N, N′-dioxide-Cu(OTf)2 complex catalyzed highly enantioselective amination reaction of N-acetyl enamide

Article abstract of DOI:10.1021/ol100540p

The N,N′-dioxide-Cu(OTf)₂ complexes were applied in the asymmetric amination reaction of N-acetyl enamides with dialkyl azodicarboxylate, giving the corresponding products in good yields with high enantioselectivities (up to 91% ee). Precursors of vicinal diamine were readily obtained with excellent diastereoselectivities (>95:5) by NaBH₄ reduction.

Full text of DOI:10.1021/ol100540p

ORGANIC
LETTERS
2010
Vol. 12, No. 10
2214-2217
N,N′-Dioxide-Cu(OTf)2 Complex
Catalyzed Highly Enantioselective
Amination Reaction of N-Acetyl Enamide
Lu Chang, Yulong Kuang, Bo Qin, Xin Zhou, Xiaohua Liu, Lili Lin, and
Xiaoming Feng*
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of
Chemistry, Sichuan UniVersity, Chengdu 610064, People’s Republic of China
xmfeng@scu.edu.cn
Received March 4, 2010
ABSTRACT
The N,N′-dioxide-Cu(OTf)2 complexes were applied in the asymmetric amination reaction of N-acetyl enamides with dialkyl azodicarboxylate,
giving the corresponding products in good yields with high enantioselectivities (up to 91% ee). Precursors of vicinal diamine were readily
obtained with excellent diastereoselectivities (>95:5) by NaBH4 reduction.
The vicinal diamine backbone, as one of the most valuable
functionalities, is a frequently recurring motif in natural products
and biologically active compounds.1 For example, many
antibiotics such as edeines A1 and B1 possess 2,3-diamino-
propanoic acid in their chemical structure.2 The 2,3-diamino-
propanamide functionality is also found in bleomycins, which
are a family of chemotherapeutic agents used for clinical
treatment of malignancies.3 Meanwhile, 1,2-diamines are
employed in many catalytic asymmetric reactions.4 Over the
past years, several approaches toward such useful structures
have been successfully developed, for instance, ring-opening
of aziridines with nitrogen nucleophiles, reductive coupling of
imines, and Mannich-type reactions.1c
In 2006, Kobayashi et al. reported the first asymmetric
amination5 of enecarbamate,6 which was established as an
attractive methodology for the synthesis of vicinal diamines.
However, the synthesis of enecarbamate usually involves the
addition of organometallic reagents to the aromatic nitriles
or the rearrangement of R,ꢀ-unsaturated carboxylic acids.7
The synthetic features of both methods potentially limit the
practical application of enecarbamate. In contrast, the ena-
mides which could be prepared directly from the correspond-
ing ketones8 provide a good way to compensate for this
limitation. Moreover, the Z and E isomers are generally stable
crystals, which facilitate its purification and separation.
Nevertheless, the amination of enamide was scarcely inves-
tigated in detail.9
(1) For reviews of vicinal diamines, see: (a) Kotti, S. R. S. S.; Timmons,
C.; Li, G. Chem. Biol. Drug Des. 2006, 67, 101. (b) Viso, A.; Fernández
de la Pradilla, R.; Garc´ıa, A.; Flores, A. Chem. ReV. 2005, 105, 3167. (c)
Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed 1998, 37,
2580, and references cited therein.
(2) Roncari, G.; Kurylo-Borowska, Z.; Craig, L. C. Biochemistry 1966,
5, 2153.
(3) (a) Stubbe, J.; Kozarich, J. W. Chem. ReV. 1987, 87, 1107. (b)
Otsuka, M.; Masuda, T.; Haupt, A.; Ohno, M.; Shiraki, T.; Sugiura, Y.;
Maeda, K. J. Am. Chem. Soc. 1990, 112, 838.
(4) (a) Bennani, Y. L.; Hanessian, S. Chem. ReV. 1997, 97, 3161. (b)
Anaya de Parrodi, C.; Juaristi, E. Synlett 2006, 2699. (c) Hems, W. P.;
Groarke, M.; Zanotti-Gerosa, A.; Grasa, G. A. Acc. Chem. Res. 2007, 40,
1340.
Chiral N,N′-dioxide compounds, as well as their metal
complexes,10 have emerged as efficient catalysts in asym-
10.1021/ol100540p  2010 American Chemical Society
Published on Web 04/19/2010

metric catalysis. As part of our ongoing research using N,N′-
dioxide compound as a structurally modified ligand,11 we
herein describe an enantioselective amination reaction of
N-acetyl enamides with azodicarboxylate catalyzed by chiral
Cu(OTf)2/N,N′-dioxide complex, giving the corresponding
adducts in excellent yields with high enantioselectivities.
A preliminary investigation12 revealed that Cu(OTf)2-N,N′-
dioxide L1 (Figure 1) could efficiently catalyze the amination
Table 1. Selected Results for the Optimization of Reaction
Conditionsa
entry
ligand
R
additive
yield (%)b
ee (%)c
1
2
3
4
5
6e
L1
L2
L3
L4
L5
L3
L3
L3
L3
L3
L3
L3
Et
Et
Et
Et
Et
Et
Et
Bn
Bn
Bn
Bn
Bn
64
61
51
22
78
99
66
48
88
88
38
95
56 (S)d
20 (R)
61 (S)
6 (S)
30 (S)
65 (S)
79 (S)
90 (S)d
89 (S)
91 (S)
61 (S)
75 (R)
7e f
,
8e f
,
9e f g
H2O
H2O/3 Å MS
3 Å MS
, ,
10e f h
, ,
Figure 1. N,N′-Dioxide ligands evaluated for this reaction.
11e f i
, ,
12e f h j
H2O/3 Å MS
, ,
,
a Unless otherwise noted, reactions were carried out with ligand (10
mol %), Cu(OTf)2 (10 mol %), 1a (0.1 mmol), and 2 (0.15 mmol) in THF
(0.4 mL) at rt for 24 h. b Isolated yield of the hydrolysis product.
c Determined by HPLC, using chiral AD-H column after hydrolysis.
d Absolute configuration was determined by comparison with the literature
data (refs 6 and 15a). e Ligand: Cu(OTf)2 ) 1:1.25. f Performed at 0 °C.
g H2O (3 µL) was added. h 3 Å MS (30 mg) and H2O (5 µL) were added.
i 3 Å MS (30 mg) was added. j 1b (0.1 mmol) was used as substrate.
of enamide, giving the corresponding product in 64% yield
with 56% ee (Table 1, entry 1). Subsequent intensive
screening of the chiral ligands disclosed the significant impact
of the amino acid backbone on the enantioselectivity (Table
1, entries 1-3). L-Ramipril acid-derived N,N′-dioxide L3 was
superior to L1 (derived from L-proline) and L2 (derived from
L-pipecolic acid) (Table 1, entry 3 vs entries 1 and 2). The
opposite configuration of the product obtained from L2
proved the decisive role of amino acid scaffold in determin-
ing the absolute stereochemical outcome of the reaction
(Table 1, entry 2). In addition, the amide moiety of the N,N′-
dioxide played an important role on the reactivity. Increasing
the steric hindrance on the ortho position of the aromatic
ring was favorable to achieve high yield (Table 1, entries 3
and 5 vs entry 4). It was considered that the introduction of
the bulky group at the ortho position led to a twisted
delocalization of the large conjugated system including the
aromatic ring, nitrogen, and the carbonyl group, which
affected the Lewis acidity of the central metal indirectly.
When a little excess of metal was used, the yield was
increased to 99% with a gentle increase of the enantiose-
lectivity (Table 1, entry 6). Decreasing the reaction temper-
ature to 0 °C improved the enantiomeric excess of the product
to 79% (Table 1, entry 7). When dibenzyl azodicarboxylate
was used as the electrophile, the enantioselectivity was
further increased to 90% ee (Table 1, entry 8).
(5) For reviews of R-amination, see: (a) Erdik, E. Tetrahedron 2004,
60, 8747. (b) Greck, C.; Drouillat, B.; Thomassigny, C. Eur. J. Org. Chem.
2004, 1377. (c) Janey, J. M. Angew. Chem., Int. Ed. 2005, 44, 4292. (d)
Na´jera, C.; Sansano, J. M. Chem. ReV. 2007, 107, 4584, and references
cited therein. For selected examples of amination of 1,3-dicarbonyl
compounds with dialkyl azodicarboxylate as nitrogen source, see: (e)
Marigo, M.; Juhl, K.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42,
1367. (f) Pihko, P. M.; Pohjakallio, A. Synlett 2004, 2115. (g) Bernardi,
L.; Zhuang, W.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 5772. (h)
Foltz, C.; Stecker, B.; Marconi, G.; Bellemin-Laponnaz, S.; Wadepohl, H.;
Gade, L. H. Chem. Commun. 2005, 5115. (i) Xu, X.; Yabuta, T.; Yuan, P.;
Takemoto, Y. Synlett 2006, 137. (j) Terada, M.; Nakano, M.; Ube, H. J. Am.
Chem. Soc. 2006, 128, 16044. (k) Kang, Y. K.; Kim, D. Y. Tetrahedron
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Lett. 2006, 47, 4565. (l) Comelles, J.; Pericas, A.; Moreno-Man˜as, M.;
Vallribera, A.; Drudis-Sole´, G.; Lledos, A.; Parella, T.; Roglans, A.; Garc´ıa-
Granda, S.; Roces-Ferna´ndez, L. J. Org. Chem. 2007, 72, 2077. For selected
examples of amination of 2-oxindoles with dialkyl azodicarboxylate as
nitrogen source, see: (m) Cheng, L.; Liu, L.; Wang, D.; Chen, Y. J. Org.
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Org. Lett., Vol. 12, No. 10, 2010
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It was exciting that water showed a positive effect on the
reactivity. Full conversion could be observed within 40 h
with H2O (3 µL) as additive. It should be noted that one of
the most challenging problems for this reaction is to obtain
the relatively unstable R-aminated imine products, which
were versatile intermediates for different transformations.
However, only a mixture of imine and the corresponding
ketone was obtained during the screening. Further investiga-
tion indicated that the addition of 3 Å molecular sieves could
suppress the hydrolysis efficiently without any influence on
the yield and enantioselectivity (Table 1, entry 10). The effect
of water on the amination reaction was further confirmed
by an independent experiment (Table 1, entry 11). Both the
yield and enantioselectivity were decreased if the moisture
was completely removed by 3 Å molecular sieves.
of the substituents on the aromatic ring, the amination
reactions proceeded smoothly and delivered the correspond-
ing R-amino imines in excellent yields (86-99%). Moreover,
the enamides with electron-withdrawing groups exhibited
somewhat better performance in terms of enantioselectivity
than those with electron-donating groups. It was noteworthy
that the scope of this reaction could also be extended to R-2-
naphthyl enamide 1o and R-thiophenyl enamide 1p (Table
2, entries 14 and 15), which have never been reported.6,9
This reaction provided an efficient approach to the
synthesis of 1,2-diamine precursors. Reduction of the product
4 with NaBH4 at low temperature (-78 to -45 °C)
proceeded smoothly in a highly diastereoselective manner
(dr >95:5) (Figure 2). The corresponding products13 5 were
Although the E isomer exhibited higher reactivity than the
Z counterpart and was converted to the corresponding adduct
with the opposite configuration, the enantioselectivity was
low (Table 1, entry 12).
With the optimized conditions (Table 1, entry 10) in hand,
the substrate scope of the catalytic asymmetric amination of
enamides was then tested. As summarized in Table 2, a wide
Figure 2. Application of the current amination reaction of enamides.
Table 2. Substrate Scope for the Direct Catalytic Asymmetric
Amination Reactiona
Figure 3. Proposed transition states for the amination reaction.
obtained in good yields without any loss of enantioselectivity.
The resulting imine could also be hydrolyzed into R-aminated
ketone 4′ by simple treatment with 1 N KHSO4 solution,14
which is also an important synthetic intermediate, especially
for the construction of optically active amino alcohol.15
To explain the stereochemical outcome of this reaction,
two possible transition states were postulated based on the
absolute configuration of the product. The sterically bulky
a Unless otherwise noted, reactions were carried out with 1 (0.1 mmol),
2b (0.15 mmol), L3 (0.01 mmol), and Cu(OTf)2 (0.0125 mmol) in THF
(0.4 mL) at 0 °C. 3 Å MS (30 mg) and H2O (5 µL) were added. b Isolated
yield. c Determined by HPLC, using commercial chiral columns after
hydrolysis.
range of N-acetyl enamides were found to be suitable
substrates for this reaction. The enantioselectivity was
significantly affected by the branch of the enamide (Table
2, entries 1-3). Prolongation of the alkyl chain of the
enamide to propyl (compound 1d) also gave smoothly the
desired product, but the ee value was decreased to 60%
(Table 2, entry 3). Regardless of the electronic or steric nature
(13) For further deprotection and N-N bond cleavage with H2-Pd/C
followed by treatment of H2-Raney Ni or Zn-acetone in acetic acid see refs
5e, 5g, 5p-5r.
(14) The hydrolysis cannot be conducted with HBr/THF.
(15) (a) Yamashita, Y.; Ishitani, H.; Kobayashi, S. Can. J. Chem. 2000,
78, 666. (b) Liu, T. Y.; Cui, H. L.; Zhang, Y.; Jiang, K.; Du, W.; He, Z. Q.;
Chen, Y. C. Org. Lett. 2007, 9, 3671.
2216
Org. Lett., Vol. 12, No. 10, 2010

phenyl group efficiently hindered the Si face of the azodi-
carboxylate, and the N-acetyl enamide could only attack the
Re face of the azodicarboxylate, which led to the desired
product with S configuration. In contrast, the steric effect
between the methyl group of the E configured enamide and
the complex made the attack disfavored in TS-2 (Figure 3).
the easy accessibility of the starting material from the ketone.
Further studies of the details of the reaction mechanism are
ongoing.
Acknowledgment. We thank the National Natural Science
Foundation of China (Nos. 20732003 and 20702033), PC-
SIRT (No. IRT0846), and National Basic Research Program
of China (973 Program) (No. 2010CB833300) for financial
support. We also thank Sichuan University Analytical &
Testing Center for NMR analysis.
In summary, we have developed a highly enantioselective
amination reaction of N-acetyl enamides catalyzed by N,N′-
dioxide/Cu(OTf)2 complexes. The reaction performed well
over a range of substituted R-aromatic N-acetyl enamides,
giving the desired products in excellent yields (up to 99%)
with high enantioselectivities (up to 91% ee). The methodol-
ogy provided a very convenient path to the optically active
vicinal diamines. Other features of this approach included
Supporting Information Available: Experimental pro-
cedures and spectral and analytical data for the products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL100540P
Org. Lett., Vol. 12, No. 10, 2010
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