Enantio- and diastereoselective mannich-type reactions of α-Cyano ketones with N-Boc aldimines catalyzed by chiral bifunctional urea

Article abstract of DOI:10.1002/adsc.200900268

The catalytic enantioselective electrophilic Mannich-type reaction promoted by chiral bifunctional organocatalysts is described. The treatment of a-cyano ketones with N-Boc-aldimines under mild reaction conditions afforded the corresponding β-amino-α-cyan

Full text of DOI:10.1002/adsc.200900268

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DOI: 10.1002/adsc.200900268
Enantio- and Diastereoselective Mannich-Type Reactions of
a-Cyano Ketones with N-Boc Aldimines Catalyzed by Chiral
Bifunctional Urea
Ju Hee Leea and Dae Young Kima,*
a
Department of Chemistry, Soonchunhyang University, Asan, Chungnam 336-745, Korea
Fax : (+82)-41-530-1247; phone: +82-41-530-1244; e-mail: dyoung@sch.ac.kr
Received: April 17, 2009; Published online: July 27, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900268.
Abstract: The catalytic enantioselective electrophil-
ic Mannich-type reaction promoted by chiral bi-
functional organocatalysts is described. The treat-
ment of a-cyano ketones with N-Boc-aldimines
under mild reaction conditions afforded the corre-
sponding b-amino-a-cyano ketones with excellent
diastereoselectivities (up to syn/anti=100/0), and
excellent enantioselectivities (up to 99% ee).
Cinchona alkaloid-derived catalysts,[9] and thiourea
organocatalysts.[10] Bifunctional organocatalysts pos-
sessing a combination of hydrogen-bonding donors
and chiral tertiary amines have been developed for
activation of both electrophilic and nucleophilic com-
ponents. They have emerged as powerful tools for the
enantioselective formation of carbon-carbon and
carbon-heteroatom bonds.[11] Recently, Shibasaki et al.
reported a highly enantio- and diastereoselective
Mannich reaction using a-cyano ketones, catalyzed by
a chiral amide ligand associated with rare earth metal
complexes.[12] However, a highly enantioselective
Mannich reaction of a-cyano ketones with simple
imines remains elusive; although, if successfully pro-
moted with a practically accessible chiral catalyst
Keywords: asymmetric catalysis; Mannich reaction;
nitriles; organic catalysis
One of the ultimate goals and challenges in organic under air- and moisture-tolerant conditions, it could
synthesis is the development of catalytic asymmetric provide a highly attractive, convergent approach to-
transformations for the creation of functionalized op- wards optically active b-amino nitriles.
tically active compounds with structural diversity
As part of a research program related to the devel-
from simple and readily available precursor mole- opment of synthetic methods for the enantioselective
cules. The efficient synthetic construction of b-amino construction of stereogenic carbon centers,[13] we re-
carbonyl compounds is one of the most intensely cently reported chiral amine-thiourea IV (Figure 1) to
studied areas in organic synthesis.[1] Chiral a-substitut- be a highly selective catalyst for the enantioselective
ed b-amino nitriles,[2] since the cyano group is easily amination of active methines.[14] This catalyst emerged
converted to other functional groups, would be versa- from our search for new organic, asymmetric bifunc-
tile synthetic intermediates for the synthesis of b- tional catalysts based around the relatively rigid bi-
amino acids and the corresponding chiral diamine de- naphthyl skeleton. Herein, we wish to describe the
rivatives which are employed as medicinal agents or direct enantioselective Mannich reaction of a-cyano
chiral ligands.[3]
ketones with simple N-Boc-imines catalyzed by using
Enantioselective Mannich reactions are efficient bifunctional organocatalysts bearing both central and
and powerful methods to prepare b-amino carbonyl axial chiral elements.
derivatives.[4] Tremendous efforts have been made in
To determine suitable reaction conditions for the
the development of efficient chiral catalysts for enan- catalytic enantioselective Mannich reaction of a-
tioselective Mannich reactions with pre-formed eno- cyano ketones, we initially investigated the reaction
lates and enolizable active methylenes and me- system with 2-cyano cyclopentanone (1a) and N-Boc-
thines.[5–7] Several groups have presented the direct benzaldimine (2a) in the presence of 10 mol% of cat-
enantioselective Mannich reactions of b-dicarbonyl alyst in toluene at room temperature. We first exam-
and related compounds in the presence of chiral orga- ined the impact of the structures of catalysts I–VI on
nocatalysts such as chiral phosphorodiamidic acid,[8] enantioselectivities (Table 1, 65–88% ee, entries 1–6).
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Ju Hee Lee and Dae Young Kim
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Table 2. Variation of the N-Boc-imines.
Entry
2, Ar
Yield[a]
[%]
syn/
ee[c]
ACHTUNGTRENN[UNG syn] [%]
anti[b]
1
2
3
4
5
6
7
8
9
2a, Ph
3a, 81
3b, 96
3c, 80
3d, 83
3e, 88
3f, 85
3g, 90
3h, 90
3i, 99
100/0
100/0
100/0
100/0
100/0
94/6
100/0
100/0
100/0
>99
>99
97
98
83
88
98
93
>99
2b, o-F-C6H4
2c, o-Cl-C6H4
2d, p-Cl-C6H4
2e, p-OMe-C6H4
2f, p-Me-C6H4
2g, 2-naphthyl
2h, 2-furyl
2i, 2-thienyl
[a]
Refers to the isolated mixture of diastereomers.
[b]
[c]
1
Figure 1. Structures of chiral urea- or thiourea-tertiary
amine catalysts.
Determined by H NMR of the crude reaction mixture.
Enantiomeric excess of the major diastereomer, deter-
mined by chiral HPLC.
The best results have been obtained with catalysts IV
and V. These results indicate that increasing the steric a-cyano ketone 1a under the optimized reaction con-
demands of the catalyst increases the selectivities. ditions. As shown in Table 2, the products 3a–i were
Concerning the solvent (entries 5, 7–10), the use of formed in high yields (81–95%), excellent diastereose-
toluene gave the best results in terms of yield and the lectivities (syn/anti=94/6–100/0), and excellent ena-
enantiomeric excess (entry 5). Lowering the tempera- tioselectivities (83–99%).
ture to À788C with catalyst V improved the diaste-
To examine the generality of the catalytic enantio-
reoselectivity (syn/anti=100/0) and enantioselectivity selective Mannich reaction of a-cyano ketones 1 by
(>99% ee, entry 12). We then explored the possibility using chiral bifunctional organocatalyst V, we studied
of using wide range of N-Boc-protected para-substi- the Mannich reaction of various a-cyano ketones 1b–
tuted aromatic and heteroaromatic aldimines 2 with g with N-Boc-benzaldimine (2a). As can be seen from
Table 1. Optimization of the reaction conditions.
Entry
Cat.
Solvent
Temp. [oC]
Time [h]
Yield[a] [%]
syn/anti[b]
ee[c] [syn] [%]
1
2
3
4
5
6
7
8
I
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
acetone
EtOAc
THF
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
À40
À78
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.8
1
85
82
83
80
81
81
85
83
81
83
80
81
93/7
66
65
75
88
88
5
74
59
53
23
87
>99
II
III
IV
V
VI
V
V
V
V
V
V
86/14
80/20
98/2
98/2
56/44
76/24
50/50
55/45
45/55
100/0
100/0
9
10
11
12
toluene
toluene
[a]
Refers to the isolated mixture of diastereomers.
Determined by H NMR of the crude reaction mixture.
Enantiomeric excess of the major diastereomer, determined by chiral HPLC.
[b]
[c]
1
1780
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Enantio- and Diastereoselective Mannich-Type Reactions of a-Cyano Ketones
Table 3. Variation of the a-cyano ketones.
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Experimental Section
Typical Procedure for the Mannich Reaction of a-
Cyano Ketone 1a with N-Boc-Benzaldimine (2a)
A mixture of 2-cyanocyclopentanone (1a, 218 mg, 0.2 mmol)
and catalyst V (13 mg, 0.02 mmol) in toluene (0.4 mL) was
stirred at room temperature for 5 min and then was cooled
to À788C. A solution of N-Boc-benzaldimine (2a, 49.2 mL,
0.24 mmol) in toluene (4 mL) was added dropwise over a
period of 10 min. The reaction mixture was stirred for 1 h at
À788C. After completion of the reaction, the resulting solu-
tion was allowed to warm to room temperature, concentrat-
ed under vacuum and the obtained residue was purified by
flash chromatography (EtOAc-hexane, 1:5) to afford the b-
aminated 2-cyanocyclopentanone 3a; yield: 50.8 mg (81%).
(S)-2-[(S)-tert-Butoxycarbonylamino]benzyl-2-cyanocyclo-
pentanone (3a): [a]D22: À42.2 (c 0.3, CHCl3, >99% ee);
1H NMR (200 MHz, CDCl3): d=7.47–7.35 (m, 5H), 5.57 (br
d, J=10 Hz, 1H), 5.02 (d, J=10 Hz, 1H), 2.80–2.55 (m,
1H), 2.53–2.30 (m, 1H), 2.24–1.98 (m, 1H), 1.40 (s, 9H);
13C NMR (50 MHz, CDCl3): d=206.5, 154.9, 136.1, 129.0,
127.6, 118.0, 80.6, 54.7, 35.8, 32.6, 28.1, 18.6; ESI-MS: m/z=
315.0 [M+H]+; HPLC (hexane/i-PrOH, 97:3, 220 nm,
1.0 mLminÀ1, Chiralpak AD-H column): tR =33.5 min
(major), tR =36.6 min (minor).
Entry
1
Time [h] Yield[a] [%] syn/anti[b] ee[c] [syn] [%]
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
1
1
1
1
1
1
3a, 81
3j, 75
3k, 77
3l, 75
3m, 84
3n, 81
3o, 80
100/0
100/0
100/0
99.8/0.2
99/1
>99
90
>99
94
95
86/14
59/41
95
1g 96
98/98[d]
[a]
Refers to the isolated mixture of diastereomers.
Determined by H NMR of the crude reaction mixture.
Enantiomeric excess of the major diastereomer, deter-
mined by chiral HPLC.
Enantiomeric excess of syn/anti diastereomer.
[b]
[c]
1
[d]
Acknowledgements
This research was financially supported by the Ministry of
Education, Science, Technology (MEST) and Korea Industri-
al Technology Foundation (KOTEF) through the Human Re-
source Training Project for Regional Innovation.
the results summarized in Table 3, the corresponding
b-aminated a-cyano ketones 3j–o were obtained in
excellent yields and enantioselectivities. The cyclic a-
cyano ketones 1a–f, with cyclic aliphatic ketones 1a–c,
and cyclic aromatic ketones 1d–f, reacted with N-Boc-
benzaldimine (2a) to give the corresponding b-ami-
nated a-cyano ketones 3a and 3j–n in 75–84% yields
and 90–99% ee (Table 3, entries 1–6). Acyclic a-cyano
ketone 1g reacted with N-Boc-benzaldimine (2a) to
afford the b-aminated a-cyano ketone 3o with 98% ee
(Table 3, entry 7). The absolute configuration of ad-
ducts 3 has been determined for some derivatives by
comparison of their optical and HPLC properties
with literature values.[12]
In conclusion, we have developed a highly efficient
catalytic enantioselective Mannich reaction of cyclic
a-cyano ketones using chiral bifunctional organocata-
lyst. The desired b-aminated products were obtained
in good to high yields, and excellent enantioselectivi-
ties (90–99% ee) were observed for all the substrates
examined in this work. To our knowledge, these re-
sults constitute the first examples of the direct catalyt-
ic asymmetric Mannich reaction of a-cyano ketones
using organocatalysts. We believe that this method
provides a practical entry for the preparation of chiral
b-amino-a-cyano ketones derivatives. Further study
of these new bifunctional organocatalysts in other
asymmetric reactions is being under investigated.
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