Thioether-phosphite: New ligands for the highly enantioselective Ir-catalyzed hydrogenation of minimally functionalized olefins

Article abstract of DOI:10.1039/c1cc13300d

We have described the first successful application of non-N-donor heterodonor ligands - thioether-phosphite ligands - in the Ir-catalyzed hydrogenation of minimally functionalized olefins. Excellent enantioselectivities (ee's up to 99%) have been obtained for a range of substrates, including challenging terminal disubstituted substrates, under standard conditions.

Full text of DOI:10.1039/c1cc13300d

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COMMUNICATION
Thioether-phosphite: new ligands for the highly enantioselective
Ir-catalyzed hydrogenation of minimally functionalized olefinsw
´
Mercedes Coll, Oscar Pamies* and Montserrat Dieguez*
Received 3rd June 2011, Accepted 24th June 2011
DOI: 10.1039/c1cc13300d
We have described the first successful application of non-N-
donor heterodonor ligands—thioether-phosphite ligands—in the
Ir-catalyzed hydrogenation of minimally functionalized olefins.
Excellent enantioselectivities (ee’s up to 99%) have been
obtained for a range of substrates, including challenging terminal
disubstituted substrates, under standard conditions.
Pharmaceuticals, agrochemicals, fragrances, fine chemicals, and
natural product chemistry all rely on enantiomerically enriched
compounds. Because of their high efficiency, atom economy
and operational simplicity, the asymmetric hydrogenation of
properly selected prochiral starting materials could be a sustain-
able and direct synthetic tool for preparing these compounds.1
For many years now olefins containing an adjacent polar group
(i.e. dehydroamino acids) have been successfully reduced by Rh-
and Ru-catalyst precursors modified with phosphorus ligands,
but the asymmetric hydrogenation of minimally functionalized
olefins is less developed because these substrates have no
adjacent polar group to direct the reaction.1
Fig. 1 Thioether-phosphite ligands L1–L8a–d.
the asymmetric Ir-catalyzed hydrogenation of minimally
functionalized olefins.6,7 These ligands are derived from natural
D-xylose and they combine the advantages of phosphite and
sugar cores: that is to say, they are readily available from
cheap feedstocks, are highly resistant to oxidation, and
have a straightforward modular construction.8 Moreover,
the introduction of a thioether moiety in the ligand design
may be beneficial because: (i) the S atoms become a stereo-
genic center when coordinated to the metal, which moves the
chirality closer to the metal, and (ii) the thioether group is
more stable than the oxazoline moiety.9 The highly modular
construction of these ligands makes it easy for us to study four
main effects on catalytic activity and selectivity: (a) the effect
of systematically varying the position of the thioether group at
either C-5 (ligands L1–L6) or C-3 (ligands L7–L8) of the
furanoside backbone, (b) the effect of the configuration at
C-3 of the furanoside backbone, (c) the effect of the substi-
tuents in the thioether group (L1–L4) and (d) the effect of
the substituents and configurations in the biaryl phosphite
moiety (a–d). By carefully selecting these ligand parameters,
we achieved high enantioselectivities for a range of substrates,
including challenging terminal disubstituted substrates.
In the last decade, Ir complexes containing chiral P,N-ligands
emerged as powerful tools in the asymmetric hydrogenation
of minimally functionalized olefins.2 They were essentially
complementary to Rh– and Ru–diphosphine catalysts. Due
to the early success of Pfaltz et al.3a and others3b–e in developing
chiral heterodonor phosphine–oxazoline ligands as chiral
mimics of Crabtree’s catalyst [Ir(cod)(py)(PCy3)]PF6,4 research
in this field has focused on maximizing the efficiency of these
ligands by: (i) modifying the structure of the chiral ligand’s
backbone, (ii) replacing the phosphine moiety with a phosphinite,
phosphite or carbene group and (iii) changing the oxazoline
moiety for other N-donor groups (such as oxazole, pyridine or
thiazole).5 However, the possibility of changing the nature of the
N-donor atom in these heterodonor ligands has never been
contemplated.
In this communication, we report a new class of non-N-
donor heterodonor ligands—thioether-phosphite(Fig. 1)—for
´
´
`
Departament de Quımica Fısica i Inorganica, Universitat Rovira i
Virgili, Campus Sescelades, C/Marcellı´ Domingo, s/n. 43007
Tarragona, Spain. E-mail: oscar.pamies@urv.cat,
montserrat.dieguez@urv.cat; Fax: +34-977559563;
Tel: +34-977558780
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization of new ligands and [Ir(cod)(L)]BArF
(L = L1–L8a–d) complexes. See DOI: 10.1039/c1cc13300d
The synthesis of the phosphite-thioether ligands L1–L8a–d
is straightforward (Scheme 1).10 They were efficiently synthesized
by reacting the corresponding sugar hydroxyl-thioether
(5–10, 12 and 14) with 1 equiv. of the corresponding biaryl
c
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Chem. Commun., 2011, 47, 9215–9217 9215

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Table 1 Selected results for the Ir-catalyzed asymmetric hydro-
genation of S1 using ligands L1–L8a–da
Entry
L
mol% Ir
% Conv.b
% eeb
1
2
3
4
5
6
7
8
L1a
L2a
L3a
L4a
L5a
L5b
L5c
L5d
L6a
L7a
L8a
L6a
2
2
2
2
2
2
2
2
2
2
2
0.5
100
100
100
100
100
100
100
100
100
100
100
82
13 (R)
15 (R)
23 (R)
30 (R)
87 (R)
87 (R)
26 (R)
24 (R)
99 (R)
68 (R)
68 (S)
99 (R)
9
10
11
12
a
b
Reactions carried out using 1 mmol of S1. Conversion and enantio-
Scheme 1 Synthesis of thioether-phosphite ligands L1–L8a–d.
(a) Tf2O, Py, CH2Cl2, ꢁ15 1C; (b) NaSR, THF, rt; (c) NH4OH/MeOH;
(d) ClP(OR)2, Py, toluene, 80 1C.
meric excesses determined by chiral GC.
From this we can also conclude that ligand backbones L5–L8
effectively control the thioether coordination to iridium leading
to the formation of a single diastereoisomer.
phosphorochloridite (ClP(OR)2; (OR)2 = a–d) in the presence
of pyridine (Scheme 1, step (d)). Compounds 5–10, 12 and 14
were synthesized very efficiently from the corresponding easily
accessible sugar-derived alcohols 1–4. These latter compounds
are easily prepared on a large scale from inexpensive D-xylose.11
Compounds 1–4 were treated with one equiv. of triflic anhydride
to produce the desired monotriflates. Subsequent reaction with
the corresponding NaSR provided direct access to the corres-
ponding hydroxyl-thioether 5–10 and benzoyl-thioether inter-
mediates 11 and 13 (Scheme 1, step (a, b)). The benzoyl
protecting group of compounds 11 and 13 was removed under
basic standard conditions to obtain hydroxyl-thioethers 12
and 14 (Scheme 1, step (c)). All the ligands were stable during
purification on neutral alumina under an atmosphere of argon
and isolated in good yields as white solids.
In the first set of experiments, we used the Ir-catalyzed
hydrogenation of (E)-2-(4-methoxyphenyl)-2-butene S1 to
scope the potential of ligands L1–L8a–d. The results are
summarized in Table 1 and indicate that enantioselectivity is
highly affected by the position of the thioether group at either
C-5 or C-3 of the furanoside backbone, the configuration of
C-3, the thioether substituent and the substituents in the biaryl
phosphite moiety (a–d). We therefore found a cooperative
effect between the position of the thioether group and the
configuration of carbon atom C-3 of the furanoside backbone
(Table 1, entries 1, 5, 10 and 11). The results indicate that the
matched combination is achieved with ligands L5–L6, which
have the thioether moiety attached to C-5 and an R configu-
ration of carbon atom C-3 (entries 5 and 9). We also found
that bulky substituents need to be present in both the biaryl
phosphite (entries 5, 6 vs. 7, 8) and the thioether (entries 5 vs. 9)
moieties if enantioselectivities are to be high. It should be
noted that the configuration of the biaryl phosphite group has
little effect on the enantioselectivity (entries 7 and 8). Excellent
enantioselectivity (99% ee, entry 9) was therefore obtained
using the Ir–L6a catalytic system, which contains the optimal
combination of ligand parameters.
The Ir-catalyst precursors [Ir(cod)(L)]BArF (L = L1–L8a–d)
were made by refluxing a dichloromethane solution of the appro-
priate ligand in the presence of 0.5 equiv. of [Ir(m-Cl)(cod)]2 for
1 h followed by counterion exchange with sodium tetrakis-
[3,5-bis(trifluoromethyl)phenyl]borate (NaBArF) (1 equiv.) in
the presence of water (eqn (1)).
1ÞL=CH2Cl2
½Irðm-ClÞðcodÞꢀ2 ꢁ! 2½IrðcodÞðLÞꢀBArF þ 2cod
2ÞNaBArF=H2O
ð1Þ
We also performed the reaction at low catalyst loading
(0.5 mol%) using ligand L6a (entry 12). The excellent enantio-
selectivity (99% (R) ee) was maintained.
All complexes were isolated as air-stable red-orange solids and
were used without further purification. VT-NMR (+40 1C to
ꢁ70 1C) experiments indicate the presence of a single isomer in
all cases except for [Ir(cod)(L1–L4a–d)]BArF in which two
isomers are present. These isomers may be attributed to the
two possible diastereoisomers formed when the thioether
coordinates to the metal atom (note that the coordinated
S atom is a stereogenic center), to the different tropoisomers
of the biphenyl moieties, or to both. However, comparing
compound Ir/L1a with related compounds Ir/L1c and Ir/L1d,
which contain enantiomerically pure binaphthyl moieties, the
presence of two isomers in them all suggests that these isomers
are due to the different configurations of the sulfur stereocentre.
Fig. 2 Selected hydrogenation results. Reaction conditions: 2 mol%
a
catalyst, CH2Cl2 as solvent, 100 bar H2, 4 h. 1 bar H2.
c
9216 Chem. Commun., 2011, 47, 9215–9217
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To study the potential of these readily available ligands in
greater depth, we also tested them in the asymmetric hydro-
genation of several other minimally functionalized olefins
(Fig. 2). The enantioselectivities are among the best observed
for these substrates.2 As expected Ir–L6a also provides high
levels of enantioselectivities (99% ee) in the reduction of other
trisubstituted E-olefins (S2 and S3). Notably, high enantio-
selectivities can also be obtained for the more demanding
Z isomer S4, which usually reacts with much lower enantio-
selectivity than that of the corresponding E-isomer S1. Ir–L6a
also proved to be an excellent catalyst for the hydrogenation
of a,b-unsaturated ester S5 (98% ee). It should be noted that
this novel class of catalyst precursors also proved to be highly
effective in one of the most challenging classes of substrates—
the 1,1-disubstituted terminal olefins.12 Thus, excellent enantio-
selectivities (98–99% ee) were achieved in the reduction of
aromatic and heteroaromatic terminal substrates S6 and S7
under mild reaction conditions (1 bar of H2).
2 For recent reviews, see: (a) K. Kallstrom, I. Munslow and P. G.
¨ ¨
Andersson, Chem.–Eur. J., 2006, 12, 3194; (b) S. J. Roseblade and
A. Pfaltz, Acc. Chem. Res., 2007, 40, 1402; (c) T. L. Church and
P. G. Andersson, Coord. Chem. Rev., 2008, 252, 513; (d) X. Cui and
K. Burgess, Chem. Rev., 2005, 105, 3272; (e) O. Pamies,
´
P. G. Andersson and M. Dieguez, Chem.–Eur. J., 2010, 16,
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3 (a) A. Lighfoot, P. Schnider and A. Pfaltz, Angew. Chem., Int. Ed.,
1998, 37, 3897; (b) D.-R. Hou, J. H. Reibenspies, T. J. Colacot and
K. Burgess, Chem.–Eur. J., 2001, 7, 5391; (c) W. Tang,
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4 R. H. Crabtree, Acc. Chem. Res., 1979, 12, 331.
5 See for instance: (a) W. J. Drury III, N. Zimmermann, M. Keenan,
M. Hayashi, S. Kaiser, R. Goddard and A. Pfaltz, Angew. Chem.,
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D.-R. Hou, J. H. Reibenspies and K. Burgess, J. Am. Chem. Soc.,
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¨
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C. Hedberg, P. Brandt, P. Bayer and P. G. Andersson, J. Am.
Chem. Soc., 2004, 126, 14308; (f) M. Dieguez, J. Mazuela,
O. Pamies, J. J. Verendel and P. G. Andersson, J. Am. Chem.
Soc., 2008, 130, 7208; (g) M. Dieguez, J. Mazuela, O. Pamies,
J. J. Verendel and P. G. Andersson, Chem. Commun., 2008, 3888;
(h) J. Mazuela, J. J. Verendel, M. Coll, B. Schaffner, A. Borner,
In summary, we have described the first successful application
of non-N-donor heterodonor ligands—thioether-phosphite
ligands—in the Ir-catalyzed asymmetric hydrogenation of
several minimally functionalized olefins. These ligands combine
the advantages of phosphite, thioether and sugar cores: that is
to say, they are readily available from cheap feedstocks, are
more resistant to oxidation than phosphines and phosphinites,
and are more stable than oxazolines. In addition, they can be
easily tuned in the sugar core, the thioether and biaryl phosphite
moieties so that their effect on catalytic performance can be
explored. By carefully selecting the ligand components, we
obtained high enantioselectivities under unoptimized reaction
conditions. This is an exceptional ligand family, which is able
to reduce in excellent ee’s (up to 99%) a range of E- and Z-
trisubstituted and disubstituted substrate types. These results
provide a new class of ligands for the highly enantio-
selective Ir-catalyzed hydrogenation of a wide range of
substrates and open up the enantioselective Ir-catalyzed hydro-
genation of minimally functionalized olefins to a type of ligand
other than N-donor heterodonor ligands. Mechanistic studies
are currently under way and further applications are being
looked into.
´
´
¨
¨
P. G. Andersson, O. Pamies and M. Die
2009, 131, 12344; (i) J. Mazuela, A. Paptchikhine, O. Pamies,
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´
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(j) J. Zhao and K. Burgess, J. Am. Chem. Soc., 2009, 131, 13236;
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X.-L. Hou, Adv. Synth. Catal., 2010, 352, 103.
6 For representative examples on the use of P,S-ligands in asymmetric
hydrogenation of enamides and ketones, see: (a) D. A. Evans,
F. E. Michael, J. S. Tedrow and K. R. Campos, J. Am. Chem.
Soc., 2003, 125, 3534; (b) E. Guimet, M. Dieguez, A. Ruiz and
´
C. Claver, Dalton Trans., 2005, 2557; (c) E. Hauptman, P. J. Fagan
and W. Marshall, Organometallics, 1999, 18, 2061; (d) E. Le Roux,
R. Malacea, E. Manoury, R. Poli, L. Gonsalvi and M. Peruzzini,
Adv. Synth. Catal., 2007, 349, 309.
7 For a recent review on the use of P,S-ligands in asymmetric
catalysis, see: R. Malacea and E. Manoury, in Phosphorus Ligands
in Asymmetric Catalysis, ed. A. Borner, Wiley-VCH, Weinheim,
2008, vol. 2, pp. 749–784.
¨
8 See for example: (a) M. Die
2004, 104, 3189; (b) S. Woodward, M. Die
Chem. Rev., 2010, 254, 2007; (c) P. W. N. M. van Leeuwen, P. C.
J. Kamer, C. Claver, O. Pamies and M. Dieguez, Chem. Rev., 2011,
111, 2077; (d) C. Claver, O. Pamies and M. Dieguez, in Phosphorus
´
guez, O. Pamies and C. Claver, Chem. Rev.,
´
guez and O. Pamies, Coord.
´
We thank the Spanish Government for providing grants
Consolider Ingenio Intecat-CSD2006-0003, CTQ2010-15835,
and 2008PGIR/07 and 2008PGIR/08, the Catalan Government
for grant 2009SGR116, and the ICREA Foundation for
´
Ligands in Asymmetric Catalysis, ed. A. Borner, Wiley-VCH,
Weinheim, 2008, vol. 2, pp. 506–528.
¨
9 A. M. Masdeu-Bulto
Coord. Chem. Rev., 2003, 242, 159.
10 Ligands L1–L3a have been previously synthesized, see: O. Pamies,
M. Dieguez, G. Net, A. Ruiz and C. Claver, Organometallics, 2000,
, M. Dieguez, E. Martin and M. Gomez,
´ ´ ´
providing M. Dieguez and O. Pamies with financial support
´
through the ICREA Academia awards. We thank Prof.
P.G. Andersson, Uppsala University, for his useful comments
´
19, 1488.
11 (a) K. P. R. Kartha, Tetrahedron Lett., 1986, 27, 3415;
(b) A. I. Vogel, Vogel’s Textbook of Practical Organic Chemistry,
Longman, New York, 5th edn, 1994; (c) P. A. Levene and
A. L. Raymond, J. Biol. Chem., 1933, 102, 317; (d) D. H.
Hollenberg, R. S. Klein and J. J. Fox, Carbohydr. Res., 1978,
67, 491; (e) G. Ritzmann, R. S. Klein, D. H. Hollenberg and
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and Y. Ishido, Carbohydr. Res., 1975, 39, 293.
Notes and references
1 (a) Asymmetric Catalysis in Industrial Scale: Challenges, Approaches
and Solutions, ed. H. U. Blaser and E. Schmidt, Wiley, Weinheim,
Germany, 2003; (b) I. Ojima, Catalytic Asymmetric Synthesis,
Wiley-VCH, New York, 2000; (c) J. M. Brown, in Comprehensive
Asymmetric Catalysis, ed. E. N. Jacobsen, A. Pfaltz and
H. Yamamoto, Springer-Verlag, Berlin, 1999, vol. I, pp. 121–182;
(d) R. Noyori, Asymmetric Catalysis in Organic Synthesis, Wiley,
New York, 1994.
12 For these substrates, few catalytic systems have provided high
enantioselectivities, see ref. 2e. So, the development of highly
enantioselective Ir-catalysts is therefore still important.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 9215–9217 9217