Copper-bipyridine-catalyzed enantioselective α-amination of β-keto esters

Article abstract of DOI:10.1016/j.tetlet.2010.02.007

The Cu(OTf)₂-bipyridine-catalyzed, enantioselective, direct α-amination of β-keto esters and β-diketones with diethyl azodicarboxylate (DEAD) has been studied. Exceptionally high enantioselectivities of up to 99% ee were found for 1-indanone-ba

Full text of DOI:10.1016/j.tetlet.2010.02.007

Tetrahedron Letters 51 (2010) 1860–1862
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Copper–bipyridine-catalyzed enantioselective
a-amination of b-keto esters
*
Subrata Ghosh, Mecheril Valsan Nandakumar, Harald Krautscheid, Christoph Schneider
Institut für Organische Chemie, Universität Leipzig, Johannisallee 29, 04103 Leipzig, Germany
Institut für Anorganische Chemie, Universität Leipzig, Johannisallee 29, 04103 Leipzig, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The Cu(OTf)2-bipyridine-catalyzed, enantioselective, direct
a
-amination of b-keto esters and b-diketones
Received 21 December 2009
Revised 28 January 2010
Accepted 1 February 2010
Available online 6 February 2010
with diethyl azodicarboxylate (DEAD) has been studied. Exceptionally high enantioselectivities of up to
99% ee were found for 1-indanone-based b-keto esters in particular even for substrates and reagents car-
rying conventional ester groups such as methyl and ethyl.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric catalysis
Amination
b-Ketoester
Copper(II)-catalyzed
Bipyridine
Diethyl azodicarboxylate
The direct
route for the synthesis of non-natural
a
-amination of b-keto esters provides an excellent
Jørgensen and co-workers established the high catalytic effi-
ciency of Cu(OTf)2 in the
-amination of b-keto esters.3a With
(S)-Ph-box as chiral ligand they were able to isolate the -aminat-
ed product with high enantiomeric excess. More recently, addi-
tional enantioselective methods have been reported based on the
use of a combination of Cu(OTf)2 and various chiral ligands.3b,c
Based upon our recent experience with chiral bipyridine 316 in me-
tal-catalyzed epoxide-opening reactions17 we envisioned that a
metal–bipyridine complex might be a good chiral catalyst for the
a
,a
-disubstituted -amino
a
a
acid derivatives through the construction of stereogenic carbon cen-
ter attached to the nitrogen atom.1 Optically active amino acids are
broadly utilized with application in pharmaceuticals, agrochemi-
cals, and after all they are the fundamental building blocks for vari-
ous natural products and biologically active molecules.2 Therefore,
a
catalytic enantioselective a-amination of b-keto esters with azodi-
carboxylates has gained huge attention for the preparation of opti-
cally active non-natural amino acid derivatives. Some of the
catalytic enantioselective systems that have been employed for this
purpose with varying degrees of success include Cu(II)-Ph-box,3
cinchonidine and cinchonine,4 b-isocupreidine,5 Cu(II)-Ph-trisox,6
chiral urea,7 chiral guanidine,8 Pd-complexes,9 Eu(III)-ip-pybox,10
La–amide complex11 quaternary phosphonium salts,12 amine–
thiourea bifunctional organocatalysts,13 quaternary ammonium
bromide,14 and Ni(II)-complexes.15
highly enantioselective a-amination of b-keto esters.
In this Letter, we wish to report the enantioselective direct
a-amination of cyclic b-keto esters 1 with diethyl azodicarboxylate
(DEAD) 2 catalyzed by an in situ-generated chiral Cu(II)–bipyridine
3-complex.18
Initially we studied various metal triflates in combination with
bipyridine 3 as chiral catalysts for the
a-amination of b-keto ester
1a with DEAD (Scheme 1). While, for example, Sc(OTf)3, Y(OTf)3,
One of the major limitations associated with most of these cat-
alytic systems is the requirement to use bulky and less convenient
b-keto esters and/or bulky azodicarboxylates such as the corre-
sponding diisopropyl and ditert-butyl derivatives in order to
achieve high enantioselectivities. Therefore, there is still a need
for the development of convenient enantioselective methods
which use synthetically more easily accessible b-keto methyl es-
ters and the commercially available and cheap reagent diethyl azo-
dicarboxylate (DEAD).
O
O
CO2Et
N
N
O
(11 mol%)
N NHCO2Et
OMe
OH
HO
3
CO2Me
Cu(OTf)2 (10 mol%),
CH2Cl2, 0 °C, 24 h
1a
+
4a
81% (97% ee)
EtO2CN NCO2Et
2
* Corresponding author. Tel./fax: +49 341 9736559.
E-mail address: schneider@chemie.uni-leipzig.de (C. Schneider).
Scheme 1. Reaction between 1-indanone-based b-keto ester 1a and diethyl
azodicarboxylate (DEAD) 2 in the presence of Cu(OTf)2 and chiral 2,20-bipyridine 3.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.007

S. Ghosh et al. / Tetrahedron Letters 51 (2010) 1860–1862
1861
and Yb(OTf)3 each were capable of catalyzing the model reaction
with full conversion, the enantioselectivities remained poor to
moderate and did not improve beyond 72% ee. On the other hand,
Having identified optimal conditions we studied the scope of
this reaction over a series of cyclic b-keto esters and b-diketones
(Table 1). In general, 1-indanone-based b-keto esters gave excel-
lent enantioselectivities for almost all substrates investigated (en-
tries 1–9). Both electron-rich and electron-poor b-keto esters
performed equally well and delivered the products with up to
99% ee. Substitution at both the 5- and 6-positions of the indanone
backbone was possible without seriously affecting the enant-
ioselectivitty of the reaction. Solely the 4-CF3-substituted indanone
gave rise to only 79% ee in this reaction (entry 9).
the Cu(OTf)2–bipyridine-catalyst (10 mol %) furnished a-aminated
product 4a in 84% yield and with 94% ee after stirring for 12 h at rt
in CH2Cl2. Lowering the temperature to 0 °C further increased the
enantioselectivity to 97% ee with almost identical chemical yield
(Scheme 1).19 Interestingly, when the temperature was further de-
creased to ꢀ55 °C, the selectivity dropped significantly to 85% ee.
More importantly, the use of tert-butyl esters and/or diisopropyl
or ditert-butyl azodicarboxylates proved to be not mandatory for a
highly enantioselective amination reaction although the use of
tert-butyl ester 1c actually further enhanced the selectivity (entry
3, 99% ee). In general, we employed the more conventional and
easily prepared b-keto methyl esters 1a and 1d–i as substrates
which furnished the amination products with high enantioselectiv-
ity as well (entries 1 and 4–9).
Changing the substrate backbone to a 1-tetralone-based or a
non-aromatic b-dicarbonyl compound significantly deteriorated
the enantioselectivity of the reaction and furnished the products
with only 45–47% ee (entries 10 and 11).
A single crystal of the chiral copper(II)–bipyridine-complex
coordinated to b-keto ester 1d suitable for X-ray diffraction
analysis was obtained from dichloromethane–pentane solution
( Fig. 1).20 The structure of the complex displays a distorted
square-pyramidal geometry around the Cu(II)-center. The two
bipyridyl nitrogen atoms N1 and N2 as well as the ketone oxygen
atom O1 and one of the hydroxyl oxygen atoms O5 are attached in
the square plane and the ester oxygen atom O2 is located in the
apical position of the complex. The b-keto ester is positioned
almost orthogonal relative to the square plane of the complex
(80°). Interestingly, the bipyridine ligand 3 binds to the copper
atom only in a three-coordinate fashion leaving one of the hydro-
xyl groups free. The enantiofacial differentiation in the amination
event is now most likely the result of hydrogen bonding of the
more acidic hydroxyl proton attached to the copper-bound oxygen
atom O5 to the basic azodicarboxylate which is thereby activated
toward nucleophilic attack and directed to the open si-face of the
enolate.
Table 1
Enantioselective amination of b-keto esters and 1,3-dicarbonyl compounds 1a–l
catalyzed by Cu(OTf)2-chiral bipyridine 3a
Entry
1
Substrate
Product
Yieldb (%)
81
Eec (%)
97
O
CO2Me
CO2Et
4a
1a
O
O
2
3
4b
4c
82
80
97
99
1b
CO2t-Bu
1c
O
CO2Me
4
5
6
4d
4e
4f
86
78
81
>99
93
MeO
Cl
1d
O
O
CO2Me
1e
1f
CO2Me
93
Br
O
Me
CO2Me
In conclusion, we have developed a chiral copper–bipyridine
7
8
4g
4h
79
82
98
97
catalyst for the highly enantioselective
ters which gives rise to non-natural
a
-amination of b-keto es-
1g
a
,a
-disubstituted -amino
a
O
acid derivatives. 1-Indanone-based b-keto esters proved to be
excellent substrates for this process which were aminated with
MeO
CO2Me
1h
O
CO2Me
9
4i
74
79d
CF3
1i
O
O
O
10
11
4j
66
68
45
47
1j
O
4k
1k
a
b
c
Typical reaction conditions: 0.2 M in CH2Cl2 at 0 °C for 24 h.
Isolated yield.
The ee was determined by chiral HPLC analysis using a Daicel Chiracel OD-
column and hexane–isopropanol mixtures as solvent.
d
The reaction was carried out at room temperature.
The assignment of absolute configuration is based upon the comparison of
e
Figure 1. ORTEP (50% ellipsoid) of Cu(OTf)2–bipyridine–1d complex. Hydrogen
atoms as well as the non-coordinating triflate anions have been omitted for clarity.
optical rotation with the literature values.12

1862
S. Ghosh et al. / Tetrahedron Letters 51 (2010) 1860–1862
15. Mang, J. Y.; Kwon, D. G.; Kim, D. Y. Bull. Korean Chem. Soc. 2009, 30, 249–252.
16. (a) Bolm, C.; Zehnder, M.; Bur, D. Angew. Chem., Int. Ed. 1990, 29, 205–207; (b)
Bolm, C.; Ewald, M.; Felder, M.; Schlingloff, G. Chem. Ber. 1992, 125, 1169–1190.
17. (a) Schneider, C.; Sreekanth, A. R.; Mai, E. Angew. Chem., Int. Ed. 2004, 43, 5691–
5694; (b) Mai, E.; Schneider, C. Chem. Eur. J. 2007, 13, 2729–2741; (c) Tschöp,
A.; Marx, A.; Sreekanth, A. R.; Schneider, C. Eur. J. Org. Chem. 2007, 2318–2327;
(d) Nandakumar, M. V.; Tschöp, A.; Krautscheid, H.; Schneider, C. Chem.
Commun. 2007, 2756–2758; (e) Mai, E.; Schneider, C. Synlett 2007, 2136–2138;
(f) Tschöp, A.; Nandakumar, M. V.; Pavlyuk, O.; Schneider, C. Tetrahedron Lett.
2008, 49, 1030–1033.
up to 99% ee in good yields whereas other 1,3-dicarbonyl com-
pounds gave rise to only moderate enantioselectivity. A crystal
structure of the substrate-bound catalyst provides information re-
lated to the origin of enantiofacial discrimination.
Acknowledgments
We thank the Deutsche Forschungsgemeinschaft for generous
financial support of this work and the Alexander von Humboldt
foundation for a postdoctoral fellowship awarded to S.G.
18. We have recently found that
a novel copper–phenanthroline-complex
catalyzes the amination of narrow range of b-keto esters with good
a
enantioselectivity, see: Nandakumar, M. V.; Ghosh, S.; Schneider, C. Eur. J.
Org. Chem. 2009, 6393–6398.
19. Typical experimental procedure: A solution of Cu(OTf)2 (1.8 mg, 10 mol %) and
chiral 2,20-bipyridine 3 (1.8 mg, 11 mol %) in dry CH2Cl2 (1 mL) was stirred
under argon atmosphere for 1 h at room temperature. Subsequently the
respective b-keto ester (0.05 mmol) and DEAD (9.57 mg, 0.055 mmol) were
added and the solution was stirred for 24 h at 0 °C. After completion of the
reaction (as judged by TLC), the crude product was purified by flash
References and notes
1. (a) Diels, O. Justus Liebigs Ann. Chem. 1922, 429, 1–55; (b) Duthaler, R. O.
Tetrahedron 1994, 50, 1539–1650; (c) Arend, M. Angew. Chem., Int. Ed. 1999, 38,
2873–2874;(d)Kotha, S. Acc. Chem. Res. 2003, 36, 342–351; (e) Genet, J.-P.;Greck,
C.; Lavergne, D. In Modern Amination Methods; Ricci, A., Ed.; Wiley-VCH:
Weinheim, 2000; (f) Duthaler, R. O. Angew. Chem., Int. Ed. 2003, 42, 975–978;
(g)Greck, C.; Drouillat, B.; Thomassigny, C. Eur. J. Org. Chem. 2004, 1377–1385;(h)
Erdik, E. Tetrahedron 2004, 60, 8747–8782; (i) Janey, J. M. Angew. Chem., Int. Ed.
2005, 44, 4292–4300; (j) Nájera, C.; Sansano, J. M. Chem. Rev. 2007, 107, 4584–
4671.
2. Williams, R. M. Synthesis of Optically Active a-Amino Acids; Oxford: Pergamon,
1989; (b) Heimgartner, H. Angew. Chem., Int. Ed. 1991, 30, 238–264; (c)
Williams, R. M.; Hendrix, J. A. Chem. Rev. 1992, 92, 889–917; (d) Bergmeier, S. C.
Tetrahedron 2000, 56, 2561–2576; (e) Yet, L. Angew. Chem., Int. Ed. 2001, 40,
875–877.
3. (a) Marigo, M.; Juhl, K.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 1367–
1369; (b) Ma, S.; Jiao, N.; Zheng, Z.; Ma, Z.; Lu, Z.; Ye, L.; Deng, Y.; Chen, G. Org.
Lett. 2004, 6, 2193–2196; (c) Huber, D. P.; Stanek, K.; Togni, A. Tetrahedron:
Asymmetry 2006, 17, 658–664; (d) Ghosh, A. K.; Bilcer, G.; Schiltz, G. Synthesis
2001, 2203–2229; (e) List, B.; Castello, C. Synlett 2001, 1687–1689.
4. Pihko, P. M.; Pohjakallio, A. Synlett 2004, 2115–2118.
5. Saaby, S.; Bella, M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 8120–8121.
6. Foltz, C.; Stecker, B.; Marconi, G.; Bellemin-Laponnaz, S.; Wadepohl, H.; Gade, L.
H. Chem. Commun. 2005, 5115–5117.
7. Xu, X.; Yabuta, T.; Yuan, P.; Takemoto, Y. Synlett 2006, 137–140.
8. Terada, M.; Nakano, M.; Ube, H. J. Am. Chem. Soc. 2006, 128, 16044–16045.
9. Kang, Y. K.; Kim, D. Y. Tetrahedron Lett. 2006, 47, 4565–4568.
10. Comelles, J.; Pericas, Á.; Moreno-Mañas, M.; Vallribera, A.; Drudis-Solé, G.;
Lledos, A.; Parella, T.; Roglans, A.; García-Granda, S.; Roces-Fernández, L. J. Org.
Chem. 2007, 72, 2077–2087.
11. Mashiko, T.; Hara, K.; Tanaka, D.; Fujiwara, Y.; Kumagai, N.; Shibasaki, M. J. Am.
Chem. Soc. 2007, 129, 11342–11343.
12. He, R.; Wang, X.; Hashimoto, T.; Maruoka, K. Angew. Chem., Int. Ed. 2008, 47,
9466–9468.
chromatography over silica gel affording the desired
a-aminated products.
Authentic racemic samples were prepared by the same reaction using Cu(OTf)2
without the chiral ligand. All the products gave satisfactory spectral and
analytical data. Some characteristic data: Product 4c (Table 1, entry 3): 99% ee
(HPLC on a Daicel Chiracel OD-phase, 95:5 n-hexane/isopropanol, flow rate
1 mL/min), tR (major) 10.95 min, tR (minor) 16.07 min; ½a D23
ꢁ
+164 (c 0.52,
CHCl3); IR (KBr): m 3311, 2981, 2934, 2359, 1720, 1608, 1591, 1466, 1377, 1338,
1305, 1237, 1152, 1081, 1061, 1044, 905, 845, 824, 787, 761, 694, 618,
462 cmꢀ1 1H NMR (300 MHz, CDCl3): d 1.15–1.31 (m, 6H, CH3), 1.39 (s, 9H,
;
CH3), 3.73–4.24 (m, 6H, CH2, OCH2), 6.99 (br s, 1H, NH), 7.37 (t, J = 7.5 Hz, 1H,
ArH), 7.47 (d, J = 7.5 Hz, 1H, ArH), 7.62 (t, J = 7.5, Hz, 1H, ArH), 7.74–7.76 (m,
1H, ArH); 13C NMR (100 MHz, CDCl3): d 14.2, 27.6, 39.3, 62.1, 62.9, 83.0, 125.0,
126.2, 127.5, 133.5, 135.5, 136.1, 155.9; HRMS-ESI: m/z calcd for
[C20H26N2O7Na]+; 429.16322; found 429.16339. Product 4e (Table 1, entry
5): 93% ee (HPLC on a Daicel Chiracel OD-phase, 95:5 n-hexane/isopropanol,
flow rate 1 mL/min), tR (minor) 19.97, tR (major) 24.29 min; ½a D23
ꢁ
+163 (c 0.51,
CHCl3); IR (KBr): m 3314, 2983, 1731, 1600, 1579, 1467, 1419, 1377, 1338, 1317,
1238, 1183, 1095, 1069, 1042, 902, 833, 788, 762, 617 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): d 1.17 (br s, 6H, CH3), 3.72 (s, 3H, OCH3), 3.80 (br s, 1H,
CH2), 4.14 (br s, 5H, CH2, OCH2), 7.05 (br s, 1H, NH), 7.33 (d, J = 8.1 Hz, 1H, ArH),
7.46 (br s, 1H, ArH), 7.65–7.68 (m, 1H, ArH); 13C NMR (100 MHz, CDCl3): d 14.2,
36.4, 38.3, 53.6, 62.3, 63.3, 77.9, 126.2, 128.6, 131.5, 142.2, 142.9, 153.2, 155.3,
155.9, 166.9, 191.8; HRMS-ESI: m/z calcd. for [C17H20ClN2O7]+; 399.09536;
found 399.09526.
20. Crystal structure data for the copper(II)–bipyridine–1d-complex: C33H39
-
CuF3N2O9S; Stoe IPDS-2T diffractometer, Mo-K radiation, k = 71.073 pm,
a
T = 180(2) K, MW = 760.26, orthorhombic, space group P212121 (no. 19),
a = 1132.24(8), b = 1201.75(7), c = 2548.2(2) pm, V = 3467.2(4) 106 pm3, Z = 4,
q
cal. = 1.456 g cmꢀ3
,
l
= 0.762 mmꢀ1
,
2
Hmax = 52°,
16572
measured
reflections, 6737 unique (Rint = 0.059), 5287 observed, 450 parameters,
H
13. (a) Jung, S. H.; Kim, D. Y. Tetrahedron Lett. 2008, 49, 5527–5530; (b) Mang, J. Y.;
Kim, D. Y. Bull. Korean Chem. Soc. 2008, 29, 2091–2092.
14. Lan, Q.; Wang, X.; He, R.; Ding, C.; Maruoka, K. Tetrahedron Lett. 2009, 50, 3280–
3282.
atom parameters of OH groups (O5, O6) refined, all other H atoms included in
idealized positions, R1 = 0.037 (observed reflections) and wR2 = 0.060 (all
data), Flack parameter—0.015(10); programs: SHELXS-97, SHELXL-97. CCDC
753510 contains the supplementary crystallographic data for this Letter.