Organocatalytic asymmetric biomimetic transamination of aromatic ketone to optically active amine

Article abstract of DOI:10.1039/c2ob26782a

An asymmetric biomimetic transamination of aromatic ketones to optically active amines with o-HOPhCH₂NH₂ as amine source catalyzed by hydroquinine-derived chiral base is described. Up to 85% ee was obtained.

Full text of DOI:10.1039/c2ob26782a

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COMMUNICATION
Organocatalytic asymmetric biomimetic transamination of aromatic ketone to
optically active amine†
Ying Xie,a Hongjie Pan,a Xiao Xiao,a Songlei Lia and Yian Shi*a,b
Received 11th September 2012, Accepted 4th October 2012
DOI: 10.1039/c2ob26782a
An asymmetric biomimetic transamination of aromatic
ketones to optically active amines with o-HOPhCH2NH2 as
amine source catalyzed by hydroquinine-derived chiral base
is described. Up to 85% ee was obtained.
Enantiomerically enriched amines are present in many bioactive
compounds, and are also important intermediates in organic
synthesis.1–3 Asymmetric transamination of ketones provides an
attractive strategy for the syntheses of chiral amines. Great pro-
gress has been made for biocatalytic transamination.4 However,
Scheme 2 Chiral base-catalyzed transamination of ketone.
non-enzymatic asymmetric transamination of unactivated
ketones still remains challenging.5–8 In 1995, Zwanenburg and
coworkers reported that chiral amines can be obtained with up to
44% ee via R*OK-catalyzed isomerization of N-benzylimines.8
Recently, we reported that α-amino esters can be obtained in
high ee’s via chiral base-catalyzed transamination of α-keto
esters with benzylamines as amine sources (Scheme 1).9 As part
of our continuing efforts on this subject, we have been investi-
gating related asymmetric transaminations of other carbonyl
compounds. Herein, we wish to report our preliminary results on
asymmetric biomimetic transamination of unactivated ketones
(Scheme 2).
Fig. 1 Selected examples of catalyst examined.
Table 1 Studies on reaction conditionsa
Initial studies were carried out with acetophenone (11) as sub-
strate and quinine derivative C1 as catalyst. Little amine products
were detected when the reactions were performed in refluxing
Entry
Cat
Solvent
Convb (%)
eec (%)
1
2
3
4
5
6
7
C1
C1
C1
C1
C2
C3
C4
Toluene
Benzene
MeCN
87
42
33
34
83
91
96
77
82
72
27
80
80
80
Scheme 1 Chiral base-catalyzed transamination of α-keto ester.
EtOH
Toluene
Toluene
Toluene
aBeijing National Laboratory of Molecular Sciences, CAS Key
Laboratory of Molecular Recognition and Function, Institute of
Chemistry, Chinese Academy of Sciences, Beijing 100190, China
bDepartment of Chemistry, Colorado State University, Fort Collins,
Colorado 80523, USA. E-mail: yian@lamar.colostate.edu;
a All reactions were carried out with acetophenone (11) (0.20 mmol),
o-HOPhCH2NH2 (12) (0.30 mmol), and catalyst (0.04 mmol) in solvent
(1.0 mL) at reflux for 72 h. b The conversion was determined by 1H
NMR of the crude reaction mixture based on ketone 11 and its ketimine.
c The ee’s were determined by chiral HPLC (Chiralpak AD-H column)
after the amines were converted into their N-benzoyl derivatives.
Fax: +001-970-4911801; Tel: +001-970-4917424
†Electronic supplementary information (ESI) available: Experimental
procedures, characterization data, HPLC data for determination of enan-
tiomeric excesses, and NMR spectra. See DOI: 10.1039/c2ob26782a
8960 | Org. Biomol. Chem., 2012, 10, 8960–8962
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Table 2 Catalytic asymmetric transamination of aromatic ketonesa
The asymmetric transamination can be extended to a variety
of aromatic ketones (Table 2). Acetophenone and various substi-
tuted acetophenones can be transaminated to give the corres-
ponding chiral amines in 44–74% yield and 71–85% ee
(Table 2, entries 1–11). Other aromatic ketones such as 2-acetyl-
naphthalene and 2-acetylthiophene were effective substrates,
giving the amines in 81% and 70% ee respectively (Table 2,
entries 12 and 13). Similar ee was obtained with propiophenone
(Table 2, entry 14).
Entry
Amineb (15)
Yieldc (%)
eed (%)
1
2
3
4
5
6
7
8
9
15a, X = H
66
65
62
74
51
61
52
47
51
80
84
71
78
82
79
83
78
76
Conclusion
15b, X = o-F
15c, X = o-Br
15d, X = m-Br
15e, X = m-CH3
15f, X = p-Cl
15g, X = p-CH3
15h, X = p-nBu
15i, X = p-tBu
In summary, we have developed an efficient asymmetric bio-
mimetic transamination of various aromatic ketones with
o-HOPhCH2NH2 as amine donor and hydroquinine derivative
C4 as catalyst, giving optically active amines in 43–74% yield
and 70–85% ee. This process illustrates the potential of trans-
amination as a viable approach to generate optically active
amines from unactivated ketones. Further understanding the
mechanism and developing more effective catalytic systems are
currently under way.
10
58
85
11
12
44
73
83
81
Acknowledgements
The authors gratefully acknowledge the National Basic Research
Program of China (973 program, 2010CB833300) and the
Chinese Academy of Sciences for the financial support.
Notes and references
13
14
47
43
70
77
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and X. Zhang, Chem. Rev., 2003, 103, 3029; (b) V. I. Tararov and
A. Börner, Synlett, 2005, 203; (c) A. F. Abdel-Magid and S. J. Mehrman,
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a All reactions were carried out with ketone 14 (1.0 mmol),
o-HOPhCH2NH2 (12) (1.50 mmol), and catalyst C4 (0.20 mmol) in
toluene (5.0 mL) at 110 °C for 72 h. b For entries 1, 6, 7, and 14, the
absolute configurations (S) were determined by comparing the optical
rotations with reported ones of chiral amines (refs. 11 and 12). The
absolute configurations of remaining amines were tentatively proposed
by analogy. c Isolated yield based on ketone 14. d The ee’s were
determined by chiral HPLC (Chiralpak AD-H column) after the amines
were converted into their N-benzoyl derivatives.
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o-MeOPhCH2NH2,
o-ClPhCH2NH2,
m-BrPhCH2NH2,
p-FPhCH2NH2, p-CNPhCH2NH2, etc. Our next attention was
then focused on o-HOPhCH2NH2 (12), which has displayed
unusually high reactivity for the transamination of certain
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delight, the desired amine product was obtained with 77% ee
when acetophenone (11) was treated with o-HOPhCH2NH2 (12)
and 20 mol% catalyst C1 in refluxing toluene (Table 1, entry 1).
Slightly higher ee’s (80% ee) were obtained with catalysts C2,
C3, and C4 (Fig. 1) (Table 1, entries 5–7). It appears that the
transamination is greatly facilitated by the o-OH group of
o-HOPhCH2NH2 (12) likely via H-bond.
7 For leading references on chiral base-catalyzed isomerization of
trifluoromethyl imines, see: (a) V. A. Soloshonok, A. G. Kirilenko,
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