Catalytic asymmetric synthesis of α,α,α- trifluoromethylamines by the copper-catalyzed nucleophilic addition of diorganozinc reagents to imines

Article abstract of DOI:10.1021/ol0607847

A copper-catalyzed asymmetric addition of diorganozinc reagents to N-phosphinoylimines has been developed for the synthesis of chiral α,α,α-trifluoromethylamines. The trifluoromethyl ketimines, generated in situ from the corresponding hemiaminals, led to

Full text of DOI:10.1021/ol0607847

ORGANIC
LETTERS
2006
Vol. 8, No. 13
2743-2745
Catalytic Asymmetric Synthesis of
-Trifluoromethylamines by the
Copper-Catalyzed Nucleophilic Addition
of Diorganozinc Reagents to Imines
Caroline Lauzon and Andre´ B. Charette*
r,r,r
De´partement de Chimie, UniVersite´ de Montre´al, P. O. Box 6128, Station Downtown,
Montre´al (Que´bec), Canada H3C 3J7
andre.charette@umontreal.ca
Received March 31, 2006
ABSTRACT
A copper-catalyzed asymmetric addition of diorganozinc reagents to N-phosphinoylimines has been developed for the synthesis of chiral
-trifluoromethylamines. The trifluoromethyl ketimines, generated in situ from the corresponding hemiaminals, led to the chiral amides in
high yields (71 89%) and excellent enantiocontrol (91 99% ee).
r,r,r
−
−
The incorporation of lipophilic trifluoromethyl groups in
bioactive compounds is a popular strategy to increase their
bioavailabilities by increasing their ability to cross mem-
branes. In addition, the strength of the carbon-fluorine bond
generally results in an increased metabolic stability relative
to that of the parent C-H analogue.1 Although there are
many known methods for the enantioselective synthesis of
tertiary chiral amines bearing a trifluoromethyl group, the
majority rely on the use of chiral auxiliaires.2,3 Even though
there are a number of catalytic asymmetric additions of di-
organozinc reagents to aldimines,4 extension of these ap-
proaches to ketimines has not been reported so far. We have
recently reported a copper-catalyzed asymmetric addition of
diorganozinc reagents to N-phosphinoylimines involving bis-
(phosphine) monoxide ligand 3 (Scheme 1).5 Herein, we
report a new method for the preparation of R-trifluoromethyl-
substituted amines based on this asymmetric transformation
and the use of a new precursor to imine 4.
Scheme 1. Synthesis of R-Chiral Amines
Although N-phosphinoylimines derived from ketones are
significantly less reactive than those synthesized from
aldehydes, it was anticipated that trifluoromethyl-substituted
imines 4 should display reactivities similar to those of the
corresponding aldimines. No addition to imine 5 was
observed upon treatment with diethylzinc (3 equiv), Cu(OTf)2
(5 mol %), and BozPHOS (3, 5 mol %) and quenching
experiments with deuterium oxide indicated that deprotona-
(1) (a) Organofluorine Compounds: Chemistry and Applications; Hiya-
ma, T., Ed.; Springer: New York, 2000. (b) Fluorine-Containing Molecules.
Structure, ReactiVity, Synthesis, and Applications; Liebman, J. F., Greenberg,
A., Dolbier, W. R., Eds.; VCH: Weinheim, 1988.
10.1021/ol0607847 CCC: $33.50
© 2006 American Chemical Society
Published on Web 05/27/2006

tion to generate the R-metalloimine was the main reaction
pathway instead of nucleophilic addition.
Scheme 3. NMR Monitoring of Hemiaminal Formation
The synthesis of an N-phosphinoylketimine using the Stec
reaction6 was accomplished in moderate to good yields from
acetophenone (Scheme 2).7
Scheme 2. Synthesis of N-Phosphinoylketimines
equiv of ketone). Although we could detect significant
quantities (up to 10%) of imine 4b by NMR monitoring of
the reaction, all of our attempts to isolate it from this reaction
mixture were unsuccessful, since it underwent rapid hy-
drolysis back to ketone 6b upon workup. However, the latter
was recycled in all of the reactions. Hemiaminal 10b was a
convenient starting material and surrogate for imine 4b
because it could be isolated as a colorless, air-stable and easy
to manipulate solid. Furthemore, previous results from our
laboratory established that ethylzinc ethoxide (the possible
byproduct resulting from the hemiaminal decomposition into
the imine) was a compatible additive in the copper-catalyzed
nucleophilic addition chemistry.9
However, when these conditions were applied to trifluoro-
acetophenone, only low yields of imine 4a were observed.8
A screening of several Lewis acids to mediate the condensation
between R,R,R-trifluoro-4-bromoacetophenone (6b) and P,P-
diphenyl phosphinamide (8) did not lead to any improvement
in the yield of 4b. However, hemiaminal 10b was obtained
when Ti(OEt)4 was used as the Lewis acid (Scheme 3). 19F
NMR monitoring of the reaction indicated that when 6b
(-72.3 ppm) was mixed with 8 and Ti(OEt)4, 9b was rapidly
formed (broad singlet between -80.5 and -81.5 ppm) along
with residual ketone. The integration of this species (9b)
slowly decreased over time, forming in its place hemiaminal
10b (-78.2 ppm) and a small amount of imine 4b (-70.8
ppm). Although this transformation was extremely slow and
the various compounds were in equilibrium, only a small
amount of imine 4b was formed (after 4 days and using 3
The isolated yield of hemiaminals 10a-10f from various
trifluoromethyl ketones ranged between 47% and 63% (Table
1).10 We envisioned that hemiaminals 10 could be used to
(2) (a) Bravo, P.; Capelli, S.; Meille, S. V.; Viani, F.; Zanda, M.Tetrahe-
dron: Asymmetry 1994, 5, 2009. (b) Bravo, P.; Capelli, S.; Meille, S. V.;
Seresini, P.; Volonterio, A.; Zanda, M. Tetrahedron: Asymmetry 1996, 7,
2321. (c) Bravo, P.; Crucianelli, M.; Vergani, B.; Zanda, M. Tetrahedron
Lett. 1998, 39, 7771. (d) Ishii, I.; Miyamoto, F.; Higashiyama, K.; Mikami,
K. Tetrahedron Lett. 1998, 39, 1199. (e) Bravo, P.; Fustero, S.; Guidetti,
M.; Volonterio, A.; Zanda, M. J. Org. Chem. 1999, 64, 8731. (f) Crucianelli,
M.; Bravo, P.; Arnone, A.; Corradi, E.; Meille, S. V.; Zanda, M. J. Org.
Chem. 2000, 65, 2965. (g) Asensio, A.; Bravo, P.; Crucianelli, M.; Farina,
A.; Fustero, S.; Soler, J. G.; Meille, S. V.; Panzeri, W.; Viani, F.; Volonterio,
A.; Zanda, M. Eur. J. Org. Chem. 2001, 1449. (h) Enders, D.; Funabiki, K.
Org. Lett. 2001, 3, 1575. (i) Surya Prakash, G. K.; Mandal, M.; Olah, G.
A. Angew. Chem., Int. Ed. 2001, 40, 589. (j) Surya Prakash, G. K.; Mandal,
M.; Olah, G. A. Org. Lett. 2001, 3, 2847. (k) Crucianelli, M.; De Angelis,
F.; Lazzaro, F.; Malpezzi, L.; Volonterio, A.; Zanda, M. J. Fluorine Chem.
2004, 125, 573. (l) Gosselin, F.; Roy, A.; O’Shea, P. D.; Chen, C.; Volante,
R. P. Org. Lett. 2004, 6, 641. (m) Wang, H.; Zhao, X.; Li, Y.; Lu, L. Org.
Lett. 2006, 8, 1379.
Table 1. Synthesis of Hemiaminals 10a-10f13
entry
Ar (ketone)
Ph (6a)
yield (%)
product
1
2
3
4
5
6
47
56
53
46
51
63
10a
10b
10c
10d
10e
10f
4-BrC6H4 (6b)
3-MeC6H4 (6c)
4- MeC6H4 (6d)
2-naphthyl (6e)
4-ClC6H4 (6f)
(3) For a catalytic asymmetric reduction of trifluoroketimines: Gosselin,
F.; O’Shea, P. D.; Roy, S.; Reamer, R. A.; Chen C.; Volante R. P. Org.
Lett. 2005, 7, 355.
(4) (a) Fujihara, H.; Nagai, K.; Tomioka, K. J. Am. Chem. Soc. 2000,
122, 12055. (b) Hayashi, T.; Ishigedani, M. J. Am. Chem. Soc. 2000, 122,
976. (c) Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. J.
Am. Chem. Soc. 2001, 123, 10409. (d) Dahmen, S.; Bra¨se, S. J. Am. Chem.
Soc. 2002, 124, 5940.
(5) (a) Boezio, A. A.; Pytkowicz, J.; Coˆte´, A.; Charette, A. B. J. Am.
Chem. Soc. 2003, 125, 14260. (b) Boezio, A. A.; Charette, A. B. J. Am.
Chem. Soc. 2003, 125, 1692.
generate the corresponding imines in situ. This was con-
firmed by spectroscopically observing the formation of the
imine when diethylzinc was added to a solution of the pure
hemiaminal in CD2Cl2. Several other titanium-based Lewis
(6) Krzyzanowska, B.; Stec, W. J. Synthesis 1982, 270.
(9) Coˆte´, A.; Boezio, A. A.; Charette, A. B. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5405.
(10) Trifluoromethyl ketones 6c and 6e were prepared according to
literature procedures: (a) Creary, X. J. Org. Chem. 1987, 52, 5026. (b)
Chong, J. M.; Mar, E. K. J. Org. Chem. 1991, 56, 893. Other ketones were
commercially available.
(7) (a) Masumoto, S.; Usuda, H.; Suzuki, M.; Kanai, M.; Shibasaki, M.
J. Am. Chem. Soc. 2003, 125, 5634. (b) Lipshutz, B. H.; Shimizu, H. Angew.
Chem., Int. Ed. 2004, 43, 2228.
(8) See also: Jennings, W. B.; O’Shea, J. H.; Schweppe, A. Tetrahedron
Lett. 2001, 42, 101.
2744
Org. Lett., Vol. 8, No. 13, 2006

acids were tested, but lower yields of the hemiaminal adduct
and/or of the imine were observed.11,12
Although the absolute stereochemistry for most entries was
not unambiguously established, an X-ray crystal structure
of the product in entry 4 was obtained with a suitable value
for the Flack parameter (-0.047(18)), confirming that the
absolute chemistry was consistent with that observed for the
addition to aldimines (Figure 1).
With the trifluoromethylimines in hand, the nucleophilic
addition chemistry was tested using our optimized set of
reaction conditions.14 When hemiaminal 10a was treated with
3.0 equiv of Et2Zn, Cu(OTf)2 (10 mol %) and (R,R)-
BozPHOS (5 mol %), the desired product was obtained in
high yield and high enantioselectivity (Table 2, entry 1). The
Table 2. Nucleophilic Addition to Hemiaminal 10a-10f
Figure 1. ORTEP Representation of protected amine 14.
entry
starting material
R (product)
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
Ph (10a)
Ph (10a)
Et (11)
Me (12)
Et (13)
Me (14)
Et (15)
Me (16)
Et (17)
Et (18)
Et (19)
83
85
71
89
78
84
77
73
71
91
99
95
97
95
99
97
94
93
The cleavage of the N-phosphinoyl group is usually quite
facile. However, in this case, the free amine was obtained
obtained by heating the phosphinamide 13 in concentrated
hydrochloric acid at 90 °C for 9 h (Scheme 4).15
4-BrC6H4 (10b)
4-BrC6H4 (10b)
3-MeC6H4 (10c)
3-MeC6H4 (10c)
4-MeC6H4 (10d)
2-naphthyl (10e)
4-ClC6H4 (10f)
Scheme 4. Cleavage of the N-Phosphinoyl Group
enantiomeric excesses ranged from 91% to 97% for the ethyl
group transfer to the various substrates. The addition of less
reactive dimethylzinc proceeded well. For the three substrates
that were tested, the enantiomeric excesses were higher for
methyl group transfer than for ethyl (Table 2, entry 1 vs 2;
3 vs 4; and 5 vs 6). This is in contrast with our previous
report for the addition to aldimines.
In summary, we have developed the first catalytic asym-
metric synthesis of R-alkyl-R-aryl-R-trifluoromethylamines.
The reaction proceeds with high stereocontrol from a novel
stable imine precursor.
(11) TiCl(OEt)3: 22% yield of ethanol adduct. Ti(OMe)4: 8% yield of
methanol adduct. TiCl4: 23% yield of ketimine.
(12) Si(OEt)4, an efficient reagent for the preparation of N-tosylimines
led to a 15% yield of the hemiaminal: Love, B. E.; Raje, P. S.; Williams,
T. C., II. Synlett 1994, 7, 493.
Acknowledgment. This work was supported by the
National Science and Engineering Research of Canada
(NSERC), Merck Frosst Canada & Co., Boehringer Ingel-
heim (Canada), Ltd., and the Universite´ de Montre´al.
(13) General Procedure for the Synthesis of the Hemiaminal. To a
solution of P,P-diphenylphosphinic amide (167 mg, 0.77 mmol, 1.1 equiv)
in CH2Cl2 (7 mL) was added the trifluoromethyl ketone (2.1 mmol, 3.0
equiv) and titanium ethoxide (294 µL, 1.4 mmol, 2.0 equiv). After stirring
at room temperature for 96 h, the reaction was quenched with a mixture of
Na2SO4‚10H2O (2 g) and sand (5 g). Then CH2Cl2 (250 mL) was added,
and the reaction was stirred at room temperature for 30 min. The suspension
was filtered and washed with CH2Cl2 (3 × 100 mL). The organic layers
were dried over Na2SO4. Concentration and purification by flash chroma-
tography gave the hemiaminal as a colorless white solid. The residual ketone
could be isolated in the first few fractions of the chromatography.
(14) General Procedure for the Addition Reaction. Anhydrous toluene
(2 mL) was added to (R,R)-BozPHOS (6.1 mg, 0.019 mmol, 0.05 equiv)
and Cu(OTf)2 (14 mg, 0.038 mmol, 0.10 equiv). The resulting heterogeneous
dark green solution was stirred for 1 h at room temperature. Neat diethylzinc
(117 µL, 1.14 mmol, 3.0 equiv) was added at room temperature, and the
resulting red-brown suspension was stirred for an additional 20 min, before
being cooled to 0 °C. After 10 min, a cooled solution (0 °C) of the
hemiaminal (0.38 mmol, 1.00 equiv) in toluene (1 mL + 1 mL for washing)
was cannulated (using a Teflon cannula) into the catalyst suspension. After
stirring 16 h at 0 °C, the reaction was quenched with saturated NH4Cl (7
mL), and the aqueous phase was washed with CH2Cl2 (3 × 15 mL). The
combined organic layers were dried over Na2SO4 and concentrated under
reduced pressure, and the residue was purified by flash chromatography to
give the corresponding addition product as a white solid.
Supporting Information Available: Experimental pro-
cedures and data for each reaction, characterization spectra
for new compounds, and a CIF file for compound 14. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0607847
(15) Representative Procedure for the Cleavage of the Phosphinoyl
Group. Compound 13 (0.446 mmol, 1.0 equiv) was dissolved in 3 mL of
concentrated aqueous HCl. The mixture was heated to 90 °C for 9 h. The
reaction was cooled to room temperature and neutralized with aqueous
NaOH (1 M). The mixture was extracted with CH2Cl2 (3 × 7 mL), and the
combined organic layers were dried over Na2SO4. The mixture was
concentrated to give the free amine. The amine was crystallized as its
hydrochloride salt from CH2Cl2 using a solution of HCl in Et2O (1 M)
(4.46 mmol, 10.0 equiv) to give a white solid.
Org. Lett., Vol. 8, No. 13, 2006
2745