Asymmetric hydrogenation of imines catalyzed by iridium complexes with phosphine-phosphite ligands: Importance of backbone flexibility

Article abstract of DOI:10.1016/j.tetlet.2005.01.144

Chiral phosphine-phosphites provide an alternative class of ligands for the iridium catalyzed enantioselective hydrogenation of imines. Optimization of ligand structure has afforded enantioselectivities up to 84% ee in the reduction of N-aryl imines. A si

Full text of DOI:10.1016/j.tetlet.2005.01.144

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2049–2052
Asymmetric hydrogenation of imines catalyzed by
iridium complexes with phosphine–phosphite ligands:
importance of backbone flexibility
*
´ ´
Sergio Vargas, Miguel Rubio, Andres Suarez and Antonio Pizzano
´
´
Instituto de Investigaciones Quımicas, Consejo Superior de Investigaciones Cientıficas-Universidad de Sevilla,
´
Avda Americo Vespucio s/n, Isla de la Cartuja, 41092 Sevilla, Spain
Received 30 November 2004; revised 25 January 2005; accepted 26 January 2005
Abstract—Chiral phosphine–phosphites provide an alternative class of ligands for the iridium catalyzed enantioselective hydro-
genation of imines. Optimization of ligand structure has afforded enantioselectivities up to 84% ee in the reduction of N-aryl imines.
A significant influence of backbone nature on enantioselectivity has also been observed.
Ó 2005 Elsevier Ltd. All rights reserved.
Asymmetric catalytic hydrogenation of imines is a very
attractive approach to the synthesis of chiral amines
due to simplicity and efficiency often associated to enan-
ð1Þ
tioselective hydrogenation.1 However, despite the great
advances achieved in the reduction of ketones and
olefins, the hydrogenation of prochiral imines is at a
substantially lower maturity.2 For instance, good to
Chiral phosphine–phosphites form a group of ligands
excellent results have been obtained in the hydrogena-
receiving a growing interest in asymmetric catalysis.10
They have been applied successfully in a variety of cat-
alytic processes, but to the best of our knowledge they
tion of several N-alkyl, -benzyl3 and cyclic imines,4 while
the hydrogenation of N-aryl imines (Eq. 1), a transfor-
mation of great interest due to the importance of corre-
have not been investigated in the hydrogenation of
sponding chiral amines,5 has offered significant
imines. We have recently described a straightforward
difficulties. Thus, intense efforts have been dedicated to
synthesis of a family of modular phosphine–phosphites
the study of this reaction and only few catalysts have
and its application in the highly enantioselective hydro-
been able to surpass the 80% ee level.6,7 The latter values
genation of several olefins.11 In this contribution we re-
are often acceptable for agrochemical applications,8
port preliminary results pointing to the usefulness of
while enantioselectivities in the 95–99% ee range have
phosphine–phosphites in the hydrogenation of N-aryl
only been reached with an iridium catalyst bearing a
strong donor ferrocenyl diphosphine described by Xiao
and Zhang.9 Upon this background, it looks clear that
both the examination of new catalytic systems and the
identification of suitable ligand properties for this reac-
tion are of great interest.
Keywords: Asymmetric hydrogenation; Chiral amines; Phosphine–
phosphites.
*
Corresponding author. Tel.: +34 9544 89556; fax: +34 9544 60565;
e-mail: pizzano@iiq.csic.es
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.144

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S. Vargas et al. / Tetrahedron Letters 46 (2005) 2049–2052
imines. In addition, the high modularity of the corre-
sponding catalysts have allowed to identify backbone
mobility as an important variable in this reaction.
Initially, we have performed a screening with some
catalyst precursors of formulation [Ir(COD)(3)]BF4
(COD = 1,5-cyclooctadiene) as well as with those pre-
pared from [Ir(Cl)(COD)]2 and 3, at a metal to ligand
ratio of 1, in the hydrogenation of model substrate N-
(1-phenylethylidene)aniline 1a (Ar = Ar0 = Ph).12 This
exploration indicated that neutral precursors were more
active than cationic ones. For instance, under reaction
conditions depicted in Table 1, conversions with 3b were
100% and 45%, respectively. Thus, all catalysts men-
tioned below were prepared in situ from the iridium
dimer and the appropriate phosphine–phosphite at a
Ir–ligand ratio of 1.
Use of compounds 3a–e led to active catalysts that com-
pleted the reaction under relatively mild conditions (Ta-
ble 1).13 Enantioselectivities were low in all cases, thus
indicating the need of a substantial structural modifica-
tion in order to improve catalyst performance. Inspired
by the mentioned study on a ferrocenyl based catalyst,9
we envisioned ligand flexibility as a plausible variable
for catalyst optimization. As ligands 3 possess a rather
rigid backbone, it is of interest the investigation of more
flexible derivatives. For that purpose we have prepared
ethane bridged phosphine–phosphites 6 (Scheme 1). As
a requisite for the latter, hydroxy-phosphines 4 are
required. Procedure described in the literature for
2-diphenylphosphinoethanol14 proved suitable for the
preparation of the rest of compounds 4. Subsequent
condensation with chiral chlorophosphite 5, in the pres-
ence of NEt3, led to ligands 6.15
Scheme 1.
Table 2. Hydrogenation of 1 with precatalysts 1/2 [Ir(Cl)(COD)]2 +
liganda
Entry
Substrate
Ligand
% Ee (conf.)
1
2
3
4
5b
6
7
8
9
1a
1a
1a
1a
1a
1b
1a
1a
1a
6a
6f
81 (S)
70 (S)
76 (S)
82 (S)
84 (S)
83 (S)
36 (S)
47 (S)
42 (S)
6g
6h
6h
6h
3a
3f
Interestingly, catalyst derived from 6a completed the
reaction under our standard conditions. The reaction
was faster than expected and was actually completed
in less than 6 h. Most noteworthy, this ligand produced
a significant increase on the enantioselectivity of the
reaction up to 81% ee (Table 2). With the intention to
further optimize the enantioselectivity of the reaction,
we have also examined other phosphine aryl substitu-
ents.16 Unfortunately, ligands 6f–h did not provide a sig-
nificant improvement and the best result was 82% ee
3h
Compound 2b: Chiralpak AD, 30 °C, hexane–PriOH (99:1), 1.0 mL/
min. Configuration was determined by comparison of optical rotation
with literature value.6a
a All hydrogenations were completed under conditions specified.
Reactions were carried out at room temperature with an initial
hydrogen pressure of 30 bar, in methylene chloride at a S/C = 100.
Reaction time 24 h. Conversion was determined by 1H NMR and
enantiomeric excess (ee) by chiral HPLC (2a: Chiralcel OJ, 30 °C,
hexane–PriOH 97:3, 1.0 mL/min).
Table 1. Hydrogenation of 1a with precatalysts 1/2 [Ir(Cl)(COD)]2
+ 3a
b Hydrogenation performed at 0 °C, reaction time 10 h.
Entry
Ligand
% Ee (conf.)
1
2
3
3a
3b
3c
1
36 (S)
25 (S)
20 (S)
obtained with the xylyl derivative 6h, which could be in-
creased to 84% ee at 0 °C. In addition, p-anisyl imine 1b
(Ar = Ph, Ar0 = 4-MeO–C6H4) of interest due to its easy
conversion into the primary amine,9 was hydrogenated
to give 2b with 83% ee (entry 6).
Conversion was determined by H NMR and enantiomeric excess (ee)
by chiral HPLC (Chiralcel OJ, 30 °C, hexane–PriOH (97:3), 1.0 mL/
min). Configuration was determined by comparison of optical rotation
with literature value.6a
a All hydrogenations were completed under conditions specified.
Reactions were carried out at room temperature with an initial
hydrogen pressure of 30 bar, in methylene chloride at a S/C = 100.
Reaction time 24 h.
The notable increase on enantioselectivity (Dee = 45%)
obtained with 6a, regarding to 3a, have prompted us
to investigate if this positive influence of the backbone
is more general. For that purpose o-tolyl (3f, Scheme 1)

S. Vargas et al. / Tetrahedron Letters 46 (2005) 2049–2052
2051
and xylyl (3h) have also been prepared.17 Most note-
worthy, the latter ligands produced amine 2a with signif-
icantly lower enantiomeric excesses than their ethane
counterparts 6f and h. Then, values of Dee in the three
couple of ligands investigated ranged from 23% to
45% ee indicating a general positive influence of the eth-
ane backbone.18
8. Blaser, H.-U.; Pugin, B.; Spindler, F. In Applied Homo-
geneous Catalysis with Organometallic Compounds; Corn-
ils, B., Herrmann, W. A., Eds.; Wiley-VCH: Weinheim,
2002; Vol. 3.
9. Xiao, D.; Zhang, X. Angew. Chem., Int. Ed. Engl. 2001,
40, 3425.
10. (a) Nozaki, K.; Sakai, N.; Nanno, T.; Higashijima, T.;
Mano, S.; Horiuchi, T.; Takaya, H. J. Am. Chem. Soc.
1997, 119, 4413; (b) Nozaki, K.; Sato, N.; Tonomura, Y.;
Yasutomi, M.; Takaya, H.; Hiyama, T.; Matsubara, T.;
Koga, N. J. Am. Chem. Soc. 1997, 119, 12779; (c)
In conclusion, we have demonstrated that chiral phos-
phine–phosphites are appropriate ligands for the iridium
catalyzed asymmetric hydrogenation of imines. Ligand
optimization have led to efficient catalysts, as well as it
has identified the nature of the backbone as an impor-
tant variable in catalyst design. Studies regarding opti-
mization and scope of this catalytic system are
currently under progress.
`
´
Deerenberg, S.; Pamies, O.; Dieguez, M.; Claver, C.;
Kamer, P. C. J.; van Leeuwen, P. W. N. M. J. Org. Chem.
2001, 66, 7626; (d) Deerenberg, S.; Schrekker, H. S.; van
Strijdonck, G. P. F.; Kamer, P. C. J.; van Leeuwen, P. W.
N. M.; Fraanje, J.; Goubitz, K. J. Org. Chem. 2000, 65,
`
´
4810; (e) Pamies, O.; Dieguez, M.; Net, G.; Ruiz, A.;
Claver, C. J. Org. Chem. 2001, 66, 8364; (f) Blume, F.;
Zemolka, S.; Fey, T.; Kranich, R.; Schmalz, H.-G. Adv.
Synth. Catal. 2002, 344, 868; (g) Yan, Y.; Chi, Y.; Zhang,
X. Tetrahedron: Asymmetry 2004, 15, 2173; (h) Jia, X.; Li,
X.; Lam, W. S.; Kok, S. H. L.; Xu, L.; Lu, G.; Yeung,
C.-H.; Chan, A. S. C. Tetrahedron: Asymmetry 2004, 15,
2273.
Acknowledgments
´
We gratefully acknowledge Ministerio de Educacion y
Ciencia for financial support (BQU-2000-1167). S.G.
and M.R. thank CSIC (I3P Program) and Ministerio
´
de Educacion y Ciencia (FPU Program), respectively,
for fellowships.
´
11. (a) Suarez, A.; Pizzano, A. Tetrahedron: Asymmetry 2001,
12, 2501; (b) Suarez, A.; Mendez-Rojas, M. A.; Pizzano,
´
´
´
A. Organometallics 2002, 21, 4611; (c) Rubio, M.; Suarez,
A.; Alvarez, E.; Pizzano, A. Chem. Commun. 2005, 628.
12. General procedure for asymmetric hydrogenation. To a
solution of [Ir(Cl)(COD)]2 (3 mg, 0.004 mmol) in CH2Cl2
(1 mL) was added 6a (6 mg, 0.009 mmol) dissolved in
CH2Cl2 (1 mL). The mixture was stirred for 15 min and
added to a solution of imine 1a (174 mg, 0.9 mmol) in
CH2Cl2 (8 mL). The mixture was transferred to an
autoclave, purged three times with hydrogen and finally
pressurized at 30 bar. The reaction was stirred for 24 h,
reactor was depressurized and resulting solution evapo-
rated to dryness. The residue was redissolved in a
hexanes–ethyl acetate mixture (1:1) and passed through
a short pad of silica. Evaporation of solvent yielded amine
2a in quantitative yield. Enantiomeric excess was deter-
mined by chiral HPLC (Chiralcel OJ, 30 °C, hexane–
PriOH (97:3), flow 1.0 mL/min, t1 = 15.1 min (S),
t2 = 16.9 min (R)).
References and notes
1. Comprehensive Asymmetric Catalysis; Jacobsen, E. N.,
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Blaser, H.-U.; Malan, C.; Pugin, B.; Spindler, F.; Steiner,
H.; Studer, M. Adv. Synth. Catal. 2003, 345, 103.
3. (a) Willoughby, C. A.; Buchwald, S. L. J. Am. Chem. Soc.
1994, 116, 8952; (b) Lensink, C.; deVries, J. G. Tetra-
hedron: Asymmetry 1992, 3, 235; (c) Bakos, J.; Orosz, A.;
Heil, B.; Laghmari, M.; Lhoste, P.; Sinou, D. Chem.
Commun. 1991, 1684.
4. (a) Willoughby, C. A.; Buchwald, S. L. J. Am. Chem. Soc.
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125, 10536; (c) Bianchini, C.; Barbaro, P.; Scapacci, G.;
Farnetti, E.; Graziani, M. Organometallics 1998, 17, 3308;
13. As ligands 3 are considerably poor donor than diphos-
phines, this observation emphasizes that it is possible to
get active iridium catalysts with P–P ligands possessing
broad electronic properties. Accordingly, there have
appeared reports on the literature of catalysts bearing
from electron rich diphosphines9 to poor donating
(d) Ringwald, M.; Sturmer, R.; Brintzinger, H. H. J. Am.
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Chem. Soc. 1999, 121, 1524.
´
diphosphites, see: Guiu, E.; Mun˜oz, B.; Castillon, S.;
Claver, C. Adv. Synth. Catal. 2003, 345, 169.
5. (a) Blaser, H.-U. Adv. Synth. Catal. 2002, 344, 17; (b)
Blaser, H.-U.; Spindler, F. Top. Catal. 1997, 4, 275.
6. (a) Cobley, C. J.; Henschke, J. P. Adv. Synth. Catal. 2003,
14. Chantreux, D.; Gamet, J.-P.; Jacquier, R.; Verducci, J.
Tetrahedron 1984, 40, 3087.
345, 195; (b) Dorta, R.; Broggini, D.; Stoop, R.; Ruegger,
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H.; Spindler, F.; Togni, A. Chem. Eur. J. 2004, 10, 267; (c)
15. Representative procedure for the synthesis of ligands. Over
a solution of 5 (0.354 g, 0.84 mmol) and NEt3 (0.24 mL,
1.68 mmol) in toluene (30;mL) was added a solution of 2-
(diphenylphosphino)ethanol (0.195 g, 0.84 mmol) in tolu-
ene (20 mL). The reaction was stirred for 12 h and the
resulting suspension filtered. The solvent was evaporated,
the residue redissolved in Et2O and filtered through neutral
alumina. Evaporation of the solution obtained led to
compound 6a as a white foamy solid (0.34 g, 70%).
´ ˆ
Schnider, P.; Koch, G.; Pretot, R.; Wang, G.; Bohnen, F.
M.; Kruger, C.; Pfaltz, A. Chem. Eur. J. 1997, 3, 887; (d)
¨
Blanc, C.; Agbossou-Niedercorn, F.; Nowogrocki, G.
Tetrahedron: Asymmetry 2004, 15, 2159; (e) Trifonova, A.;
Diesen, J. S.; Chapman, C. J.; Andersson, P. G. Org. Lett.
2004, 6, 3825; (f) Maire, P.; Deblon, S.; Breher, F.; Geier,
J.; Bo¨hler, C.; Ruegger, H.; Scho¨nberg, H.; Grutzmacher,
¨
H. Chem. Eur. J. 2004, 10, 4198.
¨
D
7. The racemization of a N-aryl amine by an Ir C–H
activation has recently been demonstrated. This transfor-
mation would difficult the achievement of high enantiose-
lectivities in the hydrogenation of N-aryl imines. See:
Dorta, R.; Broggini, D.; Kissner, R.; Togni, A. Chem. Eur.
J. 2004, 10, 4546.
½aꢀ20 117 (c 1.0, THF). 1H NMR (CDCl3, 300 MHz): d
1.37 (s, 9H, CMe3), 1.47 (s, 9H, CMe3), 1.77 (s, 6H, 2Me),
2.19 (s, 3H, Me), 2.26 (s, 3H, Me), 2.29–2.36 (m, 2H,
2CHH), 3.36 (m, 1H, CHH), 3.92 (m, 1H, CHH), 7.04 (s,
1H, H arom), 7.07 (s, 1H, H arom), 7.30 (m, 10H, H arom).
31P{1H} NMR (CDCl3, 121.5 MHz): d ꢁ24.4 (s, PC), 128.9

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S. Vargas et al. / Tetrahedron Letters 46 (2005) 2049–2052
(s, PO). HRMS (EI): m/z 612.2908, [M]+ (exact mass
calculated for C38H46O3P2: 612.2922).
16. For catalyst improvements by aryl optimization see for
instance: Evans, D. A.; Campos, K. R.; Tedrow, J. S.;
17. Compounds 3f and h have been prepared from corre-
sponding phenol-phosphines 7 as described for 1a–e.11
18. The improvement produced by ligands 6, in comparison
with 3, can be ascribed to the expected higher flexibility of
the former or, in addition, to the adoption of a more
efficient conformation by coordinated 6.
´
Michael, F. E.; Cagne, M. R. J. Am. Chem. Soc. 2000, 122,
7905.