Stable preformed chiral palladium catalysts for the one-pot asymmetric reductive amination of ketones

Article abstract of DOI:10.1021/ol802336m

(Chemical Equation Presented) The application of air stable preformed [(R)-BINAP]PdBr₂, [(S)-BINAP]PdBr₂, [(R)-Tol-BINAP] PdBr₂, and [(S,S)-CHIRAPHOS]PdBr₂ complexes in the one-pot asymmetric reductive amination

Full text of DOI:10.1021/ol802336m

ORGANIC
LETTERS
2009
Vol. 11, No. 2
265-268
Stable Preformed Chiral Palladium
Catalysts for the One-Pot Asymmetric
Reductive Amination of Ketones
Laura Rubio-Pe´rez,* F. Javier Pe´rez-Flores, Pankaj Sharma, Luis Velasco, and
Armando Cabrera
Instituto de Qu´ımica, UniVersidad Nacional Auto´noma de Me´xico, Circuito Exterior,
Ciudad UniVersitaria, Me´xico, 04510, D. F., Me´xico
laurarpz@correo.unam.mx
Received October 8, 2008
ABSTRACT
The application of air stable preformed [(R)-BINAP]PdBr2, [(S)-BINAP]PdBr2, [(R)-Tol-BINAP]PdBr2, and [(S,S)-CHIRAPHOS]PdBr2 complexes in
the one-pot asymmetric reductive amination of various carbonyl compounds, leading to chiral amines in very good yields with high
enantioselectivities (<99% ee), is reported.
Chiral amines are key compounds in pharmaceutical, agro-
chemical, and materials industries.1 Lower aliphatic amines
are used as organic intermediates for the synthesis of
bactericides, drugs, herbicides, rubber accelerators, corrosion
inhibitors, and surface-active agents.2,3 Their formation drives
the development of efficient methods as catalytic asymmetric
reactions. Some of the past studies in this field have focused
on the enantioselective reduction of a C-N double bond,
using a variety of chiral Pd, Ti, Rh, and Ir complexes.4,5
Recently, the direct reductive amination (DRA) of ketones/
aldehydes with amines is an elegant and powerful tool used
for the syntheses of structurally diverse amines in modern
organic chemistry; the advantage of this reaction is that there
is no need to isolate intermediate imines.6 A few preliminary
studies on selected asymmetric reductive aminations of
(4) For a general review of the reduction of imines, see: (a) Vilaivan,
T.; Bhanthumnavin, W.; Sritana-Anant, Y. Curr. Org. Chem. 2005, 9, 1315.
(b) Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069. (c) Cho, B. T.
Tetrahedron 2006, 62, 7621.
(5) For reduction of imines catalyzed by Ti, Ru, Rh, Ir, and Pd, see: (a)
Willoughby, C. A.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 11703.
(b) Verdaguer, X.; Lange, U. E. W.; Reding, M. T.; Buchwald, S. L. J. Am.
Chem. Soc. 1996, 118, 6784. (c) Hanson, M. C.; Buchwald, S. L. Org.
Lett. 2000, 2, 713. (d) Cheemala, M. N.; Knochel, P. Org. Lett. 2007, 9,
3089. (e) Moessner, C.; Bolm, C. Angew. Chem., Int. Ed. 2005, 44, 7564.
(1) (a) Main, B. G.; Tucker, H. In Medicinal Chemistry, 2nd ed.;
Genellin, C. R., Roberts, S. M., Eds.; Academic Press: New York, 1993;
p187. (b) Gro¨ger, H.; May, O.; Werner, H.; Menzel, A.; Altenbuchner, J.
Org. Process Res. DeV. 2006, 10, 666. (c) Chen, B.; Dingerdissen, U.;
Krauter, J. G. E.; Rotgerink, G. J. L.; Mo¨bus, K.; Ostgard, D. J.; Panster,
P.; Riermeier, T. H.; Seebald, S.; Tacke, T.; Trauthwein, H. Appl. Catal.,
A 2005, 280, 17.
´
(f) Vargas, S.; Rubio, M.; Sua´rez, A.; R´ıo, D. D.; Alvarez, E.; Pizzano, A.
Organometallics 2006, 25, 961. (g) Guiu, E.; Aghmiz, M.; Diaz, Y.; Claver,
C.; Meseguer, B.; Militzer, C.; Castillo´n, S. Eur. J. Org. Chem. 2006, 627.
(h) Iwadate, N.; Yoshida, K.; Imamoto, T. Org. Lett. 2006, 8, 2289. (i)
Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem.
Soc. 1996, 118, 4916. (j) Samec, J. S. M.; Ba¨ckvall, J. E. Chem.sEur. J.
2002, 8, 2955. (k) Cobley, C. J.; Henschke, J. P. AdV. Synth. Catal. 2003,
345, 195. (l) Abe, H.; Ammii, H.; Uneyama, K. Org. Lett. 2001, 3, 313.
(6) Hutchins, R. O.; Hutchins, M. K. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol.
8, p 25.
(2) (a) Merla, B.; Risch, N. Synthesis 2002, 1365. (b) Henkel, T.; Brunni,
R. M.; Mueller, H.; Reichert, F. Angew. Chem., Int. Ed. Engl. 1993, 38,
643. (c) Bhanushali, M.; Nandurkar, N. S.; Bhor, M. D.; Bhanage, B. M.
Tetrahedron Lett. 2007, 48, 1273
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(3) Sharp, D. B. In Herbicides: Chemistry, Degradation and Mode of
Action; Kearney, P. C., Kaufman, D. D., Eds.; Marcel Dekker: New York,
1988; Chapter 7.
10.1021/ol802336m CCC: $40.75
Published on Web 12/18/2008
2009 American Chemical Society

ketones, giving chiral branched amines in an enantioface-
differentiating process have been reported.7,8 Blaser et al.
have presented the first example of asymmetric direct
reductive amination using Ir-Xyliphos complex as catalyst.9
In other reports, organocatalytic10 and hydrogen transfer11
approaches were used. Hence, there is a continuing need for
convenient methods for the synthesis of chiral amines from
ketones. On the other hand, chiral palladium diphosphosphine
complexes have been employed as catalysts for many organic
syntheses.12 Changes in the geometry of diphosphine ligands,
steric and electronic factors, may lead to drastic variations
on the reactivity and stereocontrol.
Scheme 1. Synthesis of Chiral Pd-Catalysts
In our research on the carbonylation of imines, we found
an interesting competitive reduction process. Here we wish
to present the novel use of preformed air stable chiral
palladium catalysts in the asymmetric reductive amination
of a series of alkyl, cycloaliphatic, and aromatic carbonyl
compounds with aniline derivatives, using molecular sieves13
and hydrogen pressure to synthesize chiral secondary amines.
These results appear to be the first report on the application
of these complexes in the one-pot reductive amination
reactions of carbonyl compounds. Here we also report, the
X-ray structures of [(R)-BINAP]PdBr2 and [(S,S)-CHIRA-
PHOS]PdBr2.
1 and 2, respectively. Palladium has a distorted square planar
geometry in both complexes. The P-Pd-P bite angle of the
(R)-BINAP ligand (92.58(5)°) in 1b is similar to analogous
Table 1. Asymmetric Reductive Amination of 2aa
Scheme 1 illustrates the different preformed chiral (diphos-
phine) palladium(II) dibromide complexes employed in this
study. These were prepared by the reaction of (MeCN)2PdBr2
with the corresponding diphosphine ligands in benzene.
In our initial practice, the asymmetric reductive amination
of compound 2a with 3a was tested in the presence of the
chiral palladium catalysts in CHCl3 solvent at 70 °C for 24 h
(Table 1). Both 1b and 1d are good catalysts, as they produce
high enantioselectivities (76 and 77% ee respectively). The
best yield is obtained when complex 1b is used (81%).
However, the reaction catalyzed by 1e, is less active than
1b or 1d yielding 45% of product with 14% ee.
entry
catalyst
yieldb (%)
eec (%)
1
2
3
4
5
1a
1b
1c
1d
1e
83
81
43
55
45
76
17d
77
14
a Reactions were carried out with 2.5 mol % of catalyst, 1.0 mmol of
2-heptanone (2a), 1.5 mmol of p-anisidine (3a), 150 mg of 5 Å ms, 10 mL
CHCl3 and H2 (800 psi) at 70 °C for 24 h. b Isolated yield. c The ee values
were determined by HPLC. d Reaction was carried out at rt.
The X-ray structures of [(R)-BINAP]PdBr2 (1b) and [(S,S)-
CHIRAPHOS]PdBr2 (1e) complexes are shown in Figures
[(R)-BINAP]PdCl2 complex (92.68(8)°).14 The Pd-P and
Pd-Br distances are 2.2499(9) and 2.4766(5) Å, respectively.
On the other hand, 1e exhibits a P-Pd-P bite angle equal
to 86.05(5)°, which is shorter than that found in complex
1b, where the Pd-P and Pd-Br distances are 2.2320(6) and
2.4737(1) Å, respectively. A larger bite angle and ligand
flexibility exhibited by the ligand in complex 1bplay a crucial
role during the reaction, as noted by complex 1e being less
efficient, leading to the formation of 4a in low yield and
poor stereocontrol.
To probe the generality of catalyst 1b or 1c, a series of
alkyl and cycloaliphatic ketones were evaluated, using o-,
m- and p-substituents on aniline derivatives (Table 2). All
reactions were carried out in chloroform under 800 psi of
hydrogen pressure with 2.5 mol % of the catalyst. The results
were obtained with respect to isolated yield and enantiose-
lectivity of products, demonstrating the generality of the
asymmetric reductive amination. The reactions of 2-hep-
tanone with 3b and 3c gave the 4b and 4c in good yields
(7) For a review on asymmetric reductive amination, see: Tararov, V. I.;
Bo¨rner, A. Synlett 2005, 203
.
(8) For asymmetric reductive aminations catalyzed by metal complexes,
see: (a) Tararov, V. I.; Kadyrov, R.; Riermeier, T. H.; Bo¨rner, A. Chem.
Commun. 2000, 1867. (b) Chi, Y. X.; Zhou, Y. G.; Zhang, X. J. Org. Chem.
2003, 68, 4120. (c) Kadyrov, R.; Riermeier, T. H.; Dingerdissen, U.;
Tararov, V.; Bo¨rner, A. J. Org. Chem. 2003, 68, 4067. (d) Salmi, Ch.;
Letourneux, Y.; Brunel, J. M. Lett. Org. Chem. 2006, 3, 384. (e) Nugent,
T. C.; Wakchaure, V. N.; Ghosh, A. K.; Mohanty, R. R. Org. Lett. 2005,
7, 4967. (f) Zhang, X. Asymmetric Reductive Amination of Ketones. U.S.
Patent WO2004058982, 2004
.
(9) Blaser, H.-U.; Buser, H.-P.; Jalett, H.-P.; Pugin, B.; Spindler, F.
Synlett 1999, 867.
(10) For organocatalytic reductive aminations, see: (a) Storer, R. I.;
Carrera, D. E.; Ni, Y.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128,
84. (b) Hoffmann, S.; Seayad, A. M.; List, B. Angew. Chem., Int. Ed. 2005,
44, 7424.
(11) For transfer hydrogen in reductive aminations, see: (a) Williams,
G. D.; Pike, R. A.; Wade, C. E.; Will, M. Org. Lett. 2003, 5, 4227. (b)
Kadyrov, R.; Riermeier, T. H. Angew. Chem., Int. Ed. 2003, 42, 5472.
Reductive amination via dynamic kinetic resolution, see: (c) Hoffmann,
S.; Nicoletti, M.; List, B. J. Am. Chem. Soc. 2006, 128, 13074.
(12) (a) McCarthy, M.; Guiry, P. J. Tetrahedron 2001, 57, 3809. (b)
Shimizu, H.; Nagasaki, I.; Saito, T. Tetrahedron 2005, 61, 5405.
(13) Molecular sieves were used to absorb water molecules, which
are generated by the condensation between the ketone and the aromatic
amine.
(14) Ozawa, F.; Kubo, A.; Matsumoto, Y.; Hayashi, T.; Nishioka, E.;
Yanagi, K.; Moriguchi, K. Organometallics 1993, 12, 4188.
266
Org. Lett., Vol. 11, No. 2, 2009

Table 2. Asymmetric Reductive Amination of Alkyl Ketonesa
Figure 1. X-ray structure of [(R)-BINAP]PdBr2 complex (1b).
Selected bond lengths (Å) and angles (deg): Pd1-P1 2.2468(8),
Pd1-P1A 2.2468(8), Pd1-Br1 2.4742(4), Pd1-Br1A 2.4742(4),
P1-Pd1-P1A 92.66(4), Br1-Pd1-Br1A 93.70(2), P1-Pd1-Br1
91.12(2), P1A-Pd-Br1A 91.12(2), P1-Pd1-Br1A 157.66(2),
P1A-Pd1-Br1 157.66(2).
(51-84%, entries 1-2), but the best enantioselectivity was
observed when m-trifluoromethyl aniline (3c) is used (95%
ee). In the case of 3-heptanone with 3d and 3e gave the
Figure 2. X-ray structure of [(S,S)-CHIRAPHOS]PdBr2 complex
(1e). Selected bond lengths (Å) and angles (deg): Pd-P1 2.2305(1),
Pd-P2 2.2336(1), Pd-Br1 2.4704(6), Pd-Br2 2.4769(6); P1-C2
1.865(5), P2-C3 1.858(5), P1-Pd1-P2 86.05(5), Br1-Pd-Br2
94.10(2), P1-Pd-Br1 89.38(4), P2-Pd-Br2 90.67(4), P2-Pd-Br1
174.79(4), P1-Pd- Br2 174.00(4).
desired products with moderate enantioselectivities (entries
3-4, 49-59% ee). A marked stereochemical effect was
observed with respect to the position of the carbonyl group
of the substrate (entries 1 and 4). 2-Butanone was reductively
aminated with o-, m- and p-aniline derivatives (3g-j) and
the products were obtained in good yields (71-87%, entries
6-9). It is noted that the highest enantioselectivity (entry 6,
99% ee) was achieved when p-methylaniline (3g) was used.
Good enantioselectivities were observed in the presence of
o- and m-trifluoro methylanilines (entries 8 and 9, 82 and
75% ee, respectively). On the basis of these results, we
observed that the presence of substituents on the aniline
improves stereoselectivity with a little effect on reactivity.
R,ꢀ-unsaturated carbonyl compounds as 3-penten-2-one leads
to secondary amine 4k alone the one reduction of the double
bond C-C, giving a slight enantiomeric excess of 10% (entry
10). It is noteworthy that substituted or sterically hindered
aliphatic carbonyl compounds all reacted well to give chiral
a Reactions were carried out with 2.5 mol % of catalyst 1b, 1.0 mmol
of ketone, 1.5 mmol of aniline derivative, 150 mg of 5 Å ms, 10 mL CHCl3,
and H2 (800 psi) at 70 °C for 24 h. b Isolated yield. c The ee values were
determined by HPLC. d The de and ee values were determined by chiral
GC-MS (EI). e Realized with catalyst 1c. f Realized with catalyst 1a.
g Absolute configurations were not determined. h Absolute configuration was
determined by derivatizing to 2-butylamine hydrochloride and comparing
with the assigned optical rotation reported in the literature. i These values
correspond to two pairs of diastereomers.
amines (4l-4p) with moderate to high ee values of 51-96%
and yields of 71-83% (entries 11-15). When commercially
available, 2-sec-butylcyclohexanone (mixture of diastereo-
mers) is used, and chiral amine 4q was obtained with three
chiral centers (entry 16). One would expect a mixture of four
Org. Lett., Vol. 11, No. 2, 2009
267

pairs of diastereomers, but interestingly, the mixture has only
two pairs of diastereomers with 53 and 66% of diastereo-
meric excess respectively, which shows also the diastereo-
selectivity of the reaction using 1b complex (see Supporting
Information). 2,3-Butanedione underwent chemoselective
A series of aryl ketones (5a-e) were subjected to the
asymmetric reductive amination with substituted anilines
(Table 3). The reaction occurs generally with moderate yields
(entries 1-5, 53-67%) and low enantiomeric excess
(34-43%). The simplest aryl ketone 5a was reductively
aminated with 43% ee (entry 1). When the alkyl group of
aryl ketone was changed from Me to Et, the ee dropped from
35 to 34% respectively (entries 3 and 5).
It is interesting to note that there are some examples in
the asymmetric reductive amination of ketones where aryl
ketones are aminated in high ee and aliphatic or cy-
cloaliphatic ketones are aminated in lower ee, which is
opposite to what we observed here.15
Table 3. Asymmetric Reductive Amination of Aryl Ketonesa
In summary, chiral (diphosphine) palladium(II) dibromide
catalysts promote in one-pot the asymmetric reductive
amination of aliphatic, cycloaliphatic ketones in good yields
with moderate to high enantiomeric excess. It is evident that
these palladium systems are effective and induce enantiose-
lectivity on reduction of the iminic intermediate (formed in
situ). This stage is probably the limiting step in the
transformation.
entry cat.
R1
R2
R3
yieldb (%) eec (%) (config)
1
2
3
4
5
1b
H
Me 5a
H
64
67
65
53
57
43 (R)d
38 (+)e
35 (R)d
38 (+)e
34 (+)e
1c p-Me Me 5b p-Me
1d Me 5c p-OMe
1b p-Me Me 5d p-OMe
1d Et 5e p-OMe
H
H
a Reactions were carried out with 2.5 mol % of catalyst, 1.0 mmol of
ketone, 1.5 mmol of aniline derivative, 150 mg of 5 Å ms, 10 mL of CHCl3,
and H2 (800 psi) at 70 °C for 24 h. b Isolated yield. c The ee values were
determined by HPLC. d Absolute configurations were determined by
comparison of optical rotation reported in the literature. e Absolute
configurations were not determined.
Acknowledgment. We thank Dr. Rube´n Toscano and
Simo´n Herna´ndez (IQ-UNAM) for the X-ray structural
determination of 1b and 1e, and Carmen Ma´rquez (IQ-
UNAM) for the HPLC analyses. This work was supported
by CONACyT (166350) and DGAPA (IN209206).
Supporting Information Available: Experimental pro-
cedures, spectral data for all products, chiral GC-MS (EI)
or HPLC data, and X-ray structures for 1b and 1e (CIF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
reductive amination with 4r and 4s to yield monoaminated
products, which were isolated in good yields (entries 17-18,
83-85%) and low enantiomeric excess (20-2% ee).
In all entries, when the crude reaction products were
analyzed by GC-MS (EI), we observed that the catalytic
palladium system does not promote the reduction of ketone
to the corresponding secondary alcohol.
OL802336M
(15) See references 7, 8, and 10a.
268
Org. Lett., Vol. 11, No. 2, 2009