Catalytic highly enantioselective transfer hydrogenation of β-trifluoromethyl nitroalkenes. An easy and general entry to optically active β-trifluoromethyl amines

Article abstract of DOI:10.1039/c4cc07801b

In the presence of a thiourea catalyst, β-CF₃ nitroalkenes react with Hantzsch esters in a highly enantioselective fashion, giving a broad range of β-CF₃ amine precursors with a tertiary stereocentre at the β-position. This reaction

Full text of DOI:10.1039/c4cc07801b

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Catalytic highly enantioselective transfer
hydrogenation of b-trifluoromethyl nitroalkenes.
An easy and general entry to optically active
b-trifluoromethyl amines†
Cite this:DOI: 10.1039/c4cc07801b
Received 2nd October 2014,
Accepted 7th November 2014
Emilie Martinelli,‡a Anna Chiara Vicini,‡b Michele Mancinelli,b Andrea Mazzanti,b
DOI: 10.1039/c4cc07801b
Paolo Zani,b Luca Bernardi*b and Mariafrancesca Fochi*b
www.rsc.org/chemcomm
In the presence of a thiourea catalyst, b-CF3 nitroalkenes react with which followed by reductive amination give N-benzyl amines related
Hantzsch esters in a highly enantioselective fashion, giving a broad to 5 with a slight loss of enantioenrichment. Given the problematic
range of b-CF3 amine precursors with a tertiary stereocentre at the involvement of arylacetaldehydes in enamine catalysed processes,
b-position. This reaction represents the first general catalytic these methods do not guarantee access to b-aryl-b trifluoromethyl
enantioselective approach to this important class of b-CF3 amines. amines (i.e. R1 = aryl in 5).
To fill these gaps, we set out to study the H-bond driven10 transfer
The importance of fluorine containing compounds can hardly hydrogenation reaction of readily available b-trifluoromethyl
be overestimated. The distinctive features of the fluorine atom, nitroalkenes 111 with Hantzsch esters 212,13 (Scheme 1). Given the
characterised by a very high electronegativity and oxidation potential, ease of both the obtainment of nitroalkenes 1 from the corres-
along with a small size, strongly affect the properties of fluorinated ponding a,a,a-trifluoromethylketones11 and the reduction of the
compounds.1 The introduction of fluorine in a molecule is in fact nitro group in the adducts 4, we considered the overall sequence a
one of the workhorses of agro- and medicinal chemistry.2 Besides straightforward and general approach to b-trifluoromethyl amines 5.
increased metabolic stability, fluorinated molecules often show It must be noted that even if b-trifluoromethyl nitroalkenes 1 have
peculiar biological profiles, due to the influence exerted by fluorine already been exploited in catalytic asymmetric settings, their utilisa-
on their lipophilicity, acidity and conformations.3 On the other hand, tion has been so far directed to the preparation of some specific
the unique effects offered by fluorine are also widely exploited in the b-trifluoromethyl amine structures (tryptamine11a–c and b-hydroxy11d
realm of materials science (polymers, dyes, responsive materials, derivatives) bearing a-trifluoromethyl quaternary stereocentres.
etc.),4 and in the design and realisation of (organo)catalysts.5
We started our studies by testing various typical H-bond donor
In this context, the trifluoromethyl group occupies a prominent catalysts (thioureas, ureas, squaramides, diols, phosphoric acids,
position. Accordingly, the development of synthetic methods giving etc.) in the reaction between a,a,a-trifluoroacetophenone derived
access to trifluoromethylated compounds is an extremely active nitroalkene 1a and ethyl Hantzsch ester 2a. Even if most catalysts
research area,6 and several examples of catalytic asymmetric genera- were able to afford the desired adduct 4a with good conversion (see
tion of trifluoromethylated chiral centres have been reported.7 How- ESI†), only the 1,2-diaminocyclohexane derived amido-thiourea 3a
ever, only very few entries to enantioenriched b-trifluoromethyl gave a promising enantioselectivity in the reaction (Table 1, entry 1).
amines, and in particular to amines 5 bearing a tertiary stereocentre Taking advantage of the modularity of the catalyst structure, varia-
at the b-position, have been disclosed so far, despite the importance tions in the two thiourea N-substituents were undertaken. These
of these units in the agro- and medicinal chemistry fields.8 The only experiments showed that enantioselectivity is driven by the amide
catalytic asymmetric approaches to amines 5 are in fact represented portion of the catalyst, as catalyst 3b afforded the product with lower
by two enamine catalysed a-trifluoromethylations of aldehydes,9
a
´
´
Chimie ParisTech – Ecole Nationale Superieure de Chimie de Paris, 11,
rue Pierre et Marie Curie, 75231 Paris Cedex 05, France
b Department of Industrial Chemistry ‘‘Toso Montanari’’, School of Science,
Alma Mater Studiorum – University of Bologna, V. Risorgimento 4, 40136 Bologna,
Italy. E-mail: luca.bernardi2@unibo.it, mariafrancesca.fochi@unibo.it
† Electronic supplementary information (ESI) available: Further optimisation
results, determination of the absolute configuration of compounds 4, experimental
details and copies of NMR spectra and HPLC traces. See DOI: 10.1039/c4cc07801b
‡ These authors contributed equally to this work.
Scheme 1
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Table 1 Selected optimisation resultsa
enantioselectivity, were taken as optimal to study the scope of the
reaction (Table 2). Besides the phenyl derivative 1a, the reactions
with different substrates 1b–h bearing aromatic rings substituted at
different positions with either electron releasing or electron with-
drawing groups afforded a series of b-aryl-b-trifluoro amine pre-
cursors 4b–h with excellent results (470% yield and 493% ee,
entries 1–10). A 2-naphthyl substituent and two heteroaromatic
substituents in substrates 1i–k were also well tolerated by the
catalytic system, the corresponding adducts 4i–k being produced
with very good yields and enantioselectivities (93–97% ee, entries
11–14). It was also very pleasing to observe that the reaction could
be applied successfully to substrates 1l and 1m bearing aliphatic
chains, which furnished the expected adducts 4l and 4m with very
good results (entries 15–17). To demonstrate the superiority of
a,a,a-trifluorotoluene as reaction medium with respect to toluene,
we have performed a few reactions using toluene as the solvent
(Table 2, entries 7, 9, 12 and 16): in all the examined cases the
results in terms of enantioselectivity were slightly lower.
The absolute configuration of the products 4 was deter-
mined on compound 4g by comparing its VCD and ECD spectra
with the computed ones,16 and by chemical correlation on 4l
(for details, see ESI†).
Reduction of the nitro group in adducts 4a,g,i proved to be
straightforward as expected, furnishing the corresponding amines
5 in good yields, conveniently purified as N-tosyl derivatives 6
(Scheme 2). Two different conditions17 could be successfully
applied in the reduction of the nitro group of adduct 4a, as both
the NiCl2/NaBH4 and the Pd/C–HCO2NH4 protocols gave the
amine 5a in good yields.
Entry
2
3 (mol%) Solvent (M)
T (1C) Conv.b (%) eec (%)
1
2
3
4
5
6
7
8
2a 3a (10)
2a 3b (10)
2a 3c (10)
2b 3c (10)
2c 3c (10)
2d 3c (10)
2d 3c (10)
2d 3c (10)
2d 3c (10)
2d 3c (10)
2d 3d (10)
2d 3e (10)
2d 3c (10)
2d 3c (5)
Tol (0.125)
Tol (0.125)
Tol (0.625)
Tol (0.625)
Tol (0.625)
Tol (0.625)
CH2Cl2 (0.13)
MTBE (0.13)
THF (0.13)
Tol (0.625)
Tol (0.625)
Tol (0.625)
40
40
40
40
40
40
40
40
40
495
85
495
495
495
495
61
48
À15
77
69
70
89
66
39
4
60
60
9
10
11
12
13
14
15
16d
À20
À20
À20
495
495
495
495
495
495
495 (94)
94
77
92
95
92
97
95
PhCF3 (0.625) À20
PhCF3 (0.625) À20
2d 3c (10)
2d 3c (19)
PhCF3 (0.30)
PhCF3 (0.30)
À20
À20
a
Conditions: 1a (0.05 mmol), cat. 3 (Â mol%), solvent, 2 (0.06 mmol),
18–24 h. Determined on the crude mixture by 19F NMR analysis.
b
c
d
Determined by chiral stationary phase HPLC. On a 4.0 mmol scale,
isolated yield in parentheses.
Table 2 Scope of the reactiona
conversion and very poor and opposite selectivity(entry2).Incontrast,
the 1,2-diaminocyclohexane moiety is not a necessary requisite, the
simpler amido-thiourea catalyst 3c14 giving results even better than 3a
(entry 3 vs. 1). Whereas the utility of a 1,2-cyclohexanediamine derived
catalyst such as 3a could have been anticipated from some of the
previously reported asymmetric reactions of nitroalkenes with
Hantzsch esters,12a,b the superior efficiency of the simpler structure
3c was an unexpected yet very pleasing result. With this catalyst, the
methyl, iso-butyl and tert-butyl Hantzsch esters 2a–d were tested
(entries 4–6). The tert-butyl derivative 2d clearly outperformed the
other dihydropyridines 2a–c.15 Then, a short solvent screening con-
firmed toluene as the most suitable solvent (entries 6–9), wherein a
satisfactory 94% ee value was achieved by cooling the reaction mixture
to À20 1C (entry 10). At this temperature, catalysts 3d and 3e, closely
related to 3c but varying in the amide N-substituents, were applied
to the reaction. The N,N-diethyl derivative 3d performed rather
poorly, while the N-methyl-N-benzhydryl amide 3e did not give any
substantial improvement compared to 3c (entries 10–12). It was
instead discovered at this point that a,a,a-trifluorotoluene as solvent
provided slightly better results than toluene, when catalyst 3c was
employed (entry 13 vs. 10), even if a lower catalyst loading gave a small
decrease in the enantioselectivity of the product 4a (entry 14). Moving
back to 10 mol% loading, slightly better results were obtained by
lowering the reaction concentration (entry 15).
Entry
1
R
Solvent
4
Yieldb (%) eec (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
C6H5
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
Tol
PhCF3
Tol
PhCF3
PhCF3
Tol
4a
4b
4c
4d
4e
4f
70
80
80
75d
77
80
86
70
65
85
82
88
83
78
79
77
97
94
97
96
93
96
95
98
94
94
97
95
95
93
90
85
91
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-FC6H4
4-BrC6H4
4-BrC6H4
4-MeOC6H4
4-MeOC6H4
4-CF3C6H4
2-Naphthyl
2-Naphthyl
3-Thienyl
1f
4f
1g
1g
1h
1i
1i
1j
1k
1l
1l
4g
4g
4h
4i
4i
4j
4k
4l
4l
9
10
11
12
13
14
15
16
17
PhCF3
3-(N-Tosyl)indolyl PhCF3
PhCH2
PhCH2
PhCF3
Tol
PhCF3
1m CH3(CH2)8
4m 79
a
Conditions: 1 (0.10 mmol), cat. 3c (0.010 mmol, 10 mol%), 2d
b
(0.12 mmol), PhCF3 (0.30 M), À20 1C, 24 h. Pure product 4, isolated
c
These conditions, applicable also on a preparative scale
(4 mmol, Table 1, entry 16) although with a small erosion in the phase HPLC. Reaction performed at 0 1C.
by chromatography on silica gel. Determined by chiral stationary
d
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Notes and references
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Scheme 2
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Scheme 3
Building upon the previously determined conformations and
mode of action of amido-thiourea catalysts related to 3c,14a it is
possible to propose a tentative reaction model, involving the double
coordination and resulting stabilisation of a dipolar transition state
of the reaction leading to the (R)-adducts 4 (Scheme 3). In this
speculative model, the thiourea moiety binds and stabilises the
negative charge at the nitro group, whereas the amide oxygen
coordinates the Hantzsch ester at its NH proton, positively charged
during the hydride-transfer step. An irreversible proton transfer then
leads to the reaction products ((R)-4 and the pyridine derivative), with
concomitant release of the catalyst. Regardless of the structural
accuracy of this model, it might serve to visualise that stereo- 12 Catalytic asymmetric transfer hydrogenation of nitroalkenes with
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esters 212 is not due to steric clashes between the catalyst and
substrates, but mainly due to a good geometrical fit between the
functionalities of the catalyst and a transition state leading to
(R)-products, which are electrostatically complementary. Therefore,
such a model in which the catalyst interacts simply with the nitro
and the NH functionalities explains both the tolerance of the
reactions to substrates featuring different steric properties (aromatic
and aliphatic substrates) and the observation previously reported
that the major enantiomer obtained in these transfer hydrogenation
reactions depends on nitroalkene geometry12b and not on the steric
hindrance displayed by the substituents at the pro-chiral centre (i.e.
(E)-nitroalkenes give (R)-products and (Z)-nitroalkenes (S)-products).
In conclusion, we have developed a catalytic asymmetric
approach to b-trifluoromethyl amines 5 featuring unprecedented
directness and generality, by demonstrating that a simple thiourea
catalyst can promote the reaction between b-trifluoromethyl
nitroalkenes 1 and Hantzsch ester 2 in a highly enantioselective
fashion.
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We acknowledge financial support from the University of
Bologna (RFO program).
17 G. W. Kabalka and R. S. Varma, in Comprehensive Organic Synthesis,
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