2R
Pd cat.
O
O
CO2R
HN
N
(5 mol%)
N
N
CN
R1
R1
*
acetone, r.t.
R2
RO2C
NC
R2
3
4
5
O
O
O
CN
CN
CN
Ph
R
n
n
3a n = 0
3b n = 1
3c n = 0
3d n = 1
3e R = Ph
3f R = allyl
3g R = benzyl
Entry
3
4, R
Catalyst
1a (PF6)
1a (BF4)
1a (BF4)
1a (BF4)
1a (BF4)
2c (BF4)
2c (BF4)
2c (BF4)
Time (min)
Yield (%)a
5a, 93
5a, 95
5b, 95
5c, 95
5d, 90
5e, 87
5f, 94
ee (%)b
92
1
3a
3a
3b
3c
3d
3e
3f
4d, t-Bu
4d, t-Bu
4d, t-Bu
4d, t-Bu
4d, t-Bu
4d, t-Bu
4d, t-Bu
4a, Et
15
2
10
92
3
10
95
4
10
85
5
2.5 h
20 h
1 h
5 h
83
6c
7d
8d
86
91
3g
5g, 90
81
a Yield of isolated product.
b Enantiopurity of 5 was determined by HPLC analysis with Chiralpak AD (for 5a,c,f,g), AS (for 5b), (S,S)-Whelk-O1 (for 5d) and Chiralcel
OD-H (for 5e) columns.
c Reaction carried out in t-BuOH–i-PrOH, 1:1.
d Reaction carried out in t-BuOH.
(2) For reviews on a-amino acids, see: (a) Williams, R. M.
Synthesis of Optically Active a-Amino Acids; Pergamon:
Oxford, 1989. (b) Duthaler, R. O. Tetrahedron 1994, 50,
1539. (c) Hanessian, S.; McNaughton-Smith, G.; Lombart,
H.-G.; Lubell, W. D. Tetrahedron 1997, 53, 12789.
(d) Arend, M. Angew. Chem. Int. Ed. 1999, 38, 2873.
(e) Kotha, S. Acc. Chem. Res. 2003, 36, 342. (f) Maruoka,
K.; Ooi, T. Chem. Rev. 2003, 103, 3013.
(3) (a) Matier, W. L.; Owens, D. A.; Comer, W. T.; Dietchman,
D.; Ferguson, H. C.; Seidehamel, R. J.; Young, J. R. J. Med.
Chem. 1973, 16, 901. (b) Weinstock, L. M.; Davis, P.;
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dium complexes. The desired a-aminated products were
obtained in good to high yields, and excellent enantiose-
lectivities (81–95% ee) were observed for all the sub-
strates examined in this work. To our knowledge, these
results constitute the first examples of the direct catalytic
asymmetric amination of a-cyanoketones. We believe
that this report provides a practical method for the prepa-
ration of chiral a-amino a-cyanoketones derivatives, and
the availability of these compounds should facilitate me-
dicinal chemical studies in various fields. Further details
and application of this amination will be presented in due
course.
(5) See, for example: (a) Sigman, M. S.; Vachal, P.; Jacobsen,
E. N. Angew. Chem. Int. Ed. 2000, 39, 1279. (b) Takamura,
M.; Hamashima, Y.; Usuda, H.; Kanai, M.; Shibassaki, M.
Angew. Chem. Int. Ed. 2000, 39, 1650. (c) Corey, E. J.;
Grogan, M. J. Org. Lett. 1999, 1, 157. (d) Ishitani, H.;
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Soc. 2000, 122, 762. (e) Ooi, T.; Uematsu, Y.; Maruoka, K.
J. Am. Chem. Soc. 2006, 128, 2548.
Acknowledgment
This research was financially supported by the Ministry of Educa-
tion, Science, Technology (MEST) and Korea Industrial Technolo-
gy Foundation (KOTEF) through the Human Resource Training
Project for Regional Innovation.
(6) For reviews on asymmetric a-amination reactions, see:
(a) Genet, J.-P.; Greck, C.; Lavergne, D. Modern Amination
Methods; Ricci, A., Ed.; Wiley-VCH: Weinheim, 2000,
Chap. 3. (b) Greck, C.; Drouillat, B.; Thomassigng, C. Eur.
J. Org. Chem. 2004, 1377. (c) Erdik, E. Tetrahedron 2004,
60, 8742. (d) Janey, J. M. Angew. Chem. Int. Ed. 2005, 44,
4292.
References and Notes
(1) Enders, D.; Shilvock, J. P. Chem. Soc. Rev. 2000, 29, 359.
Synlett 2008, No. 12, 1821–1824 © Thieme Stuttgart · New York

1824
J. H. Lee et al.
LETTER
(7) For 1,3-dicarbonyl compounds, see: (a) Juhl, K.; Jørgensen,
K. A. J. Am. Chem. Soc. 2002, 124, 2420. (b) Marigo, M.;
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K.; Kim, D. Y. Tetrahedron Lett. 2006, 47, 4565.
(g) Terada, M.; Nakano, M.; Ube, H. J. Am. Chem. Soc.
2006, 128, 16044. (h) Comelles, J.; Pericas, A.; Moreno-
Manas, M.; Vallribera, A.; Drudis-Sole, G.; Lledos, A.;
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I. D.; Ikariya, T. J. Am. Chem. Soc. 2008, 130, 2158.
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(13) General Procedure for the Amination of a-Cyanoketone
To a stirred solution of a-cyanoketone 3 (0.2 mmol) and
catalyst 1a (BF4) (9.6 mg, 0.01 mmol) in acetone (2 mL) was
added tert-butyl azodicarboxylate (4d, 46 mg, 0.2 mmol) at
r.t. The reaction mixture was stirred for 10 min to 20 h at r.t.
The mixture was diluted with sat. NH4Cl solution (10 mL)
and extracted with EtOAc (2 × 10 mL). The combined
organic layers were dried over MgSO4, filtered,
concentrated, and purified by flash chromatography
(EtOAc–hexane, 1:3) to afford the a-aminated a-cyano-
ketone 5.
2-Aminated 2-Cyano-1-indanone 5a
[a]D22 –21.5 (c 1.45, CHCl3, 92% ee). 1H NMR (200 MHz,
CDCl3): d = 7.90–7.82 (m, 1 H), 7.74–7.66 (m, 1 H), 7.56–
7.43 (m, 2 H), 7.01 (br s, 1 H), 4.07–3.83 (m, 2 H), 1.62–
1.22 (m, 18 H). 13C NMR (50 MHz, CDCl3): d = 190.1,
155.5, 149.3, 136.9, 136.6, 132.2, 128.6, 126.5, 125.9,
115.6, 84.3, 82.2, 68.4, 40.9, 28.2, 27.8. MS (MSI): m/z
(%) = 387 [M+], 356 (10), 332 (70), 275 (32), 232 (8), 213
(12), 188 (7.5), 158 (8). ESI-HRMS: m/z calcd for
C20H25N3O5 [M]+: 387.1794; found: 387.1802. HPLC
(hexane–i-PrOH, 8:2, 254 nm, 1.0 mL/min, Chiralpak AD
column): tR = 5.8 min (minor), tR = 7.7 min (major).
Synlett 2008, No. 12, 1821–1824 © Thieme Stuttgart · New York

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