Stereoselective metal-free catalytic synthesis of chiral trifluoromethyl aryl and alkyl amines

Article abstract of DOI:10.1039/c3cc43821j

The enantioselective organocatalytic reduction of trifluoromethyl aryl and alkyl ketoimines afforded the corresponding fluorinated amines with high chemical and stereochemical efficiency. The Lewis base catalyzed reaction with trichlorosilane led to chiral products with a trifluoromethyl group directly linked to the newly generated stereocenter typically in >90% yield and up to 98% e.e.

Full text of DOI:10.1039/c3cc43821j

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Stereoselective metal-free catalytic synthesis of chiral trifluoromethyl
aryl and alkyl amines.
Andrea Genoni, Maurizio Benaglia,* Elisabetta Massolo and Sergio Rossi
Dipartimento di Chimica, Università di Milano, Via Golgi 19, 20133, Milano, Italy.
Fax: ++390250314159; Tel: ++390250314171; E-mail: maurizio.benaglia@unimi.it
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The
enantioselective
organocatalytic
reduction
of
trifluoromethyl aryl and alkyl ketoimines afforded the
corresponding fluorinated amines with high chemical and
stereochemical efficiency. The Lewis base catalyzed reaction
with trichlorosilane led to chiral products with
a
trifluoromethyl group directly linked to the newly generated
stereocenter typically in >90% yield and up to 98% e.e.
Organofluorine compounds find applications in several fields of
scientific research, like pharmaceutical, agrochemical and
veterinary, but also in material science.1 In particular, fluorinated
molecules have gained lately an extraordinary importance as
drug candidates.2 Special attention has been recently devoted to
the preparation of chiral molecules featuring stereocenters
bearing directly a fluorine atom or a trifluoromethyl group.3
Despite the great interest of the last years in the topic, the highly
stereochemically efficient synthesis of chiral organfluorine
compounds still represents a challenge for the synthetic chemist.4
Two approaches have been followed so far: in one case the direct
introduction of a fluorine atom or a fluorinated residue is
involved;5 the second methodology, that has been preferred so
far, is based on the stereoselective transformation of a fluorine-
containing building block.
Figure 1. Biologically active trifluromethylated chiral amines.
We have decided to investigate the use of trichlorosilane in the
presence of a chiral catalyst to perform stereoselectively that
specific transformation.10 The reaction with trichlorosilane in
the presence of catalytic amounts of a chiral Lewis base is a
well-established methodology to perform enantioselective
reductions of carbon nitrogen double bonds11. In the last decade
different classes of enantiomerically pure Lewis bases have been
developed, including N-formyl derivatives, oxazolines,
imidazole-derivatives, sulfonamides and picolinamides.12
We started our investigation by screening different typologies of
chiral activators, developed by us and other groups. The
catalysts, shown in Figure 2, were employed to promote the
enantioselective reduction of ketoimines derived from the
trifluoromethyl phenyl ketone, selected as model compounds to
identify the catalyst and the experimental conditions of choice.
Chiral picolinamides derived from ephedrine (catalyst A),13
binaphthyl diamine (catalyst C)14 and from prolinol (catalyst
B)15 were employed, as well other Lewis bases like (S)-prolinol-
derived phosphoroamides (catalyst D)16 and chiral biphosphine
oxides, like compound E.17
In this context enantiopure trifluoromethylated compounds are
attracting an extraordinary attention due to their increasing
occurrence in numerous biologically active molecules, but also
for their use as fundamental components in materials for
optoelectronic devices.6 Among others, chiral amines play a
fundamental role in medicinal chemistry (Figure 1).
Considering that trifluoromethyl ketones are readily accessible,
the catalytic enantioselective reduction of the corresponding keto
imine derivatives offers a viable approach for the synthesis of
enantiomerically pure trifluoromethylated amines. Indeed only
very few enantioselective hydrogenations have been reported on
those substrates;7 but in one case the Pd catalyzed reduction is
limited to fluorinated iminoesters,7a while in the second case,
although the enantioselectivities are good to high, the use of
relatively high pressures of hydrogen and of an expensive and
toxic transition-metal catalyst are significant drawbacks.7b Lately
a highly enantioselective organocatalyzed procedure has been
reported, but it is limited to trifluoromethyl aryl ketones,
involves the use of a consistent amount of a quite expensive
sterically hindered phosphoric acid and relies on the use of
stoichiometric amount of benzothiazolines as reducing agents.8
More recently the stereoselective synthesis of amines, via
catalytic isomerization of imines, either derived from
trifluoromethyl aryl or alkyl ketones, has been described.9
Figure 2. Chiral catalysts employed in the HSiCl3-mediated
reduction of fluorinated ketoimines.
In a typical procedure the reaction was performed at 0°C in
dichloromethane for 12 hours in the presence of 10 mol%
amount of chiral Lewis base (Scheme 1).
From preliminary investigations it emerged that N-aryl protected
imines behaved better than N-benzyl derived substrates (see
entries 1-4 of Table 1). Ephedrine-derived picolinamide A was
able to promote the reduction of N-4-methoxyphenyl imine of
2,2,2-trifluoroacetophenone in 83% yield after 15 hours at 0°C
in dichloromethane and 87% e.e.† With prolinol-based catalyst
The catalytic highly stereoselective synthesis of such compounds
remains
a
challenge, especially relatively to chiral
trifluoromethyl alkyl amines, documented only in two works.7b, 9
†
Electronic Supplementary Information (ESI) available: [details of
any supplementary information available should be included here]. See
http://www.rsc.org/suppdata/cc/b0/b000000a/
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B both imines 1 and 3 were reduced in good yield, but with
different enantioselectivities: a higher e.e. was observed with
imine 1. Therefore, N-PMP substituted imines were selected as
preferred substrates for further studies.
and work up procedures were attempted (a few selected results
are reported in Table 2). Those studies led to identify a
methodology involving the quench with limited and controlled
amount of NaOH solution that allowed to isolate the chiral
amine 2 in 91% yield (quantitative conversion by NMR on the
crude reaction mixture) and 91% e.e. (entry 6).
Finally, operating under the best experimental conditions, it was
attempted to lower the catalyst loading; we were happy to see
that catalyst still worked efficiently at 5 mol%, leading to the
product in quantitative yield and 90% e.e.; however, also at 1%
chiral Lewis base A catalyzed the reaction with 89% e.e. albeit
in lower yield. It is worth mentioning that, by performing the
reaction with 5 mol% of chiral base, the ACE (Asymmetric
Catalyst Efficiency) of catalyst A is 14,3. But ACE reaches the
value of 55,65 for the reaction performed with 1 mol% of
catalyst (values calculated on the basis of data of entries 8-9,
Table 2). The definition of ACE was recently proposed18 in the
attempt to compare and evaluate the efficiency of different
catalysts, taking in consideration not only the level of
enantioselectivity and the yield guaranteed by the catalyst, but
also the molecular weight of the product and of the catalysts
itself. Noteworthy picolinamide A favourably compares both
with chiral phosphoric acids (ACE value 4)8 and even with
organometallic catalysts7b (ACE value 15,7).19
Scheme1. Enantioselective reduction of trifluoromethyl phenyl
ketone-derived imines.
Table 1 Enantioselective imine reduction catalyzed by A-E catalysts.
Entrya Catalyst Imine
Yield b (%) Yield b (%) e.e.c (%)
(isolated)
1
2
3
4
5
6
7
A
A
B
B
C
D
E
1
3
1
3
1
1
1
83
15
71
67
99
47
75
25
n.d.
51
65
77
87
n.d.
53d
15d
73
A further improvement in the stereoselectivity of the process was
obtained by performing the reduction of fluorinated chiral
ketoimine 5 in the presence of catalyst A (Scheme 2).20
n.d.
61
35
25
areaction run for 15 hours in dry DCM at 0°C; byields determined by
NMR on the crude reaction mixture and confirmed on the isolated
product after chromatographic purification; cenantiomeric excess
determined by HPLC on chiral stationary phase; dthe enantiomer with
opposite absolute configuration was obtained.
The screening of other catalysts showed that the bispicolinamide
catalyst C promoted the reaction in quantitative yield and 73%
e.e., while phosphoroamide and phosphine oxide catalysts D and
E were less efficient, both chemically and stereochemically.
In further studies different experimental parameters were
investigated (Table 2). Chlorinated solvents afforded the most
reliable and interesting results, therefore dichloromethane was
selected as preferred reacion medium.
Scheme2. Enantioselective reduction of trifluoromethyl phenyl
ketone-derived chiral imines.
Therefore (R)-1-phenylethylamine and trifluoromethyl phenyl
ketone were reacted to synthesize imine 5 that was reduced in
the presence of catalyst A to give chiral amine 6 in almost
quantitative yield and 98/2 diastereoisomeric ratio.21§
Noteworthy the enantiomeric ketoimine 7 led to amine 8 with
the opposite absolute configuration in 97/3 d.r. by performing
the reaction in the presence of catalytic amounts of B. #
The general applicability of the methodology was then
investigated (Table 3). High yields and enantioselectivities were
generally obtained, indipendently from the electronic nature of
the aromatic ring substituents. For example the reduction of
imine derived from trifluoromethyl 4-chlorophenyl ketone was
accomplished in quantitative yield and 90% e.e.; comparable
levels of enantioselectivity were obtained also with substrates
Table 2 Reduction of 2,2,2-trifluoroacetophenone-derived imine 1.
Entrya Catalyst Temp.
(°C)
Yield b (%)
Yield b (%) e.e.c (%)
(isolated)
1
2
3
4
5
6
7
8
9
A (10%)
A (10%)
A (10%)
B (10%)
A (10%)
A (10%)
A (10%)
A (5%)
0
-50
20
-50
0
0
0
0
0
83
61
77
67
93
99
98
99
73
25
57
51
55
83
91
51
90
53
87
77d
85
45d
89e
91f
90g
91f
89f
bearing
either electronwithdrawing groups (F, CF3) and
electronrich residues (Me, OMe).
A (1%)
Even more interestingly, the methodology was successfully
employed in the reduction of imines derived from
trifluoromethyl alkyl ketones. It is important to note that
although numerous fluorinated compounds of relevant biological
importance are trifluoromethyl alkyl amines, their preparation
through reduction is much less studied. In performing the
reduction of 1,1,1-trifluoro-2-butanone-derived imine in the
presence of picolinamide A, chiral amine (R)-10 was isolated in
98% yield and 90% e.e. (Scheme 3). Similar results were
observed also with other linear alkyl trifluoromethyl ketoimines,
whose reduction led to the products with enantioselectivities
areaction run for 15 hours in dry DCM at 0°C; byields determined by
NMR on the crude reaction mixture and confirmed on the isolated
product after chromatographic purification; cenantiomeric excess
determined by HPLC on chiral stationary phase; dreaction run for 40
hours in dry DCM; ereaction quench: stoichiometric amount of NaHCO3
sat. sol.; freaction quench: stoichiometric amount 10% sol. NaOH;
greaction quench: 10% HCl then 10% sol. NaOH.
Regarding the yields we observed often a discrepancy among the
conversion value determined by NMR and the isolated yield
after chromatographic purification. Therefore different quench
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constatly around 90%. A branched alkyl fluorinated ketoimine
was also considered: chiral amine 15 was obtained with 98% e.e.
With a ACE value of about 55, picolinamide A established itself
as one of the most efficient and versatile catalyst for the
reduction of a wide range of fluorinated imines. The well
documented possibility to easily remove the N-PMP residue22 or
the benzyl group23 makes the present method a viable and
attractive synthesis also for chiral fluorinated primary amines.
Table
3 Enantioselective reduction of N-PMP imines of different
trifluoromethyl aryl ketones.
MB thanks MIUR (Rome) within the national project "Nuovi
metodi catalitici stereoselettivi
e sintesi stereoselettiva di
molecole funzionali"; MB thanks the European COST Action
CM0905-Organocatalysis.
Entrya Cat.
Ar group
Yield b Yield (%)
e.e.c
(%)
(%)
(isolated)
1
2
3
4
5
6
7
8
9
A
A
C
A
A
A
A
A
A
A
Ph
4-ClPh
4-ClPh
4-FPh
4-CF3Ph
3-MePh
4-OMePh
4-MePh
99
99
90
83
99
99
99
80
80
99
91
93
65
77
90
87
90
70
70
75
91
90
65
89
90
91
91
90
75
67
Notes and references
† The absolute configuration was established by comparison of optical
rotation value with data reported in the literature.
§ The reduction of 7 (enantiomer of 5) with trichlorosilane in the
presence of
A led to the product in 98% yield and 82/18
diastereoisomeric ratio (match and mismatch combination).
# The reduction of 5 (or 7) with trichlorosilane in the presence of DMF
led to the product in 73% yield and 70/30 diastereosiomeric ratio.
4-NMe2Ph
4-OCH2COOR-Ph
10
1
2
J.-A. Ma, D. Cahard, Chem. Rev. 2008, 108, PR1; A. M. Thayer,
Chem. Eng. News 2006, 84, 15.
D. O’Hagan, J. Fluorine Chem. 2010, 131, 1071-1081.
areaction run for 15 hours in dry DCM at 0°C; byields determined by
NMR on the crude reaction mixture and confirmed on the isolated
product after chromatographic purification; cenantiomeric excess
determined by HPLC on chiral stationary phase (see Supporting
Information for chromatographic details).
3. M. Shimizu, T. Hiyama, Angew. Chem. Int. Ed. 2005, 44, 214-231.
4
Review: J. Nie, H.-C. Guo, D. Cahard, J.-A. Ma, Chem. Rev. 2011,
111, 455-529.
5
J.-A. Ma, D. Cahard, J. Fluorine Chem. 2007, 128, 975. See also
ref.11; for some recent contributions see: J.-H. Lin, G. Zong, R.-N.
Du, J.-G. Xiao, S. Liu, Chem. Commun. 2012, 48, 7730-7740; L.
Bernardi, E. Indrigo, S. Pollicino, A. Ricci, Chem. Commun. 2012,
48, 1428-1430; F.-G. Zhang, X.-Y. Zhu, S. Li, J. Nie, J.-A. Ma,
Chem. Commun. 2012, 48, 11552-11554.
6
7
J. Lim, B. Taoka, R. D. Otte, K. Spencer, C. J. Dinsmore, M. D.
Altman, G. Chan, C. Rosenstein, S. Sharma, H.-P. Su, A. A.
Szewczak, L. Xu, H. Yin, J. Zugay-Murphy, C. G. Marshall, J. R.
Young, J. Med. Chem. 2011, 54, 7334; P. D. O’Shea, C.-Y. Chen,
D. Gauvreau, F. Gosselin, G. Hughes, C. Nadeau, R. P. Volante, J.
Org. Chem. 2009, 74, 1605; N. Zhang, S. Ayral-Kaloustian, T.
Nguyen, J. Afragola, R. Hernandez, J. Lucas, J.Gibbons, C. Beyer,
J. Med. Chem. 2007, 50, 319. See also ref. 4.
Scheme3. Reduction of trifluoromethyl alkyl ketones-derived
imines.
a) H. Abe, H. Amij, K. Uneyama Org. Lett. 2001, 3, 313-316; b) M.-
W. Chen, Y. Duan, Q.-A. Chen, D.-S. Wang, C.-B. Yu, Y.-G. Zhou,
Org. Lett. 2010, 12, 5075-5078.
A. Henseler, M. Kato, K. Mori, T. Akiyama, Angew. Chem. Int. Ed.
2011, 50, 8180-8183.
In a tentative model of stereoselection the pyridine nitrogen and
the CO amidic group of the picolinamide activate trichlorosilane
by coordination;20 the hydrogen atom of hydroxyl group might
coordinate the imine through hydrogen bonding. In the proposed
stereoselection model A, leading to the observed major
enantiomer, the steric interaction between the pyridine ring and
the aryl group is much less significant than that observed in
adduct B, that is thus disfavored (Figure 3).
8
9
Y. Wu, L. Deng, J. Am. Chem. Soc. 2012,134, 14334-14337.
10 M. Benaglia, A. Genoni, M. Bonsignore, Enantioselective
organocatalytic reductions in Stereoselective Organocatalysis: From
C-C to C-heteroatom bond formation, 2012, ed. R. Rios Torres,
Wiley.
11 S. Guizzetti, M. Benaglia, Eur. J. Org. Chem. 2010, 5529.
12 S. Jones, C. J. A. Warner, Org Biomol. Chem. 2012,10, 2189.
13 S. Guizzetti, M. Benaglia, F. Cozzi, R. Annunziata, Tetrahedron,
2009, 65, 6354.
14 S. Guizzetti, M. Benaglia, G. Celentano, Eur. J. Org. Chem. 2009,
22, 3683.
15 Y. Matsumura, K. Ogura, Y. Kouchi, F. Iwasaki, O. Onomura, Org.
Lett. 2006, 17, 3789.
16 M. Bonsignore, M. Benaglia, R. Annunziata, G. Celentano, Synlett
2011, 1085.
17 S. Rossi, M. Benaglia, F. Cozzi, A. Genoni, T. Benincori, Adv.
Synth. Catal. 2011, 353, 848.
18 S. El-Fayyoumy, M. H. Todd and C. J. Richards, Beilstein J. Org.
Chem. 2009, 5, 67.
19 For a discussion of the activity of different organocatalysts in the
trichlorosilane-mediated reduction see ref.11 and 12.
20 S. Guizzetti, M. Benaglia, S. Rossi, Org. Lett. 2009, 11, 2928.
21 S. Guizzetti, M. Benaglia, C. Biaggi, G. Celentano, Synlett, 2010,
134.
Figure 3. Proposed model of stereoselection.
In conclusion, the enantioselective organocatalytic reduction of
imines derived both from aryl and alkyl trifluoromethyl ketones,
in good yields and high enantioselectivities, typically of 90% e.e.
and up to 98% e.e., was successfully realized by using
trichlorosilane as reducing agent in the presence of catalytic
amounts of an inexpensive and readily available picolinamide.
22 M. CHen, Y. Duan, Q. Chen, D. Wang, C. Yu, Y. Zhou, Org. Lett.
2010, 12, 5075. The N-PMP deprotection promoted by CAN has
been succesfully performed on
Supporting Information).
amine 12 (80% yield, see
23 B. Torok, G. K. S. Prakasha, Adv. Synth. Catal. 2003, 345, 165.
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