New C2- and C1-symmetric phosphorus ligands based on carbohydrate scaffolds and their use in the iridium-catalysed hydrogenation of ketimines

Article abstract of DOI:10.1002/ejoc.200500523

The C₂-symmetric diphosphinite ligands 10a-d, which have different electron-donating or electron-withdrawing groups in the aryl group, and C₁-symmetric phosphinite-phosphite ligands 11a,b, were directly prepared from glucosamine. Various procedures for synthesising the phosphinite function were explored in order to improve the yield of the reaction. Results were best when Ph₂PNEt₂ was used in the presence of tetrazol as catalyst. These ligands were added to iridium complexes to give catalyst precursors that are active in the hydrogenation of imines 17 and 19. Cationic iridium complexes gave rise to catalytic systems that were more active than the neutral iridium complexes. The use of additives was, in general, detrimental to both the conversion and the enantioselectivity. In the hydrogenation of 17, results were best with ligand 11a (76 % ee), but in the hydrogenation of 19 (70 % ee) they were best with ligand 10b. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200500523

FULL PAPER
DOI: 10.1002/ejoc.200500523
New C2- and C1-Symmetric Phosphorus Ligands Based on Carbohydrate
Scaffolds and Their Use in the Iridium-Catalysed Hydrogenation of Ketimines
Ester Guiu,[a] Mohamed Aghmiz,[a] Yolanda Díaz,[a] Carmen Claver,*[b] Benjamí Meseguer,[c]
Christian Militzer,[c] and Sergio Castillón*[a]
Keywords: Asymmetric catalysis / Hydrogenation / Imines / Iridium / P ligands / Carbohydrates
The C2-symmetric diphosphinite ligands 10a–d, which have
different electron-donating or electron-withdrawing groups
in the aryl group, and C1-symmetric phosphinite–phosphite
ligands 11a,b, were directly prepared from glucosamine.
Various procedures for synthesising the phosphinite function
were explored in order to improve the yield of the reaction.
Results were best when Ph2PNEt2 was used in the presence
of tetrazol as catalyst. These ligands were added to iridium
complexes to give catalyst precursors that are active in the
hydrogenation of imines 17 and 19. Cationic iridium com-
plexes gave rise to catalytic systems that were more active
than the neutral iridium complexes. The use of additives was,
in general, detrimental to both the conversion and the
enantioselectivity. In the hydrogenation of 17, results were
best with ligand 11a (76% ee), but in the hydrogenation of
19 (70% ee) they were best with ligand 10b.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
Introduction
In recent decades carbohydrates have been widely used
as chiral synthons for the synthesis of enantiomerically pure
compounds.[1] A variety of structures can be obtained from
carbohydrates, mainly pyranoses and furanoses, through
well-established procedures. Ligands with C1- and C2-sym-
metry based on carbohydrates have been synthesised and
successfully used in asymmetric catalysis and, because hy-
droxy groups are present, phosphinite, phosphonite and
phosphite functional groups are easily introduced, which
means that they can be used as ligands in metal-catalysed
reactions in addition to the more commonly used phospha-
nes. Selke[2] has found that diphosphinite 1 (Figure 1) pro-
vides excellent enantioselectivity in the hydrogenation of en-
amido acids, and RajanBabu has reported successful exam-
ples of rhodium-catalysed hydrogenation of enamido ac-
ids[3] and nickel-catalysed hydrocyanation of alkenes[4] using
this ligand electronically modified by changing the elec-
tronic properties of the aryl groups bonded to the phospho-
rus atoms.[5]
Figure 1. C1-Symmetric ligands derived from carbohydrates. b) C2-
Symmetric ligands derived from carbohydrates.
[a] Departament de Química Analítica i Química Orgànica, Uni-
versitat Rovira i Virgili,
Pl. Imperial Tàrraco 1, 43005 Tarragona, Spain
Fax: +34-977-559-563
E-mail: castillon@quimica.urv.es
Our group has prepared ligands such as 2 and its ana-
logues, which have proved to be efficient in rhodium-cata-
lysed hydrogenation[6,7] and hydroformylation,[8,9] and pal-
ladium-catalysed allylic alkylation.[10]
[b] Departament de Química Física i Inorgànica, Universitat Ro-
vira i Virgili,
Pl. Imperial Tàrraco 1, 43005 Tarragona, Spain
Fax: +34-977-559-563
E-mail: claver@quimica.urv.es
Notable examples of C2-symmetric carbohydrate ligands
[c] Bayer AG, Central Research, Building Q18,
51368 Leverkusen, Germany
are the duphos analogues 3[11] and 4,[12] where the phos-
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E. Guiu, M. Aghmiz, Y. Díaz, C. Claver, B. Meseguer, C. Militzer, S. Castillón
FULL PAPER
pholane ring is prepared from d-mannitol. The diop ana- acyclic substrates.[20a,20b] Similar Ir/diphenylphosphanylimid-
logue 5[13] and the related diphosphinite 6[14] have also been azoline catalytic systems provided 51% ee.[20c] It has also
prepared from mannitol and provide excellent enantio- been shown that the cationic iridium catalyst [Ir(COD)-
selectivity in asymmetric hydrogenation.
{(S,S)-BDPP}]PF6 adsorbed on montmorillonite[21] can be
Recently, our group[15] has reported two new families of reused several times with no loss of enantioselectivity. How-
C2-symmetric diphosphinites (7 and 8; Figure 2) based on ever, there are only a few examples of rhodium and iridium
2,5-anhydromannitol and 2,5-anhydroiditol backbones, complexes with chiral diphosphinite and diphosphite li-
respectively. A comparative study of the asymmetric rho- gands used in the asymmetric hydrogenation of imines.[22,23]
dium-catalysed hydrogenation of enamido esters using li-
In this paper, we report the synthesis of a family of C2
gands 7–9 showed that the remote stereocentres (C2 and C5 diphosphinite ligands 10a–d related to structure 7 (R =
of the tetrahydrofuran ring) in ligands 7 and 8 have a strong TBDPS) with different electronic properties, and the C1
influence on the enantioselectivity. The results were best phosphinite/phosphite ligands 11a,b as a strategy for con-
with ligand 7 (R = TBDPS).
trolling the regio- or stereoselectivity in the iridium-cata-
lysed asymmetric reduction of imines.
Results and Discussion
C2-Diphosphinites 10a–c (Scheme 1, Table 1), and C1-
phosphinite–phosphites 11a,b (Scheme 3) were prepared
from the 2,5-anhydro-d-mannitol derivative 12, which can
be easily obtained from d-glucosamine in three steps.[24]
Figure 2. Diphosphinite and phosphinite–phosphite ligands with a
tetrahydrofuran backbone obtained from d-glucosamine (7, 8, 10,
and 11) and from diethyl tartrate (9).
The synthesis of enantiomerically enriched amines from
prochiral compounds is of considerable industrial interest,
and, consequently, developing efficient catalysts for the
enantioselective conversion of prochiral imines into the cor-
responding chiral amines is a major research target.[16] Al-
though the enantioselective hydrogenation of olefins and
ketones has been successfully achieved with several catalytic
systems using phosphorus ligands, in the hydrogenation of
imines enantioselectivities are only high in a few cases.[17]
The most remarkable achievement in this field is pro-
vided by the ferrocenylphosphane ligand Xyliphos,[18]
which provides a very active iridium catalyst that can hydro-
genate the MEA-imine with a turnover frequency (TOF)
greater than 180000 h–1 and an ee of 79% (precursor of
Metolachlor, one of the most important grass herbicides)
with high enantioselectivity. The highest enantioselectivity
(Ͼ99% ee) achieved in the asymmetric hydrogenation of
imines to date has been obtained with the Ir-ferrocene bina-
phane complex.[19] Cationic IrI complexes with diphenyl-
phosphanyloxazolines as ligands have been used in the re-
Scheme 1. Synthesis of diphosphinite ligands 10a–c from glucos-
amine.
Table 1. Synthesis of ligands 10a–d from 12.
Entry Reagents Solvent
T
Time Product Conv. Yield
[°C] [h]
[%]
[%]
1
2
3
13a
14b
14c
14b[a]
14d[a]
14d[c]
–
–
–
10a
10b
10c
–
81[15]
toluene
toluene
CH3CN/
CH2Cl2
CH3CN/
CH2Cl2
110 24
110 24
100 23
100 28
4
5
6
r.t. 0.5
10b
100 59
100 n.d.
100 41
10d/
15[b]
10d/
15[d]
r.t.
3
CH3CN
r.t. 24
[a] 4 Equiv. of 4d and 5.6 equiv. of tetrazole. [b] Ratio 10d/15 = 1:3.
duction of imines, with enantioselectivities up to 89% in [c] 8 Equiv. of 4d and 11.2 equiv. of tetrazole. [d] Ratio 10d/15 = 1:1.
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Iridium-Catalysed Hydrogenation of Ketimines
FULL PAPER
Ligand 10a was prepared by treating 12 with Ph2PCl
(13a) in basic medium[15] (Table 1, entry 1). Ligands 10b
and 10c were prepared in low yield (23% and 28%, respec-
tively) by a non-optimised direct reaction of diol 12 with
aminophosphanes 14b or 14c in refluxing toluene[25]
(Table 1, entries 2 and 3). In an attempt to find milder reac-
tion conditions, aminophosphane 14b was treated with the
weak acid 1H-tetrazole before 12 was added.[26] This reac-
tion to form ligand 10b was more efficient, and the yield
increased to 59% (Table 1, entry 4).
The synthesis of diphosphinite 10d turned out to be more
difficult than expected. Initially, we tried the reaction with
THF as the solvent and NEt3 at room temperature, and
obtained the monodentate ligand 15 in a 48% yield together
with significant amounts of the secondary product Ph2P(O)- Scheme 3. Synthesis of phosphinite–phosphite ligands 11a,b.
PPh2 (Scheme 2).
pressure in CH2Cl2. However, together with the desired sec-
ondary amine 18, hydrogenolysis products formed by cleav-
age of the nitrogen–benzyl bond were also detected.[28] In
general, the phosphane–phosphite 11 provided better con-
versions (entries 4 and 8) than the diphosphinites 10. Li-
gand 11a gave full conversion under these conditions with
both catalyst precursors (entries 4 and 8). For the catalytic
systems with the diphosphinites 10a–10c, the use of the pre-
cursor [Ir(COD)Cl]2/10 (Table 2 entries 1–3) led to activities
higher than the cationic [Ir(COD)2] BF4/10 precursors
(Table 2, entries 5–7). The systems based on ligand 10a pro-
vided the highest conversion and selectivity. The system
based on 10b (entries 2 and 6), which is a stronger electron
donor than 10c, gave lower conversion than the systems
based on ligand 10c.
Scheme 2. Synthesis of compounds 10d and 15 from 12.
Upon treating diol 12 with the aminophosphane 14d and
1H-tetrazol under standard conditions[26] we managed to
obtain a mixture of the di- and monosubstituted ligands
10d and 15 in a ratio of 1:3 (Table 1, entry 5); no secondary
products were obtained. Several attempts were made to
force the reaction in order to obtain the disubstituted com-
pound 10d. When the temperature and reaction time were
increased only the starting material was recovered. This
seems to indicate that the reaction is reversible under these
conditions. A 1:1 ratio of 10d and 15 was obtained when
we used an excess of aminophosphane 14d and 1H-tetrazole
(Table 1, entry 6).
The phosphinite–phosphite ligands 11a and 11b
(Scheme 3) were isolated after purification in 40% and 32%
yield, respectively, by treating 15 with the phosphorochlor-
idites 16a and 16b, respectively, in a mixture of toluene and
pyridine.[27]
The diphosphinites (10a–d) and phosphinite–phosphites
(11a,b) were used in the iridium-catalysed asymmetric hy-
drogenation of acyclic and cyclic ketimines to evaluate their
potential as ligands in the reduction of C=N. Two acyclic
imines were chosen as model substrates to be reduced: N-
(phenylethylidene)benzylamine (17) and N-(phenylethyl-
idene)aniline (19).
Table 2. Hydrogenation of 17 with Ir/L catalytic systems. Effect of
the precatalyst.[a]
Entry
Precatalyst
Conv.
[%]
Select.
[%]
ee[b]
[%]
1
2
3
4
5
6
7
8
[Ir(COD)Cl]2/10a
[Ir(COD)Cl]2/10b
[Ir(COD)Cl]2/10c
[Ir(COD)Cl]2/11a
[Ir(COD)2]BF4/10a
[Ir(COD)2]BF4/10b
[Ir(COD)2]BF4/10c
[Ir(COD)2]BF4/11a
100
74
93
100
82
70
95
85
92
90
76
68
76
85
0
0
5 (–)
0
9 (–)
0
85
100
11 (–)
73 (–)
[a] Reaction conditions: 1 mol-% [Ir], 1.25 mol-% ligand, 70 bar
H2, 16 h, 25 °C, CH2Cl2. [b] Absolute configuration was not deter-
mined.
Catalytic systems involving ligands 10a–c gave very low
enantioselectivities in the hydrogenation of 17. Börner has
The catalytic systems were generated in situ from both studied the hydrogenation of 17 using the catalytic system
[Ir(COD)Cl]2 and [Ir(COD)2]BF4 by adding diphosphinites Rh/1 and Rh/(R,R)-bdpch [(R,R)-1,2-cyclohexanolbis(di-
10a–d or phosphinite–phosphite 11a (Table 2). These cata- phenylphosphinite)], obtaining total conversion with
lysts provided hydrogenation of imine 17 with conversions enantioselectivities up 72% with the second catalytic sys-
of between 70 and 100% within 16 hours at 70 bar of H2 tem. The use of iridium complexes with the same ligands
Eur. J. Org. Chem. 2006, 627–633
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E. Guiu, M. Aghmiz, Y. Díaz, C. Claver, B. Meseguer, C. Militzer, S. Castillón
FULL PAPER
provided less active catalytic systems and very low enantio- 10). Furthermore, the ee dropped to almost zero when the
selectivity, in agreement with our observations. experiments were carried out in the presence of 10 mol-%
However, the use of the Ir/11a catalytic system afforded of I2 at 25 °C (Table 3, entries 5 and 10). The addition of
a remarkable 73% ee. It should be pointed out that the phthalimide and benzylamine did not have a strong influ-
different results obtained depend on the catalyst precursor. ence, at least at 25 °C, and both conversion and enantio-
Thus, while a racemate was obtained with [Ir(COD)Cl]2/ selectivity were maintained (Table 4, entries 6, 7, 11 and 12).
11a, a 73% ee was obtained with [Ir(COD)2]BF4/11a A similar behaviour has been observed in previous reports
(Table 2, entries 4 and 8). This finding is in agreement with with diphosphinite ligands.[22] This indicates that these
other reports and highlights the influence of the catalytic amines, which are also the reaction products, do not deacti-
precursor on the enantioselectivity.[22,29] When shorter reac- vate the catalyst, since conversion of the substrate is almost
tion times or lower temperatures (0 °C) were used (Table 3, total.
entries 2 and 3), the activity of the catalytic system and the
Table 4. Hydrogenation of imine 19 using the [Ir(COD)2]BF4/L
optical yield decreased. After half an hour conversion was
catalytic system. Effect of the additive.[a]
only 24%, which gives a TOF of 48 h–1 (Table 3, entry 2).
The lower enantiomeric excess obtained at shorter times or
at low temperatures suggests that the catalytic species re-
sponsible for enantiocontrol needs longer reaction times or
higher temperatures to be formed.
Table 3. Hydrogenation of 17 with [Ir(COD)2]BF4/11a,b. Study of
the effect of temperature and additive.[a]
Entry Ligand Time Additive[b]
[h]
Conv.
[%]
Select. ee[c]
[%]
[%]
1
2
3
4
5
6
7
8
10a
10b
10b
10b
10c
10d
11a
10a
10a
10a
10a
10b
10b
10b
10b
10c
10c
10c
10c
16
16
1
0.25
16
1
16
16
16
16
16
16
16
16
16
16
16
16
16
–
–
–
–
–
–
–
100
100
98
26
100
6
99
42
100
100
100
100
100
100
100
100
100
100
100
97
100
100
100
94
100
100
100
90
65 (+)
70 (+)
70 (+)
n.d.[d]
31 (–)
15 (–)
0
19 (–)
10 (–)
66 (+)
42 (+)
19 (+)
5 (–)
70 (+)
52 (+)
12 (+)
4 (–)
9 (–)
10 (–)
Entry Ligand Additive[b] Temp. Time Conv. Select. ee[c]
[°C]
[h]
[%]
[%]
[%]
Bu4NI
I2
phthalimide 98
BnNH2
Bu4NI
I2
1
2
3
4
5
11a
11a
11a
11a
11a
11a
–
–
–
25
25
0
25
25
25
16
0.5
2
16
16
16
100
24
4.3
9.5
100
85
73 (–)
68 (–)
40 (–)
16 (–)
1.4 (–)
9
100
100
100
67
10
11
12
13
14
15
16
17
18
19
52
71.1
100
Bu4NI
I2
Phthali-
mide
BnNH2
–
Bu4NI
I2
Phthali-
mide
BnNH2
phthalimide 99.3
6
100
89
75 (–)
BnNH2
Bu4NI
I2
phthalimide 99
BnNH2 25
43.6
100
100
7
11a
11b
11b
11b
25
25
25
25
25
16
2
16
16
16
97
17
9
91
93
100
87
76 (–)
52 (–)
11 (–)
0
8[d]
9
10
100
11
12
11b
11b
63
91
100
81
54 (–)
58 (–)
[a] Reaction conditions: 1 mol-% [Ir(COD)2]BF4, 1 mol-% ligand,
70 bar, 25 °C, 16 h, CH2Cl2. [b] 4 mol-% additive. [c] Absolute con-
figuration was not determined. [d] Not determined.
25
16
[a] Reaction conditions: 1 mol-% catalyst, 1.2 mol-% ligand, 70 bar
H2, 25 °C, 16 h, CH2Cl2. [b] 10 mol-% additive. [c] Absolute config-
uration was not determined. [d] 30 Bar H2.
A rather broad screening of different ligands and reac-
tion conditions was also carried out with N-arylimine 19.
The catalytic system [Ir(COD)2]BF4/11a, with tert-butyl The homogeneous catalysts were based on iridium and
substituents on the phosphite moiety, gave higher enantio- modified by adding diphosphinites 10a–d or phosphinite–
selectivity than [Ir(COD)2]BF4/11b, which contains cyclo- phosphite 11a. The effect of the catalyst precursor and ad-
hexyl substituents (entries 1 and 8).
ditives on the conversion to the amine and the optical yield
Several reports have shown that additives may improve were also investigated. Both iridium systems [IrCODCl]2/L
catalytic activity and enantioselectivity.[29a,30] Halides and and [Ir(COD)2]BF4/L (L = 10a–d, 11a) behave as catalytic
amines are the most widely used additives.[31] The results precursors for the hydrogenation of imine 19 to secondary
obtained with both our catalysts depend heavily on the amine 20 at 70 bar of H2 pressure in CH2Cl2. Whereas the
presence of iodide ions. Addition of Bu4NI deactivates the catalysts [IrCODCl]2/L provided low enantioselectivities
catalyst and causes a sharp decrease in conversion and (up to 10%), the [Ir(COD)2]BF4/L systems proved to be
enantioselectivity (Table 3, entries 1 and 4, and 8 and 9). more efficient and gave ee values as high as 70%. The re-
Iodine also has a dramatic effect on the selectivity and sults obtained with the systems [Ir(COD)2]BF4/L are pre-
enantioselectivity of the catalytic system: the selectivity in sented in Table 4.
the desired amine 18 decreased strongly and the hydro-
The catalytic system [Ir(COD)2]BF4/10a afforded total
genolysis of imine 17 was favoured (Table 3, entries 5 and conversion in 16 hours with 65% ee, while when ligand 10b
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Iridium-Catalysed Hydrogenation of Ketimines
FULL PAPER
was used the ee reached 70% (Table 4, entries 1–3). The ligand 10b was used the ee was 70%. In this case, the elec-
substrate was almost completely reduced within one hour tronic effect on the enantioselectivity are considerable. Re-
(entries 3–4). The catalytic system [Ir(COD)2]BF4/10c, with sults were best when electron-donating groups are present
an electron-poorer ligand, gave low enantioselectivities and on the phenyl rings. The use of additives was, in general,
promoted the formation of the opposite enantiomer detrimental to both conversion and enantioselectivity.
(Table 4, entry 5). When the catalytic system was based on
the diphosphinite ligand 10d, which contains methyl groups
on the aromatic rings to increase both the electron density
Experimental Section
on phosphorus and the steric hindrance, conversion was
General Remarks: All reactions were carried out under argon using
only 6% with an ee of 15% in one hour (Table 4, entry 6).
standard Schlenk techniques. Solvents were distilled and degassed
In this case the cationic iridium complex with phosphinite–
phosphite 11a provided the racemic mixture (Table 4, en-
try 7).
prior to use. 1H, 13C{1H}, 31P{1H} and 19F{1H} NMR spectra
were recorded with a Varian Gemini spectrometer at 300 and
400 MHz. Chemical shifts are reported relative to tetramethylsilane
1
for H and 13C{1H} as internal reference, 85% H3PO4 for 31P{1H}
The effect of adding halide ions or amine derivatives to
these catalytic systems was also examined. When Bu4NI or
I2 were added to [Ir(COD)2]BF4/10a–c the enantio-
selectivity dropped sharply (Table 4, entries 8, 9, 12, 13, 16
and 17), favouring the formation of the reduced product
with the opposite configuration. This behaviour seems to
be general for the hydrogenation of acyclic imines 17 and
19 with these catalytic systems when iodine derivatives are
used as additives. In general, when amines were used as
additives there was no notable effect on the enantio-
selectivity (Table 4, entries 10, 11, 14, 15, 18 and 19). Never-
theless, the addition of benzylamine slowed the reaction
down considerably and the activity of the catalytic system
decreased.
Concerning the effect of electron-withdrawing or -donat-
ing groups present in the diphosphinite function, in the case
of ligands 10a–c we observed an increase in the enantio-
selectivity when donating groups were used, which is similar
to the tendency observed in the hydrogenation of enamino
acids using other metals.[32] A general conclusion about the
role of electron-withdrawing or -donating substituents in li-
gands used in imine hydrogenation cannot be established at
the moment and will require additional studies.
and trichlorofluoromethane for 19F{1H} as external references. Ele-
mental analyses were carried out with a Carlo–Erba Microanalyser
EA 1108. A VG-Autospec apparatus was used for FAB mass spec-
tral analyses with 3-nitrobenzyl alcohol as matrix. EI mass spectra
were obtained with an HP 5989 A spectrometer at an ionizing volt-
age of 70 eV. Optical rotations were measured on a Perkin–Elmer
241 MC polarimeter.
Single hydrogenation reactions were carried out in a Berghof or
Parr 100-mL, stainless-steel autoclave and multi-screening hydro-
genations were performed in a home-made 96-micro-titer plate by
Bayer AG (Leverkusen, Germany). The catalytic reactions were
monitored by GC on a Hewlett–Packard 5890A. Conversion was
measured in an Ultra-2 (5% diphenylsilicone/95% dimethylsili-
cone) column (25 m×0.2 mm Ø). The enantiomeric excess was
measured directly in the reaction crude by NMR spectroscopy or
gas chromatography. N-(Phenylethylidene)benzylamine (17) was
1
determined by H NMR spectroscopy (with mandelic acid as the
resolution agent) or by GC, after derivatisation into the trifluo-
roacetamide compound, in a β-cyclodextrin phase. The enantio-
meric excess of N-(phenylethylidene)aniline (19) was determined by
GC, after derivatisation into the acetamide compound, in an MN
Hydrodex-6-TBDM (25 m × 0.25 mm × 0.25 m) column.
3,4-Bis-O-[bis(4-methoxyphenylphosphanyl)]-1,6-di-O-(tert-butyldi-
phenylsilyl)-2,5-anhydro-D-mannitol (10b). Procedure A: A flask
On the other hand, diphosphinites 10a–c and phosphin-
ite–phosphites 11a,b show a high substrate selectivity for
ketimines 17 and 19, which should be related to the confor-
mation and steric interaction of the coordinated ligands in
the complexes.[15,33]
equipped with a reflux condenser was charged with 2,5-anhydro-d-
mannitol derivative 12 (100 mg, 0.156 mmol). A solution of (dieth-
ylamino)bis(4-methoxyphenyl)phosphane (14b; 109 mg,
0.343 mmol) in anhydrous toluene (2.2 mL) was added. The mix-
ture was refluxed overnight and followed by TLC (hexane/ethyl
acetate, 5:1; Rf = 0.25). The residue was then purified by column
chromatography on silica gel under argon to give 40 mg (22.7%
yield) of compound 10b as a foam.
Conclusions
Procedure B: A solution of (diethylamino)bis(4-methoxyphenyl)-
phosphane (14b; 569 mg, 1.79 mmol) and tetrazole (5.1 mL, 0.45 m
in CH3CN) was stirred for 10 min at room temperature under ar-
We have synthesised new tunable diphosphinite (10a–d)
and phosphinite–phosphite (11a,b) ligands for use in asym-
metric catalysis from aminoglucose, and we have optimised gon. A solution of 12 (288 mg, 0.45 mmol) in anhydrous dichloro-
methane (3 mL) was then added and stirred for 30 min at room
temperature. The reaction was followed by TLC (hexane/ethyl ace-
tate, 5:1; Rf = 0.25). The residue was then purified by column
chromatography on silica gel under argon to give 301.2 mg (59%
yield) of compound 10b as a foam. [α]2D0 = 6.5 (c = 0.83, CH2Cl2).
MS (FAB): m/z (%) = 1129.31 (2.73) [M+]. HRMS (L-SIMS):
calcd. for C66H75O9P2Si2 1129.4069; found 1129.4130. 1H NMR
(400 MHz, C6D6, 25 °C): δ = 7.93 (m, 8 H, arom.), 7.67 (m, 8 H,
arom.), 7.26 (m, 12 H, arom.), 6.84 (m, 8 H, arom.), 5.38 (dd, J =
7.9, J = 4 Hz, 2 H, CH), 4.59 (m, 2 H, CH), 4.09 (dd, J = 10.9, J
the formation of the phosphinite function. These ligands
form catalytic systems in the presence of neutral or cationic
iridium complexes that are active in imine hydrogenation.
Precursors based on cationic [Ir(COD)2]BF4 provided bet-
ter yields and enantioselectivities than the neutral ones. The
catalytic systems [Ir(COD)2]BF4/10a–c did not afford sig-
nificant enantioselectivities in the hydrogenation of the im-
ine 17. However, when [Ir(COD)2]BF4/11a was used the ee
was 76%. Diphosphinite ligands 10, on the other hand,
were more effective in the reduction of imine 19, and when = 4.2 Hz, 2 H, CH2), 3.99 (dd, J = 10.9, J = 4.2 Hz, 2 H, CH2),
Eur. J. Org. Chem. 2006, 627–633
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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631

E. Guiu, M. Aghmiz, Y. Díaz, C. Claver, B. Meseguer, C. Militzer, S. Castillón
FULL PAPER
3.37 (s, 6 H, CH3O), 3.35 (s, 6 H, CH3O), 1.32 (s, 9 H, CH3), 1.27 tion of 4,8-di-tert-butyl-6-chloro-2,10-dimethyl-12H-di-
(s, 9 H, CH3) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 160.7–
benzo[δ,γ][1,3,2]dioxaphosphocine (18a; 100 mg, 0.252 mmol) in
113.9 (arom.), 85.0 (m, CH), 84.5 (CH), 64.1 (CH2), 55.25 (CH3O), anhydrous toluene (1 mL) and anhydrous pyridine (100 µL) was
55.23 (CH3O), 27.0 [C(CH3)3], 19.4 [C(CH3)3] ppm. 31P NMR added dropwise. The reaction mixture was then warmed to room
(161.9 MHz, CDCl3, 25 °C): δ = 115.1 ppm.
temperature and stirred, following the reaction by TLC (hexane/
ethyl acetate, 10:1; Rf = 0.55). Purification by column chromatog-
raphy on silica gel gave 100 mg (39.6% yield) of compound 11a as
a foam. [α]2D0 = 17.4 (c = 0.42, CH2Cl2). MS (FAB): m/z (%) =
1249.12 (3.91) [M+]. HRMS (L-SIMS): calcd. for C77H95O7P2Si2
3,4-Bis-O-[bis(4-trifluoromethylphenylphosphanyl)]-1,6-di-O-(tert-
butyldiphenylsilyl)-2,5-anhydro-D-mannitol (10c): A flask equipped
with a reflux condenser was charged with 2,5-anhydro-d-mannitol
derivative 12 (213 mg, 0.332 mmol). A solution of (diethylamino)-
bis(4-trifluoromethylphenyl) phosphane (14c; 352 mg, 0.897 mmol)
in anhydrous toluene (2.5 mL) was added. The mixture was re-
fluxed overnight and followed by TLC. The residue was then puri-
fied by column chromatography on silica gel under argon to give
40 mg (28% yield) of compound 10c as a foam. HRMS (L-SIMS):
calcd. for C66H63F12O5P2Si2 1281.3498: found 1281.3583. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 7.65–7.25 (m, 36 H, arom), 5.01 (m,
1
1249.6092; found 1249.6030. H NMR (400 MHz, CDCl3, 25 °C):
δ = 7.69–6.73 (m, 30 H, arom.), 5.79 (m, 1 H, CH), 4.92 (m, 1 H,
CH), 4.67 (m, 1 H, CH), 4.30 (m, 1 H, CH2), 4.13 (d, 2J = 12.4 Hz,
2
CH2), 3.98–3.72 (m, 4 H, CH2), 3.15 (d, J = 12.4 Hz,1 H, CH2),
2.31 (s, 3 H, CH3), 2.28 (s, 3 H, CH3), 2.26 (s, 9 H, CH3), 2.19 (s,
3 H, CH3), 1.29 (s, 9 H, CH3), 1.22 (s, 9 H, CH3), 1.04 (s, 9 H,
CH3), 0.98 (s, 9 H, CH3) ppm. 13C NMR (100.6 MHz, CDCl3,
25 °C): δ = 145.6–126.8 (CH, C, arom.), 85.9 (m, CH), 85.4 (CH),
85.2 (CH), 80.3 (m, CH), 64.3 (CH2), 63.9 (CH2), 34.8 (CH2), 31.2
[C(CH3)3], 31.1 [C(CH3)3], 27.0 [C(CH3)3], 26.9 [C(CH3)3], 21.5
2
3
2 H, CH), 4.18 (m, 2 H, CH), 3.82 (dd, J = 11.2, J = 4 Hz, 2 H,
CH2), 3.62 (dd, 2J = 11.2, 3J = 4 Hz, 2 H, CH2), 1.05 (s, 9 H,
CH3) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 134.3–125.3
(arom.), 122.7 (CF3), 86.2 (m, CH), 83.4 (CH), 63.6 (CH2), 27.0
[C(CH3)3], 19.5 [C(CH3)3] ppm. 31P NMR (161.9 MHz, CDCl3,
25 °C): δ = 110.5 ppm.
3
(CH3), 21.4 (CH3), 21.3 (CH3), 20.8 (d, J = 13.7 Hz, CH3), 20.6
(d, 3J = 13.7 Hz, CH3), 19.5 [C(CH3)3], 19.4 [C(CH3)3] ppm. 31P
NMR (161.9 MHz, CDCl3, 25 °C): δ = 127.9, 102.8 ppm.
1,6-Di-O-(tert-butyldiphenylsilyl)-4-O-{2,10-dimethyl-4,8-bis(1-
methylcyclohexyl)-12H-dibenzo[δ,γ][1,3,2]dioxaphosphocine}-3-O-
(2,4-dimethylphenylphosphanyl)-2,5-anhydro-D-mannitol (11b): Di-
3,4-Bis-O-[bis(2,4-dimethylphenylphosphanyl)]-1,6-di-O-(tert-butyl-
diphenylsilyl)-2,5-anhydro-
methylphenylphosphanyl)]-1,6-di-O-(tert-butyldiphenylsilyl)-2,5-anhy-
dro- -mannitol (15): A solution of (diethylamino)bis(2,4-dimeth-
D-mannitol (10d) and 3-O-[Bis(2,4-di-
phosphinite 15 (145 mg, 0.164 mmol) was dissolved in anhydrous
toluene (0.5 mL) and anhydrous pyridine (100 µL) and cooled to
0 °C. A solution of 6-chloro-2,10-dimethyl-4,8-bis(1-methylcyclo-
hexyl)-12H-dibenzo[δ,γ][1,3,2]dioxaphosphocine (18b; 100 mg,
0.252 mmol) in anhydrous toluene (1 mL) and anhydrous pyridine
(100 µL) was added dropwise. The reaction mixture was then
warmed to room temperature and stirred. Dry hexane was then
added to the mixture and the solution was filtered under argon.
Purification by column chromatography on silica gel under argon
gave 71 mg (32.4% yield) of compound 11b as a foam. [α]2D0 = 22.6
D
ylphenyl)phosphane (14d; 3.4 g, 10.9 mmol) and tetrazole (34 mL,
0.45 m in CH3CN, 15.3 mmol) was stirred for 10 min at room tem-
perature under argon. Compound 12 (878 mg, 1.37 mmol) was
added to this solution and stirred for 2 h at room temperature. The
reaction was followed by TLC (hexane/ethyl acetate, 10:1; Rf =
0.47). The residue was then purified by column chromatography on
silica gel under argon to give 630 mg (41% yield) of compound 10d
and 446 mg (37% yield) of 15.
10d: [α]2D0 = 8.0 (c = 0.71, CH2Cl2). HRMS (L-SIMS): calcd. for
1
(c = 0.50, CH2Cl2). MS (FAB): m/z (%) = 1328.16 (1.45) [M+]. H
1
C70H83O5P2Si2 1121.5254; found 1121.5290. H NMR (400 MHz,
NMR (400 MHz, CDCl3, 25 °C): δ = 7.71–6.74 (m, 30 H, arom.),
CDCl3, 25 °C): δ = 7.55–6.70 (m, 32 H, arom.), 4.66 (m, 1 H, CH),
4.09 (m, 1 H, CH), 3.65 (m, 2 H, CH), 3.54 (m, 2 H, CH), 2.14 (s,
6 H, CH3), 2.13 (s, 6 H, CH3), 2.12 (s, 6 H, CH3), 2.11 (s, 6 H,
CH3), 0.74 (s, 18 H, CH3) ppm. 13C NMR (100.6 MHz, CDCl3,
25 °C): δ = 141.0–126.7 (arom.), 85.5 (m, CH), 84.5 (CH), 64.2
(CH2), 27 [C(CH3)3], 20.7 (d, 3J = 7.74 Hz, CH3), 20.5 (d, 3J =
6.84 Hz, CH3), 20.5 (br., CH3), 19.4 [C(CH3)3] ppm. 31P NMR
(161.9 MHz, CDCl3, 25 °C): δ = 102.6 ppm.
5.67 (m, 1 H, CH), 4.85 (m, 1 H, CH), 4.62 (m, 1 H, CH), 4.30
(m, 1 H, CH), 4.12 (d, J = 12.8 Hz, 1 H, CH2), 4.01–3.74 (m, 4
2
H, CH2), 3.15 (d, 2J = 12.8 Hz, 1 H, CH2), 2.36 (s, 3 H, CH3), 2.29
(s, 2 H, CH3), 2.28 (s, 3 H, CH3), 2.27 (br., 6 H, CH3), 2.24 (s, 3
H, CH3), 1.54–1.12 (m, CH2), 1.16 (s, 3 H, CH3), 1.09 (s, 3 H,
CH3), 1.05 (s, 9 H, CH3), 0.97 (s, 9 H, CH3) ppm. 31P NMR
(161.9 MHz, CDCl3, 25 °C): δ = 127.8, 103.2 ppm.
General Procedure for the Ir-Catalysed Hydrogenation of Imines:
The initial screening of ligands used a homemade micro-titer plate,
and the best results were then tested in a single reactor using the
following procedure. [Ir(COD)Cl]2 (0.022 mmol) or [Ir(COD)2]BF4
(0.045 mmol) was dissolved in 10 mL of dry, degassed CH2Cl2 in a
Schlenk tube. The corresponding ligand (0.055 mmol) was then
added, followed by the corresponding imine (4.4 mmol for a 100:1
imine/Ir ratio). The solution was transferred under argon into the
autoclave with a syringe. The reaction mixture was stirred over-
night at room temperature under 70 bar of H2 pressure.
15: [α]2D0 = 17.8 (c = 0.89, CH2Cl2). MS (FAB): m/z (%) = 881.46
(4.39) [M+]. HRMS (L-SIMS): calcd. for C54H65O5PSi2 881.2357;
found 881.2385. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.59–6.87
(m, 26 H, arom.), 4.47 (m, 1 H, CH), 4.31 (m, 1 H, CH), 3.99 (m,
2 H, CH), 3.69 (m, 3 H, CH2), 3.54 (dd, 1 H, CH2), 2.79 (s, OH),
2.30 (s, 3 H, CH3), 2.17 (s, 3 H, CH3), 2.11 (s, 3 H, CH3), 2.06 (s,
3 H, CH3), 0.96 (s, 9 H, CH3), 0.94 (s, 9 H, CH3) ppm. 13C NMR
(100.6 MHz, CDCl3, 25 °C): δ = 138.1–127.6 (CH, C, arom.), 86.0
(2JC,P = 18 Hz, CH), 84.9 (CH), 83.9 (3JC,P = 6.13 Hz, CH), 78.0
(3JC,P = 4.5 Hz, CH), 64.7 (CH2), 64.1 (CH2), 27.2 [C(CH3)3], 27.0
[C(CH3)3], 21.44 [C(CH3)3],21.45 [C(CH3)3], 20.5 (d, 3J = 12.17 Hz,
CH3), 20.3 (d, 3J = 12.27 Hz, CH3), 19.6 (s, CH3), 19.5 (s, CH3) Acknowledgments
ppm. 31P NMR (161.9 MHz, CDCl3, 25 °C): δ = 102.7 ppm.
Financial support by Bayer AG, and the PROFIT program (FIT-
040000-2002-50) is acknowledged. Technical assistance by the
Servei de Recursos Cientifics (URV) is also acknowledged.
1,6-Di-O-(tert-butyldiphenylsilyl)-4-O-(4,8-di-tert-butyl-2,10-di-
methyl-12H-dibenzo[δ,γ][1,3,2]dioxaphosphocine)-3-O-(2,4-dimeth-
ylphenylphosphanyl)-2,5-anhydro-D-mannitol (11a): Monophosphin-
ite 15 (178 mg, 0.202 mmol) was dissolved in anhydrous toluene
(1 mL) and anhydrous pyridine (100 µL), cooled to 0 °C and a solu-
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FULL PAPER
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