Catalytic asymmetric animation of enecarbamates

Article abstract of DOI:10.1002/anie.200603776

(Chemical Equation Presented) A little catalyst goes a long way: The title reaction was attained using a chiral Cu^II-diamine complex as catalyst. Azodicarboxylates react with various enecarbamates derived from aromatic and aliphatic ketones and

Full text of DOI:10.1002/anie.200603776

Angewandte
Chemie
Asymmetric Catalysis
and enantioselectivities are generally high for various kinds
of enecarbamates derived from aromatic and aliphatic
ketones, and aldehydes, and lower levels of catalyst loadings
have been attained (in some cases, 0.2 mol% of the catalyst
was sufficient). We also describe the facile synthesis of
optically active trans-1,2-diamine compounds by using this
method.
DOI: 10.1002/anie.200603776
Catalytic Asymmetric Amination of
Enecarbamates**
We first investigated the amination of propiophenone-
Ryosuke Matsubara and Shu¯ Kobayashi*
derived enecarbamate 2a (Table 1).[13] When AgClO4-binap
Asymmetric electrophilic amination reactions have recently
received much attention.[1] In particular, the asymmetric
amination of carbonyl compounds has been developed to
obtain biologically important a-amino acids and their deriv-
atives. A number of compounds, such as sulfonyl azides,[2] 1-
chloro-1-nitroso reagents,[3] and nitroso benzenes,[4] are
known to act as electrophilic nitrogen sources, but perhaps
the most prominent are azodicarboxylates. A catalytic
asymmetric a-amination of carbonyl compounds using azo-
dicarboxylates was pioneered by Evans and Nelson, who used
a chiral magnesium bis(sulfonamide) complex as a catalyst.[5]
Subsequently, Evansꢀs group[6] and our group[7] reported the
catalytic asymmetric amination using silicon enolates. List
and Jørgensen and co-workers reported asymmetric proline-
catalyzed amination of linear aldehydes using azodicarbox-
ylates,[8] and furthermore Jørgensen and co-
Table 1: Optimization of reaction conditions.[a]
workers examined the direct use of ketones
in proline-catalyzed amination of azodicar-
boxylates.[9] Direct a-amination of 2-
ketoesters and b-ketoesters in the presence
of a chiral bisoxazoline-CuII complex[10] and
direct organocatalytic amination of a-sub-
stituted a-cyanoacetates[11] are also alterna-
tive methods for the synthesis of enantioen-
riched a-amino carbonyl compounds.
Whereas those methods gave excellent
enantioselectivities (in general over 90%
ee), relatively high catalyst loadings (in
almost all cases, not less than 5 mol%)
were necessary to obtain high enantioselec-
tivies and substrates are limited in many
reactions.[12] Herein, we report the first
catalytic asymmetric amination of enecar-
bamates catalyzed by a chiral diamine-CuII
complex using azodicarboxylates. Yields
Entry
R1
Catalyst
n [mol%]
2a
Solvent
t [h]
Yield [%]
ee [%]
1[b]
2[b]
3[b]
4[b]
5[d]
6[d]
7[d]
8[d]
9
Bn
Bn
Bn
Bn
Bn
Bn
iPr
iPr
iPr
iPr
AgClO4 + (S)-binap
Zn(OTf)2 + 3a
Cu(OTf)2 + 3a
Cu(OTf)2 + 3a
Cu(OTf)2 + 3b
Cu(BF4)2·xH2O + 3b
Cu(BF4)2·xH2O + 3b
Cu(BF4)2·xH2O + 3b
Cu(BF4)2·xH2O + 3b
Cu(OTf)2 + 3b
10
10
10
10
10
10
10
1
Z
Z
Z
E
E
E
E
E
E
E
THF
72
144
30
1.5
6
7
77
51
96
98
99
100
100
34
97
94
36
CH2Cl2
CH2Cl2
CH2Cl2
toluene
toluene
toluene
toluene
toluene
toluene
32[c]
66[c]
70[c]
85
87
93
88
89
4
52
36
6
1
1
10
95
[a] Reactions conducted with 1.1 equivalents of 1 relative to 2 in the indicated solvent (0.067m in
substrate). Bn=benzyl, OTf=trifluoromethanesulfonate. [b] 08C. [c] Opposite enantiomer. [d] 3-Š
molecular sieves (M.S.; 100 mgmmolÀ1) were added.
complex, which gave high enantioselectivity in the reaction of
azodicarboxylate with silicon enolates,[7] was used as a
catalyst, the ketone product 4 was obtained after hydrolysis
with low enantioselectivity (Table 1, entry 1). While the
catalytic activity of Zn(OTf)2-diamine 3a was also found to
be low (Table 1, entry 2),[14] Cu(OTf)2-3a complex[15] gave
higher enantioselectivity (entry 3). Moreover, it was found
that changing the enecarbamate geometry from Z to E
resulted in a dramatic improvement of the reactivity (Table 1,
entry 4), and that the use of diisopropyl azodicarboxylate in
toluene improved enantioselectivity significantly (entries 5–
7).[16] The yield was decreased when the catalyst loading was
reduced to 1 mol% (Table 1, entry 8), but was improved
[*] R. Matsubara, Prof. Dr. S. Kobayashi
Graduate School of Pharmaceutical Sciences
University of Tokyo
HFRE Division, ERATO
Japan Science Technology Agency (JST)
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax: (+81)3-5684-0634
E-mail: skobayas@mol.f.u-tokyo.ac.jp
[**] This work was partially supported by a Grant-in-Aid for Scientific
Research from the Japan Society for the Promotion of Sciences
(JSPS). We thank Nissan Chemical Co. Ltd. for providing us with
ligand 3b.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2006, 45, 7993 –7995
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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when the reaction was conducted in the absence of 3-Š M.S.
amine 7, whose structure was unambiguously determined by
(entry 9). Finally, the best result was obtained when Cu(OTf)2
was used as the metal source (Table 1, entry 10). The absolute
configuration of the product was determined to be R by
comparison with literature data by HPLC analysis.
X-ray crystallographic analysis. Deprotection of the carba-
À
mate moieties followed by N N bond cleavage using Raney
Ni and benzoylation afforded trans-1,2-diamine derivative 8
in high yield (Scheme 1).
The scope of the catalytic asymmetric amination of
enecarbamates was then surveyed under the optimized
reaction conditions (Table 2). A wide range of azodicarbox-
Table 2: Catalytic asymmetric a-amination of enecarbamates.[a]
Scheme 1. Synthesis of trans-1,2-diamine derivatives 7 and 8.
Cbz=carbobenzyloxy, TMS=trimethylsilyl, Bz=benzoyl.
Entry R1
2
n [mol%] t [h] Yield [%] ee [%] Product[b]
On the basis of the absolute configuration and the fact
that both E- and Z-enecarbamates gave the same absolute
configuration (Table 1, entries 3 and 4),[19] we propose an
acyclic concerted transition-state model (Figure 1).[20] We
1[c]
2
3
iPr
iPr
iPr
iPr
2a
2b
2c
2d
0.2
1
22
25
24
24
24
24
6
84
90
87
62
83
91
99
84
93
90
81
79
82[f]
70
82
98
92
84
83
82
84
85
96
97
94
90
96
82
86
67[h]
C
B
B
B
B
B
B
A
B
B
C
C
C
C
C
1
1
3
3
4
5
Me 2a
6
Et
2a
2a 10
7[d]
8
Bn
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
2e
2 f
2g
2h
2i
2j
2k
2l
5
1
5
3
20
24
10
6
9
10
11[c]
12[c]
13[e]
14[g]
15[e]
0.2
2
24
6
5
4
5
26
[a] Reactions conducted with 1.1 equivalents of 1 relative to 2 in toluene
(0.067m in substrate). [b] A: Acylimine (no treatment); B: ketone by
hydrolysis; C: 1,2-diamino derivative by reduction (syn/anti=<5:>95).
[c] À108C. [d] 3-Š M.S. were added (100 mgmmolÀ1). [e] Ligand 3a was
used instead of 3b. [f] syn/anti=28:72. [g] 3-Š M.S. were added
(50 mgmmolÀ1). [h] See reference [17].
Figure 1. Proposed transition-state model.
assume that a diamine ligand and azodicarboxylate coordi-
nate to the copper in bidentate fashion, and that the copper
adopts a slightly distorted square-planar geometry.[15c] The Re
face of the azodicarboxylate is shielded by the neighboring
benzyl group of the diamine ligand, and an enecarbamate
attacks from the Si face predominantly (see the Supporting
Information). As for the facial selectivity of the enecarba-
mate, TS-1 and TS-2 in which the enecarbamate reacts with
azodicarboxylate through an antiperiplanar transition state
are reasonable to minimize steric repulsions between the
enecarbamate and the copper catalyst or the carbamate group
of the azodicarboxylate. TS-1, which gives the R-configured
product, is more plausible because of the critical steric
repulsion between the substituent of the enecarbamate and
the copper catalyst in TS-2.
ylates and enecarbamates derived from aromatic ketones
bearing substituents with various electronic and steric proper-
ties, aliphatic ketones, and aldehydes were found to react with
azodicarboxylates efficiently to afford the desired products in
good yields with high enantioselectivities. The initially formed
acylimines 5(A) were readily converted into ketone products
5(B) after hydrolysis or 1,2-diamine derivatives 5(C) after
highly stereoselective reduction (see footnote of Table 2). It is
of particular note that the amination reaction of enecarba-
mates followed by NaBH4 reduction can be conducted on a
gram scale. The reaction of 3 g enecarbamate (E)-2a with
diisopropyl azodicarboxylate was catalyzed with 0.6 mol% of
the catalyst Cu(OTf)2 (24mg of Cu(OTf) 2 as used), followed
by reduction with NaBH4 to provide 4.9 g of the 1,2-diamino
compound (92% yield; syn/anti = < 5: > 95; 96% ee for anti).
trans-1,2-Diamine derivatives, which are seen in many
biologically important compounds as well as in useful chiral
ligand skeletons,[18] can be obtained using this new method-
ology. The product 6a was efficiently converted into the free
In conclusion, we have developed the first catalytic
asymmetric amination of enecarbamates using a Cu(OTf)2-
diamine complex as catalyst. Yields and enantioselectivities
are high in most cases, and catalyst loadings are generally low.
This new reaction provides not only a-amino carbonyl
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Angewandte
Chemie
[19] Contrary to this result, in reference [6] the sense of asymmetric
compounds but also a-amino acylimines, which can be readily
converted into 1,2-diamine derivatives stereoselectively. We
have also shown that this amination reaction can be con-
ducted on a gram scale. Moreover, a transition-state model to
explain the absolute configuration observed in this amination
reaction of enecarbamates is proposed. Further investigations
to apply this new protocol to the synthesis of biologically
important compounds are in progress.
induction is dependent on the geometry of the silicon enolates.
[20] a) R. Matsubara, N. Kawai, S. Kobayashi, Angew. Chem. 2006,
118, 3898; Angew. Chem. Int. Ed. 2006, 45, 3814; b) R.
Matsubara, P. Vital, Y. Nakamura, H. Kiyohara, S. Kobayashi,
Tetrahedron 2004, 60, 9769; c) R. Matsubara, Y. Nakamura, S.
Kobayashi, Angew. Chem. 2004, 116, 3320; Angew. Chem. Int.
Ed. 2004, 43, 3258.
Received: September 14, 2006
Published online: November 10, 2006
Keywords: amination · asymmetric catalysis ·
.
azodicarboxylates · copper · enecarbamates
[1] a) C. Greck, B. Drouillat, C. Thomassigny, Eur. J. Org. Chem.
2004, 7, 1377; b) E. Erdik, Tetrahedron 2004, 60, 8747; c) J.-P.
Genet, C. Greck, D. Lavergne, Modern Amination Methods
(Ed.: A. Ricci), Wiley-VCH, Weinheim, 2000, chap. 3.
[2] D. A. Evans, T. C. Britton, J. A. Ellman, R. L. Dorow, J. Am.
Chem. Soc. 1990, 112, 4011.
[3] W. Oppolzer, O. Tamura, Tetrahedron Lett. 1990, 31, 991.
[4] N. Momiyama, H. Yamamoto, J. Am. Chem. Soc. 2003, 125, 6038,
and references therein.
[5] D. A. Evans, S. G. Nelson, J. Am. Chem. Soc. 1997, 119, 6452.
[6] D. A. Evans, D. S. Johnson, Org. Lett. 1999, 1, 595.
[7] Y. Yamashita, H. Ishitani, S. Kobayashi, Can. J. Chem. 2000, 78,
666.
[8] a) B. List, J. Am. Chem. Soc. 2002, 124, 5656; b) A. Bøgevig, K.
Juhl, N. Kumaragurubaran, W. Zhuang, K. A. Jørgensen, Angew.
Chem. 2002, 114, 1868; Angew. Chem. Int. Ed. 2002, 41, 1790; see
also, c) C. Thomassigny, D. Prim, C. Greck, Tetrahedron Lett.
2006, 47, 1117.
[9] N. Kumaragurubaran, K. Juhl, W. Zhuang, A. Bøgevig, K. A.
Jørgensen, J. Am. Chem. Soc. 2002, 124, 6254.
[10] a) K. Juhl, K. A. Jørgensen, J. Am. Chem. Soc. 2002, 124, 2420;
b) M. Marigo, K. Juhl, K. A. Jørgensen, Angew. Chem. 2003, 115,
1405; Angew. Chem. Int. Ed. 2003, 42, 1367.
[11] a) S. Saaby, M. Bella, K. A. Jørgensen, J. Am. Chem. Soc. 2004,
126, 8120; b) X. Liu, H. Li, L. Deng, Org. Lett. 2005, 7, 167.
[12] Catalyst loadings were not less than 1 mol% in all cases except
those reported in references [10b] and [11a].
[13] Compound 2a can be synthesized from benzonitrile in one step:
Y. H. Suen, A. Horeau, H. B. Kagan, Bull. Soc. Chim. Fr. 1965, 5,
1454.
[14] T. Hamada, K. Manabe, S. Kobayashi, J. Am. Chem. Soc. 2004,
126, 7768.
[15] This complex was successfully employed as a catalyst for
nucleophilic additions to acylimines. a) S. Kobayashi, H. Kiyo-
hara, Y. Nakamura, R. Matsubara, J. Am. Chem. Soc. 2004, 126,
6558; b) R. Matsubara, Y. Nakamura, S. Kobayashi, Angew.
Chem. 2004, 116, 1711; Angew. Chem. Int. Ed. 2004, 43, 1679;
c) S. Kobayashi, R. Matsubara, Y. Nakamura, H. Kitagawa, M.
Sugiura, J. Am. Chem. Soc. 2003, 125, 2507.
[16] After screening various ligands, such as diamines bearing 1,2-
diphenylethylenediamine and 1,2-dicyclohexane diamine back-
bones, ligand 3b was found to be the best.
[17] When aldehyde-derived enecarbamate 2l was used, the initially
formed product after Cu-catalyzed reaction was not acylimine
but a cyclic product, which was reduced by using triethylsilyl
hydride and trimethylsilyl triflate instead of NaBH4. See the
Supporting Information for details.
[18] S. R. S. S. Kotti, C. Timmons, G. Li, Chem. Biol. Drug Des. 2006,
67, 101, and references therein.
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