Catalytic asymmetric hydrogenation of N-iminopyridinium ylides: Expedient approach to enantioenriched substituted piperidine derivatives

Article abstract of DOI:10.1021/ja0525298

We have developed an efficient catalytic enantioselective hydrogenation of pyridine derivatives. Enhanced reactivity was possible by an optimization of the electronic properties of the catalyst through ligand modification. This methodology shows the parti

Full text of DOI:10.1021/ja0525298

Published on Web 06/04/2005
Catalytic Asymmetric Hydrogenation of N-Iminopyridinium Ylides: Expedient
Approach to Enantioenriched Substituted Piperidine Derivatives
Claude Y. Legault and Andre´ B. Charette*
De´partement de Chimie, UniVersite´ de Montre´al, P.O. Box 6128, Station Downtown,
Montre´al (Que´bec) Canada H3C 3J7
Received April 19, 2005; E-mail: andre.charette@umontreal.ca
Table 1. Effect of Additives in the Hydrogenation
Since the piperidine unit is an extremely important pharmacoph-
ore that can be found in many natural and synthetic bioactive
compounds, numerous methodologies have been developed to
access them.1 Recently, our group became interested in the
asymmetric synthesis of these chiral building blocks using nucleo-
philic addition to pyridinium salts2 and N-benzoyliminopyridinium
ylides.3 Although the methods are quite successful, the regioselec-
tivity of attack of the nucleophile is critical and can lead to multiple
regioisomers.
The wide spectrum of structurally diverse commercially available
substituted pyridines and the numerous methods to generate them4
led us to investigate the asymmetric catalytic hydrogenation of
pyridine derivatives to access enantiomerically enriched piperidine
derivatives. This has been a long-standing problem in synthesis,
and it is only recently that an efficient chiral auxiliary-based method
was developed by Glorius.5,6 Although the asymmetric hydrogena-
tion of quinoline derivatives is feasible in high enantiomeric
excesses,7 the only known examples of catalytic asymmetric
hydrogenation of substituted pyridines are rare, limited in scope,
and give modest enantioselectivities (<30% ee).8 In this com-
munication, we wish to report our initial findings on the develop-
ment of the first highly enantioselective catalytic asymmetric
hydrogenation of N-acyliminopyridinium ylides.
entry
additive
x (mol %)
conv. (%)a
ee 5a (%)b
1
2
3
4
5
none
TBAI
I2
I2
I2
24
45
>95 (86)
94
8
8
13
9
5
2
10
50
<5
a Conversions were determined by 1H NMR; isolated yield shown in
parentheses. b Enantiomeric excesses were determined by HPLC using a
chiral stationary phase. The absolute stereochemistry was determined by
derivatization (see Supporting Information for details).
Table 2. Catalyst Optimizationa
Since the iridium-catalyzed hydrogenation of imines is among
the best catalytic system for the reduction of imines,9 we decided
to initially focus our attention on these complexes to test the
reactivity of different pyridine derivatives. The preliminary catalyst
screening indicated that among compounds 1-4, only pyridinium
4a10 was hydrogenated (>95% conversion) upon treatment with
H2 (550 psi) and the iridium catalyst ([Ir(COD)Cl]2 (1.2 mol %),
BINAP (2.6 mol %), I2 (8 mol %), CH2Cl2, rt, 20 h).
entry
Ar (cat.)
conv.(%)b
7a/5ab
yield (%)c
ee 5a (%)d
1e
2
3
4
5
6
7
Ph (8a)
Ph (8b)
>95
>95
10
>95
>95
>95
59
9/91
11/89
82
89
<5
83
>95
>95
20
68
87
o-tolyl (8c)
p-OMe (8d)
p-F (8e)
p-CF3 (8f)
C6F5 (8g)
13/87
13/87
12/88
7/93
84
90
81
4
a Unless otherwise stated, X ) BArF tetrakis(3,5-bis(trifluorometh-
1
yl)phenyl)borate. b Conversions and ratios were determined by H NMR.
c Yields of 5a + 7a determined by 1H NMR using an internal standard.
d Reported after hydrogenation of 7a to 5a. e X ) Cl.
An extensive screening of different ligands12 based on the above
protocol led to the finding that iridium complexes derived from
Pfaltz’s13 phosphinooxazolines (PHOX) ligands proved to be the
most promising in terms of enantioselectivities (Table 2, entry 1).
However, although the starting materials were completely con-
sumed, the yields of isolated products 5 were highly variable. Our
previous work on the addition of nucleophiles to pyridinium ylides3
and a closer look at the reaction process led us to conclude that
the rate of hydrogenation of the dihydropyridine intermediate 6 to
tetrahydropyridine 7 was critical to prevent its decomposition and
observing high yields for this reaction (Scheme 1).
As outlined in Table 1, the effect of added iodine is very
important in this reaction. We believe it mainly serves as an
oxidizing agent to convert an Ir(I) species to the active Ir(III)
catalyst. It has been already reported that Ir(III) catalysts are quite
efficient in the hydrogenation of imines.9b,e,f While TBAI has been
previously used as an activator of Ir(I) catalysts,9c,11 no noticeable
improvement in the catalytic activity was observed in our case,
indicating that oxidation of the metal is probably initially involved.
Replacement of the [Ir(COD)Cl]2 by [Rh(COD)Cl]2 renders the
system completely inactive. Attempts at generating directly an active
Ir(III) complex from IrCl3 failed. In addition, several other
complexes were tested (Ru‚BINAP, etc.), and they all proved to
be either inactive or not as active.
To resolve this issue, we optimized the catalyst structure by fine-
tuning the electronic properties of the phosphine substituents on
the ligand and by changing the nature of the counterion of the metal
9
8966
J. AM. CHEM. SOC. 2005, 127, 8966-8967
10.1021/ja0525298 CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1
can be converted to the corresponding piperidine derivatives by a
facile N-N bond cleavage (>85% yield) using either Raney
nickel3,17 or lithium in ammonia.3,18
In conclusion, we have developed an efficient catalytic enantio-
selective hydrogenation of pyridine derivatives. Enhanced reactivity
was possible by an optimization of the electronic properties of the
catalyst through ligand modification. We are currently investigating
the mechanistic aspects of the hydrogenation process as well as
improving the scope of the reaction through novel ligand design.
Table 3. Hydrogenation of N-Benzoyliminopyridinium Ylides
Acknowledgment. This work was supported by the National
Science and Engineering Research Council (NSERC) of Canada,
Merck Frosst Canada, Boehringer Ingelheim (Canada), and the
Universite´ de Montre´al. C.Y.L. is grateful to NSERC (PGS A and
B) and FCAR (B2) for postgraduate fellowships.
entry
R
yield 5 (%)a
ee 5 (%)b
products
1
2
2-Me
2-Et
2-Et
2-nPr
2-Bn
2-Bn
2-CH2OBn
2-(CH2)3OBn
2,3-Me2
98 (84)
96 (78)
60
98 (75)
97
65
85
88
90 (97)
83 (94)
78
84 (95)
58
50
76
88
54
5a
5b
5b
5c
5d
5d
5e
5f
Supporting Information Available: Experimental procedures and
spectral data of selected compounds (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
3c
4
5
6c
7
References
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Tetrahedron 2004, 60, 1701-1729. (b) Felpin, F.-X.; Lebreton, J. Eur. J.
Org. Chem. 2003, 3693-3712. (c) Weintraub, P. M.; Sabol, J. S.; Kane,
J. M.; Borcherding, D. R. Tetrahedron 2003, 59, 2953-2989. (d) Laschat,
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8
9
10
91 [>95:5]
92 [57/43]
5g
5h, 5h′
2,5-Me2
86/84
a Isolated yield after recrystallization is shown in parentheses; diaster-
eomeric ratios are shown in brackets. b Determined by HPLC. Enantiomeric
excesses after recrystallization are shown in parentheses. c Catalyst 8b was
used.
complex (Table 2). We screened a variety of counterions (BF4, OTf,
CF3CO2) and found that a cationic species bearing the tetrakis-
(3,5-bis(trifluoromethyl)phenyl)borate (BArF) counterion was su-
perior (entries 1 and 2).14 The use of a bulkier phosphine (entry 3)
led to a dramatic decrease of reactivity and almost no conversion.
Although the effect on the enantioselectivity was minimal, the use
of moderately electron-withdrawing substituents led to an increase
in yields (entries 5 and 6), the p-fluoro derivative being optimal.
However, in all the cases, there is a noticeable amount of remaining
tetrahydropyridine 7a upon reducing 4a, even with prolonged
reaction times. This can be attributed to a slower hydrogenation
rate of the isolated double bond and the inactivation of the catalyst
by formation of a hydride-bridged iridium trimer.15
(6) Other examples of diastereoselective hydrogenation of pyridines: (a)
Solladie´-Cavallo, A.; Marsol, C.; Yaakoub, M.; Azyat, K.; Klein, A.; Roje,
M.; Suteu, C.; Freedman, T. B.; Cao, X.; Nafie, L. A. J. Org. Chem.
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M.; Pinel, C. Tetrahedron Lett. 2003, 44, 6991-6993. (c) Douja, N.;
Besson, M.; Gallezot, P.; Pinel, C. J. Mol. Catal. A 2002, 186, 145-151.
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(7) (a) Lu, S.-M.; Han, P.-Y.; Zhou, Y.-G. AdV. Synth. Catal. 2004, 346,
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Y.-G. J. Am. Chem. Soc. 2003, 125, 10536-10537.
Using the optimized catalyst and procedure, we proceeded to
explore the scope and limitation of the methodology. We submitted
different substituted N-benzoyliminopyridinium ylides to the hy-
drogenation conditions, and the results are summarized in Table 3.
Although for every substrate the conversions were complete, in
some cases, small quantities of the remaining tetrahydropyridine
were detected. To avoid this, we proceeded to hydrogenate the crude
mixture over Pd/C.12
In most cases, the yields obtained are excellent, indicating that
a fast and efficient hydrogenation of the key dihydropyridine
intermediate takes place. This is in sharp contrast with the results
obtained with the unoptimized catalyst 8b (entries 3 and 6), where
a drop in yields and enantioselectivities was observed. These
findings clearly demonstrate the importance of the electronic
properties of the ligand in this reaction. Pyridinium ylide 4g afforded
only the cis diastereomer, albeit in low enantioselectivities. It
appears that the substitution at the 3-position is detrimental to the
enantioselectivities with this catalytic system.16 The low diastereo-
selectivity observed for substrate 4h, however, tends to indicate
that the enantioselectivity for the hydrogenation of a substituted
tetrahydropyridine 7 is low. It is also noteworthy to mention that
the reduced products are highly crystalline solids that can easily
be enriched by single recrystallization from boiling ethyl acetate
(entries 1, 2, and 4). Finally, the hydrogenation adducts obtained
(8) (a) Raynor, S. A.; Thomas, J. M.; Raja, R.; Johnson, B. F. G.; Belle, R.
G.; Mantle, M. D. Chem. Commun. 2000, 1925-1926. (b) Studer, M.;
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Exl, C. J. Mol. Catal. A 1999, 139, 253-257.
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Am. Chem. Soc. 2004, 126, 16142-16147. (b) Dorta, R.; Broggini, D.;
Stoop, R.; Ru¨egger, H.; Spindler, F.; Togni, A. Chem.sEur. J. 2004, 10,
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(10) The pyridinium ylides were synthesized from the corresponding pyridines
in one step using a one-pot amination/benzoylation procedure. Yields:
76-98%. For further information, see: Legault, C.; Charette, A. B. J.
Org. Chem. 2003, 68, 7119-7122 and references therein.
(11) (a) Morimoto, T.; Nakajima, N.; Achiwa, K. Synlett 1995, 748-750. (b)
Morimoto, T.; Nakajima, N.; Achiwa, K. Chem. Pharm. Bull. 1994, 42,
1951-1953.
(12) See Supporting Information for further details.
(13) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336-345.
(14) Use of BArF counterion in iridium-catalyzed hydrogenation: Lightfoot,
A.; Schnider, P.; Pfaltz, A. Angew. Chem., Int. Ed. 1998, 37, 2897-2899.
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(16) The hydrogenation of the 3-methylpyridinium ylide led to a low yield
and low enantiocontrol.
(17) Alexakis, A.; Lensen, N.; Tranchier, J.-P.; Mangeney, P.; Dupont-Feneau,
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