Convenient enantioselective synthesis of β-trifluoromethyl-β-aminoketones by organocatalytic asymmetric Mannich reaction of aryl trifluoromethyl ketimines with acetone

Article abstract of DOI:10.1016/j.tetasy.2008.02.023

The l-proline-catalyzed asymmetric Mannich reaction has been performed between aryl trifluoromethyl ketimines and acetone to provide, for the first time, chiral β-aryl-β-trifluoromethyl-β-aminoketones in high yields and with 74-92% enantiomeric excesses.

Full text of DOI:10.1016/j.tetasy.2008.02.023

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 761–764
Convenient enantioselective synthesis of b-trifluoromethyl-b-
aminoketones by organocatalytic asymmetric Mannich
reaction of aryl trifluoromethyl ketimines with acetone
Volodymyr A. Sukach, Nataliya M. Golovach, Volodymyr V. Pirozhenko,
Eduard B. Rusanov and Mykhaylo V. Vovk*
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmans’ka 5, Kyiv 02094, Ukraine
Received 7 February 2008; accepted 27 February 2008
Abstract—The L-proline-catalyzed asymmetric Mannich reaction has been performed between aryl trifluoromethyl ketimines and ace-
tone to provide, for the first time, chiral b-aryl-b-trifluoromethyl-b-aminoketones in high yields and with 74–92% enantiomeric excesses.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
noketones, as fluorine atoms are known to substantially af-
fect physical, chemical and biological properties of
compounds.7 b-Aminocarbonyl compounds containing
the geminal amino and fluoroalkyl groups are scarcely de-
scribed in the literature, and the reports on asymmetric ac-
cess to them are scarce.8,9 For instance, the groups of
Kitazume et al. and Brigaut et al. succeeded in applying
the auxiliary-based approach,9a–c whereas Fustero et al.
and Funabiki et al.9d,e conducted the organocatalytic Man-
nich reaction of N-p-metoxyphenyl polyfluoroalkyl aldi-
mines with aliphatic aldehydes or acetone used as
nucleophilic components. As found, such conversions are
efficiently catalyzed by L-proline but the yields of the target
products are usually moderate (no more than 55%) due to
side reactions. The above-mentioned studies involved thor-
oughly optimized reaction conditions; also, elimination of
the protecting N-p-methoxyphenyl group was necessary
in order to further react the resulting b-amino-substituted
aldehydes and ketones.
Modern organic chemistry calls for the development of effi-
cient enantioselective synthetic routes to biologically active
compounds. This challenge has arisen from the progres-
sively higher requirements on the enantiomeric purity of
the known and newly developed therapeutic agents, as well
as the building blocks for preparing them.1 Among the cor-
responding precursors, a prominent place is occupied by b-
aminoketone derivatives, including some commonly used
pharmaceuticals with a broad activity spectrum and the re-
cently discovered biologically important species.2,3
In this context, there has been considerable recent interest
in the preparation of enantiomerically pure b-aminoketone
derivatives. Various synthetic routes to them have been
found, the most widespread of which is based on the Man-
nich reaction between CH-acidic carbonyl compounds and
imines or their precursors.2,4 Catalytic enantioselective ap-
proaches to conversions of this kind are currently under ac-
tive research.5 It is notable that most of these recent papers
address organocatalytic versions of the asymmetric Man-
nich reaction,6 thus indicating the increasingly important
role of this line of research.
To obtain new chiral fluorine-containing b-aminoketone
derivatives, we have studied the reactions of aryl trifluoro-
methyl ketimines 110 with acetone in the presence of L-pro-
line. To the best of our knowledge, ketimines have not been
hitherto applied in organocatalyst-mediated asymmetric
Mannich reactions because of their low electrophilicity
and increased steric hindrance to nucleophilic attack on
the C@N bond. It is, therefore, intriguing theoretically to
determine the ketimine behaviour in these conversions and
to gain an insight into their stereochemistry. Compounds 1
Particularly promising are the new enantioselective
synthetic strategies affording fluorine-substituted b-ami-
*
Corresponding author. Fax: +380 44 5732643; e-mail: mvovk@i.com.ua
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.02.023

762
V. A. Sukach et al. / Tetrahedron: Asymmetry 19 (2008) 761–764
bear the imino group activated by the neighbouring trifluo-
romethyl substituent and thus are likely to react with ace-
tone in the presence of the L-proline catalyst. The bare
nitrogen atom in 1 may additionally influence the reaction
course and stereoselectivity, and also dictate the configura-
tion of the resulting stereogenic centre, as is typical in the
reactions of this kind.11
2. Results and discussion
As found, ketimine 1a reacts with 5 equiv excess of acetone
in the presence of 10 mol % L-proline in DMSO at room
temperature (18 °C) within 3 days to furnish 4-amino-
5,5,5-trifluoro-4-phenylpentan-2-one 2a with a 100% 19F
NMR-monitored conversion and in 81% isolated yield
(see Scheme 1 and Table 1). An essentially quantitative
yield of the reaction is somewhat reduced as a result of
the separation of the raw product (by a simple non-chro-
matographic procedure) from the mesityl oxide impurity
formed in the acetone self-condensation.
NH2
O
O
NH
S-Pro
CF3
Ar
+
Figure 1. 19F NMR spectra of the racemic (upper) and enantiomerically
enriched (lower) compound 2a in the presence of 100 mol % of tris(3-
heptafluorobutyryl-d-camphorato)europium (III).
Ar
CF3
2a-e
1a-e
Scheme 1. Preparation of b-aminoketones 2a–e.
the addition reaction between imine 1a and acetone is too
slow being only 42% complete within 10 days; nevertheless,
the resulting product has a high degree of enantiomeric
purity (82%).
The enantiomeric purity of the synthesized aminoketone 2a
expressed as enantiomeric excess (ee) is equal to 80%; it has
been determined by 19F NMR spectroscopy using the
chiral lanthanide shift reagent (LSR), tris(3-heptafluoro-
butyryl-d-camphorato)europium (III).12 A complex of
compound 2a with the chiral LSR gives rise to a poorly
diastereomerically resolved 1H NMR spectrum, but its
19F resonances from the trifluoromethyl group are clearly
distinct for the two diastereomers thus allowing signal inte-
gration and hence straightforward and fairly accurate
determination of the reaction enantioselectivity (see Fig. 1).
The reactions run in acetonitrile or dioxane under the same
conditions yield only trace amounts of product 2a. In boil-
ing dichloromethane, the imine conversion does not exceed
44% but the enantioselectivity remains practically un-
changed. Using more catalyst (20 mol % and over) had
no significant effect on the reaction rate.
The same strategy extended to the reactions of other keti-
mines 1b–e resulted in a number of chiral b-aminoketones
2b–e prepared in excellent yields and with high ee values
(see Table 1).13 It has been found that the reaction rate
and enantioselectivity are nearly insensitive to the nature
DMSO appears to be the optimal solvent for the reaction
concerned, but similar results have also been obtained in
DMF. If conducted in pure acetone at room temperature,
Table 1. Compound structures, reaction conditions, product yields and enantiomeric excesses for the 1?2 conversion
Compounds 1, 2
Ar
Solvent
Time (h)
Temp (°C)
Conversiona (%)
Isolated yield (%)
eeb (%)
a
a
a
a
a
b
c
Ph
Ph
Ph
Ph
DMSO
DMF
CH2Cl2
CH3CN or dioxane
Acetone
DMSO
DMSO
DMSO
72
72
48
120
240
72
72
72
72
20
20
40
20
20
20
20
20
20
100
100
44
<5
42
100
100
100
100
86
77
25
—
23
80
82
82
75
80
78
82
—
82
92
74
84
78
Ph
3-CH3C6H4
4-CH3C6H4
4-FC6H4
4-CH3OC6H4
d
e
DMSO
a Determined by 19F NMR spectroscopy.
b Determined by 19F NMR spectroscopy using the chiral lanthanide shift reagent.

V. A. Sukach et al. / Tetrahedron: Asymmetry 19 (2008) 761–764
763
of substituents on the phenyl ring of ketimines except for
the m-tolyl group, which provides the 92% enantiomeric
purity of the corresponding product. Aminoketones 2 were
isolated as stable colourless oils with the exception of com-
pound 2c, a solid (mp 67–68 °C) obtainable in an enantio-
merically pure form by recrystallization from a 3:1
benzene–hexane mixture.
to the carboxyl group of L-proline. With such relative posi-
tions of the molecular moieties involved in the reaction, the
bulkiest substituent at the C@N bond (therefore this is an
aryl substituent) is oriented pseudoaxially (see model A
shown in Fig. 3).
O
O
H
N
Although the trifluoromethyl substituent reduces the nucle-
ophilicity of the geminal amino group, the latter can be
acylated with acyl chlorides and carbamoylated with aryl
isocyanates. Acylation of compound 2a with p-bromoben-
zoyl chloride followed by recrystallization from a 3:1 ben-
zene–hexane mixture afforded the corresponding optically
pure p-bromobenzamide. Its absolute configuration was
determined by X-ray structural analysis of a suitable single
crystal (see Fig. 2).14 As the nature of an aryl substituent in
ketimines does not affect the direction of the nucleophilic
attack on their C@N bond, one can assume that the S-con-
figuration of the asymmetric centre is an inherent feature of
all aminoketones 2.
N
H
H
N
O
N
CF3
O
Ar
Me
H
Ar
Me
CF3
B
A
(Z)-syn
(Z)-anti
O
CF3
N
O
H
N
Ar
H
O
N
O
N
CF3
Me
Me
H
H
Ar
D
C
(E)-syn
(E)-anti
Figure 3. Possible stereochemical patterns of the L-proline-catalyzed
reaction between ketimines 1 and acetone.
However, one cannot completely rule out transition state
models B, C and D because, on the one hand, the E- and
Z-forms of ketimines 1 are not significantly different in en-
ergy (as evidenced by their comparable contributions to the
equilibrium mixture existing in a DMSO solution) while,
on the other hand, the imino hydrogen atom is much less
sterically demanding than either substituent at the carbon
end of the double bond.
Taking advantage of the carbonyl group of compounds 2,
we have derivatized them to obtain chiral trifluoromethyl-
substituted 1,3-aminoalcohols 3a,c,d and 1,3-diamines
NaBH4
NH2 OH
NH2
O
CF3
Ar
CF3
Ar
MeOH, r . t., 2h
2a,c,d
3a: 79% (d. r. 1:5.1)
3c: 80% ( d. r. 1:5.5)
3d: 76% ( d. r. 1:4.5)
Figure 2. Molecular structure of 4-bromo-N-[3-oxo-1-phenyl-1-(trifluoro-
methyl)butyl] benzamide.
NH2OH
Since the literature lacks theoretically calculated transition
state energies for L-proline-catalyzed asymmetric Mannich
reactions of ketimines, we studied the data on absolute ste-
reochemistry so as to suggest some plausible stereochemi-
cal patterns of the reaction between compounds 1 and
acetone. According to the previously performed quantum
chemical calculations for the related organocatalytic reac-
tions between aldimines and ketones,11 the most energeti-
cally favourable transition state model implies that the
aldimine is in the more stable E-configuration, whereas
the enamine formed from the acetone and the catalyst
adopts the anti-conformation of the double bond relative
EtOH,Δ
NH2 NH2
CF3
NH2 NOH
H2, Raney Ni
r. t., 6 h
CF3
Ar
Ar
4a: 65% (d. r. 1:1.9)
4c: 74% (d. r. 1:2.4)
4d: 63% (d. r. 1.2.7)
5a,c,d
Scheme 2. Transformations of b-aminoketones 2a,c,d.

764
V. A. Sukach et al. / Tetrahedron: Asymmetry 19 (2008) 761–764
Heidelberg, Germany, 2000; (b) Special issue on Fluorine in
the Life Sciences, ChemBioChem 2004, 5, 557; (c) Seebach, D.
Angew. Chem., Int. Ed. 1990, 29, 1320; (d) Duewel, H. S.;
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4a,c,d. The former resulted from the reduction of aminok-
etones 2a,c,d with sodium borohydride while the latter
were produced by treating the aminoketones with hydrox-
ylamine followed by hydrogenation of the corresponding
oximes 5a,c,d with hydrogen in the presence of Raney nick-
el (see Scheme 2). These reactions exhibited high yields but
low diastereoselectivity, with a diastereomer ratio of 1:5.5
for compounds 3 and no more than 1:2.7 for compounds 4.
8. For racemic fluorinated aminocarbonyl compounds, see: (a)
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3. Conclusion
Based on the L-proline-catalyzed asymmetric Mannich reac-
tion between aryl trifluoromethyl ketimines and acetone, we
have developed a facile and efficient synthetic access to chiral
b-aryl-b-trifluoromethyl-b-aminoketones obtained in high
yields and with 74–92% enantiomeric purity. The resulting
aminoketones were derivatized to give trifluoromethyl-
substituted 1,3-aminoalcohols and 1,3-diamines.
9. For chiral fluorinated aminocarbonyl compounds, see: (a)
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13. To a solution of aryl trifluoromethyl ketimine (0.036 mol) in
DMSO (50 ml) and acetone (20 ml), L-proline (0.42 g,
10 mol %) was added. The reaction mixture was stirred for
72 h at room temperature and filtered, followed by dilution of
the filtrate with water (50 ml) and extraction with dichloro-
methane (3 ꢀ 15 ml). After washing the organic layer with
15% hydrochloric acid (30 ml), the aqueous layer was
separated and neutralized with a concentrated solution of
potassium carbonate. The oily product was extracted with
dichloromethane (2 ꢀ 15 ml), dried over Na2SO4, filtered,
and evaporated. (S)-(+)-4-Amino-4-phenyl-5,5,5-trifluoro-2-
pentanone 2a. Yield 86%, oily substance, n2D0 ¼ 1:4848. 1H
NMR (CDCl3/TMS), d (ppm): 2.05 s (3H, CH3), 2.33 s (2H,
NH2), 3.04 d (1H, J = 27 Hz, CH2), 3.42 d (1H, J = 27 Hz,
CH2), 7.26–7.39 m (3H, Ar), 7.54 d (2H, J = 15 Hz, Ar). 19F
20
NMR (CDCl3/CFCl3), d (ppm): ꢁ80.29. ½aꢂD ¼ þ26:6 (c 1.8,
MeOH).
14. All crystallographic measurements were performed at room
temperature on a Bruker Smart Apex II diffractometer
operating in the x and u scans mode. Flack parameter
0.050(19). Full crystallographic details have been deposited at
Cambridge Crystallographic Data Centre (CCDC). Any
request to the CCDC for this material should quote the full
literature citation and the reference number CCDC 670156.
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Rev. 2008, 37, 29; (b) Ting, A.; Schaus, S. E. Eur. J. Org.
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7. (a) Hiyama, T. In Yamamoto, H., Ed.; Organofluorine
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