Expanded scope of the asymmetric hydrogenation of minimally functionalized olefins catalyzed by iridium complexes with phosphite-thiazoline ligands

Article abstract of DOI:10.1002/cctc.201300189

We have replaced the oxazoline group with a thiazoline moiety in one of the most successful of the phosphite-oxazoline ligand families for the Ir-catalyzed hydrogenation of minimally functionalized olefins. A small but structurally important library of Ir phosphite-thiazoline precatalysts (Ir-L1-L2a-e) has been developed by changing the substituents/configurations at the biaryl phosphite group. We found that the replacement of the oxazoline with a thiazoline moiety in the ligand design is beneficial in terms of substrate scope.

Full text of DOI:10.1002/cctc.201300189

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DOI: 10.1002/cctc.201300189
Expanded Scope of the Asymmetric Hydrogenation of
Minimally Functionalized Olefins Catalyzed by Iridium
Complexes with Phosphite–Thiazoline Ligands
Javier Mazuela, Oscar Pꢀmies,* and Montserrat Diꢁguez*[a]
We have replaced the oxazoline group with a thiazoline
moiety in one of the most successful of the phosphite–oxazo-
line ligand families for the Ir-catalyzed hydrogenation of mini-
mally functionalized olefins. A small but structurally important
library of Ir phosphite–thiazoline precatalysts (Ir-L1–L2a–e) has
been developed by changing the substituents/configurations
at the biaryl phosphite group. We found that the replacement
of the oxazoline with a thiazoline moiety in the ligand design
is beneficial in terms of substrate scope.
Introduction
The synthetic challenges that arise from the high degree of
enantiopurity required in life-science products have stimulated
the development and industrial application of asymmetric cat-
alysis.[1] Asymmetric hydrogenation is a fundamental technique
in the modern organic chemist’s repertoire of reliable catalytic
methods to construct optically active compounds. High enan-
tioselectivity, low catalyst loadings, essentially quantitative
yields, perfect atom economy, and mild conditions are attrac-
tive features of this transformation as is evident in the ever
growing list of publications that use these methods.[1] Al-
though the reduction of olefins that contain an adjacent polar
group (i.e., dehydroamino acids) by Rh- and Ru-based catalyst
precursors modified with P ligands has a long history, the
asymmetric hydrogenation of minimally functionalized olefins
is less developed because these substrates have no adjacent
polar group to direct the reaction.[2] A breakthrough in the hy-
drogenation of this type of substrate was made when Pfaltz
and co-workers used Ir complexes, [Ir(PHOX)(cod)]BArF (COD=
cyclooctadiene, BArF =tetrakis[3,5-bis(trifluoromethyl)phenyl]-
borate), modified with phosphane–oxazoline (PHOX) ligands as
chiral analogues of Crabtree’s catalyst ([Ir(py)(PCy3)(cod)]PF6)
(py=pyridine, PCy3 =tricyclohexylphosphane).[3] Since then,
the composition of the ligands has been extended by intro-
ducing P-donor groups (or carbene analogues) other than
phosphanes and N-donor groups other than oxazolines and
varying the chiral backbone.[4] More recently, the ligand scope
has also been extended to the use of other non-N-containing
heterodonor ligands such as P,O and P,S ligands.[5] However,
most of the chiral catalysts that have been developed are still
highly substrate dependent and the development of efficient
chiral ligands that tolerate a broader range of substrates, with
the aim to synthesize more complex molecules, remains a -
challenge.[2]
Some years ago, we discovered that the presence of biaryl
phosphite moieties in ligand design is highly advantageous in
this process.[6] Ir phosphite–oxazoline catalytic systems provide
greater substrate versatility and high activities and enantiose-
lectivities for several largely unfunctionalized E- and Z-trisubsti-
tuted and 1,1-disubstituted olefins than previous Ir phosphin-
ite–oxazoline systems. In this context, we have successfully
used an amino-acid-derived phosphite–oxazoline ligand library
(LP-Ox, Figure 1) to reduce minimally functionalized olefins,[6b,c]
and this is one of the two phos-
phite-containing ligand families
with the broadest substrate sco-
pe.[6a–c,e] Although this phosphite–
oxazoline ligand library proved to
be highly efficient in the hydroge-
nation of unfunctionalized aryl
alkyl E-trisubstituted and 1,1-disub-
stituted olefins, some substrates
(such as Z-trisubstituted olefins,
a,b-unsaturated ketones, and tri-
fluoromethyl olefins) still need im-
proved enantioselectivities.
Figure 1. Basic structure
of LP-Ox
.
[a] Dr. J. Mazuela, Dr. O. Pꢀmies, Prof. M. Diꢁguez
Departament de Quꢂmica Fꢂsica i Inorgꢀnica
Universitat Rovira i Virgili
To address this point, in this study we designed a new
family of ligands in which the oxazoline group of LP-Ox is re-
placed by a thiazoline moiety to give ligands L1–L2a-e
(Figure 2).[7] We expected the subtle variation in the basicity of
the N-donor group (the thiazoline group is more basic than
the oxazoline) and the steric properties[8] caused by the sub-
stituent at the N-heteroatom ring that replaces the non-coordi-
nating heteroatom to allow the catalysts to be fine-tuned for
the most challenging substrates. We report here the applica-
C/Marcel·li Domingo
s/n. 43007 Tarragona (Spain)
Fax: 34-977559563
Tel: 34-977558780
E-mail: oscar.pamies@urv.cat
montserrat.dieguez@urv.cat
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201300189.
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line alcohol 2 is prepared from R-cysteine methyl ester hydro-
chloride (1) as shown in Scheme 1. L1d–e were stable during
purification on neutral alumina under Ar and isolated in good
yields as white solids. They were stable at room temperature
and very stable to hydrolysis. The elemental analyses were in
agreement with the assigned structures. The 1H, 13C, and
31P NMR spectra were as expected for these C1-symmetric
ligands.
Synthesis of Ir catalyst precursors
Ir complexation and subsequent chloride abstraction with
NaBArF were performed in a one-pot process using a literature
procedure[6] to afford [Ir(cod)(L)]BArF (L=L1–L2a–e) complexes
in almost quantitative yields in a pure form as air-stable
orange solids (Scheme 2).
Figure 2. Phosphite–thiazoline L1–L2a–e and phosphite–oxazoline L3a–e
The complexes were characterized by elemental analysis and
1H, 13C, and 31P NMR spectroscopy. The spectral assignments
ligands.
1
were based on information from H-1H and 13C-1H correlation
tion of a small but structurally relevant library of Ir phosphite–
thiazoline precatalysts (Ir-L1–L2a–e) in the asymmetric hydro-
genation of a wide range of E- and Z-trisubstituted and 1,1-dis-
ubstituted terminal olefins, which include examples with
neighboring polar groups. We
measurements and were as expected for these C1-symmetric Ir
complexes. The variable-temperature NMR (VT-NMR) spectra in-
dicate that only one isomer is present in solution. One singlet
in the 31P{1H} NMR spectra was obtained in all cases.[10]
have compared the effective-
ness of L1–L2a–e and related
privileged phosphite–oxazoline
ligands (L3, Figure 2). To this
end, we have expanded our
[6b–c]
previous work on LP-Ox
to
cover the asymmetric reduction
Scheme 2. Synthesis of [Ir(cod)(P-N)]BArF (P-N=L1–L2a–e).
of a wider range of challenging
minimally functionalized olefins.
Interestingly, we found that the reactivity and selectivity of the
new Ir phosphite–thiazoline catalysts are excellent and similar
to those of their phosphite–oxazoline analogues for most sub-
strates and they performed better for the more challenging
substrates.
Asymmetric hydrogenation of trisubstituted olefins
Minimally functionalized E- and Z-trisubstituted olefins
To evaluate the potential of L1–L2a–e in the Ir-catalyzed hy-
drogenation of E-trisubstituted olefins, a comparative study
that used substrates S1–S4 was performed, and the results are
shown in Table 1. Excellent activities and enantioselectivities
(up to 99%) were obtained. We found that the enantioselectiv-
ity is slightly affected by the substituents at the biaryl phos-
phite moiety (Table 1, entries 1 and 2 vs. 3). The best enantio-
selectivities were obtained with L1c, which contains bulky tri-
methylsilyl groups at the ortho position of the biphenylphos-
phite moiety (Table 1, entry 3). We also found that the configu-
ration at the biaryl phosphite moiety does not affect the
enantioselectivity (Table 1, entries 4 and 5). This is in contrast
with the positive effect on enantioselectivity observed in the
related phosphite–oxazoline ligands if enantiopure S config-
ured biaryl phosphite moieties were used.[6b]
Results and Discussion
Ligand synthesis
The new phosphite–thiazoline ligands L1d–e were synthesized
straightforwardly by using the procedure described previously
for L1–L2a–c (Scheme 1).[7] L1d–e were efficiently synthesized
by reacting the corresponding thiazoline alcohol 2 with one
equivalent of the appropriate in situ formed phosphorochlori-
dite (ClP(OR)2; (OR)2 =d–e) in the presence of pyridine. Thiazo-
Finally, if we compared the results obtained with L1a and
L2a we found that the different configuration of the alkyl
backbone controls the enantioselectivity (Table 1, entries 1 vs.
6). Both enantiomers of the reduced products are, therefore,
accessible in high enantioselectivities. Overall, catalyst Ir-L1c
offers the best enantioselectivity and compares well with the
Scheme 1. Synthesis of L1d–e. a) Ethyl benzimidate hydrochloride,[9]
b) MeMgBr/THF/Et2O,[7] c) ClP(OR)2, (OR)2 =d–e/Py/toluene.
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has an R-biaryl configuration (Table 2, entries 4 and
5). However, the enantioselectivities were best with
the tropoisomeric biphenyl-containing ligand L1a,
which contained tert-butyl groups at both the ortho
and para positions. This confirms that although the
configuration of the biaryl phosphite moiety affects
the enantioselectivity, the presence of a tert-butyl
group at the para position of the biaryl phosphite
moiety is crucial if enantioselectivities are to be
high.
Table 1. Ir-catalyzed asymmetric hydrogenation of E-trisubstituted S1–S4 using L1–
L3a–e.[a]
Entry Ligand ee [%][b]
ee [%][b]
ee [%][b]
ee [%][b]
1
2
3
4
5
6
7
L1a
L1b
L1c
L1d
L1e
L2a
L3c
97 (R)
98 (R)
99 (R)
97 (R)
97 (R)
97 (S)
98 (R)[6b]
96 (R)
97 (R)
99 (R)
96 (R)
96 (R)
96 (S)
98 (R)
96 (R)
96 (R)
98 (R)
97 (R)
96 (R)
95 (S)
98 (R)
96 (R)
96 (R)
98 (R)
95 (R)
95 (R)
96 (S)
98 (R)
Interestingly, if the results of the reduction of E-
and Z-trisubstituted olefins are compared with the
enantioselectivities obtained with the correspond-
ing Ir phosphite–oxazoline systems, we can con-
clude that the introduction of a thiazoline moiety
into the ligand design is advantageous (Table 2,
entry 1 and 6 vs. 7). Therefore, although for E-trisub-
stituted olefins comparable, excellent enantioselec-
[a] Reactions performed at RT by using 0.5 mmol of substrate and 0.25 mol% of Ir cata-
lyst precursor at 50 bar of H2 using CH2Cl2 (2 mL) as solvent. Full conversions were ob-
tained in all cases after 2 h. [b] ee determined by HPLC (S1 and S2) or GC (S3 and S4).
analogous phosphite–oxazoline catalyst (Table 1, entries 3 vs.
7).[6b]
tivities were obtained, for Z-trisubstituted olefins, the enantio-
selectivities were improved by using phosphite–thiazoline li-
gands. In summary, by appropriately tuning the thiazoline-
based ligands, excellent enantioselectivities were achieved in
the hydrogenation of a broad range of E- and Z-trisubstituted
olefins.
To further assess the scope of L1–L2a–e, we investigated
the asymmetric hydrogenation of more demanding Z isomers
(S5–S7), which are usually hydrogenated with a lower enantio-
selectivity than the corresponding E isomers. By carefully se-
lecting the ligand parameters, we were able to obtain both
enantiomers of the hydrogenated products in high enantiose-
lectivities (ee values up to 96%) by using Ir-L1a and Ir-L2a.
The results followed a different trend than those for E config-
ured substrates (Table 2). The enantioselectivities were, there-
Trisubstituted olefins that contain a neighboring polar group
Substrates that bear a neighboring polar group need to be re-
duced because they are important intermediates in the synthe-
sis of high-value chemicals and their reduced products allow
further functionalization. Therefore, the development of sus-
tainable enantioselective routes to these compounds is of
great value. We decided to further study the potential of L1–
L2a–e in the reduction of a wide range of trisubstituted al-
kenes that contain several types of polar groups, and the re-
sults are summarized in Figure 3. Again, excellent enantioselec-
tivities were obtained in both enantiomers of the reduction
products (ee values up to 99%) for a range of substrates under
mild reaction conditions by suitable tuning of the ligand
parameters.
Table 2. Ir-catalyzed asymmetric hydrogenation of Z-trisubstituted S5–S7
using L1–L3a–e.[a]
Entry
Ligand ee [%][b]
ee [%][b]
ee [%][b]
1
2
3
4
5
6
7
L1a
L1b
L1c
L1d
L1e
L2a
L3a
95 (S)
83 (S)
79 (S)
58 (S)
74 (S)
94 (R)
92 (S)[6b]
94 (S)
84 (S)
79 (S)
61 (S)
73 (S)
94 (R)
91 (S)
96 (S)
83 (S)
80 (S)
72 (S)
81 (S)
95 (R)
93 (S)
We first studied the hydrogenation of several a,b-unsaturat-
ed ketones (S8–S12) for which the related Ir phosphite–oxazo-
line catalytic systems were not optimal. Enantioselectivities of
up to 99% for both enantiomers of the hydrogenated product
were obtained by using Ir-L1a and Ir-L2a. Notably, the ee
values are independent of the electronic nature of the sub-
strate phenyl ring and the substituent in the ketone functional-
ity. Ir-L1a and Ir-L2a also provided excellent enantioselectivi-
ties in the reduction of allylic alcohol S13 and allylic acetate
S14. If we compare all these results with those achieved by
using the related Ir phosphite–oxazoline catalysts, again the in-
troduction of a thiazoline group was beneficial for enantiose-
lectivity (i.e., for S8, the ee improved from 93% with the relat-
ed phosphite–oxazoline ligand[11] to 99%).
[a] Reactions performed at RT by using 0.5 mmol of substrate and
0.25 mol% of Ir catalyst precursor at 50 bar of H2 using CH2Cl2 (2 mL) as
solvent. Full conversions were obtained in all cases after 2 h. [b] ee deter-
mined by GC.
fore, affected by both the substituents and the configuration
of the biaryl phosphite moiety. Unlike the hydrogenation of E
configured substrates, the enantioselectivities improved with
the introduction of bulky substituents at the para positions of
the biaryl phosphite moiety (i.e., tBu>OMe>H; Table 2, en-
tries 1–3). We also found a cooperative effect between the
configurations of the biaryl phosphite moiety and the ligand
backbone that leads to a matched combination for L1e, which
We then studied the hydrogenation of several a,b-unsaturat-
ed esters (S15–S18). We were pleased to find that the excel-
lent enantioselectivities achieved with phosphite–oxazoline li-
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vide high enantioselectivities for these substrates,
and those that do usually have a limited substrate
scope.[2d,e,12a,b,14] LP-Ox is one of the two most versatile
ligand families for the hydrogenation of this class of
substrates.[6c]
In an initial set of experiments, we used the Ir-cata-
lyzed asymmetric hydrogenation of 2-(4-methoxyphe-
nyl)but-1-ene (S20), and the results for the optimized
conditions are shown in Table 3. We were again able
to fine-tune the ligand parameters to produce high
activities and enantioselectivities (ee values up to
99%) in the hydrogenation of S20 using L1e at low
catalyst loadings (0.25 mol%) and H2 pressures [1 bar
(100 kPa)]. Again, both enantiomers of the hydrogen-
ated product can be obtained simply by changing
the configuration of the alkyl backbone (i.e., Table 3,
entries 1 vs. 6). In contrast to the reduction of E-tri-
substituted substrates, the enantioselectivity is
mainly affected by the configuration at the biaryl
phosphite moiety (Table 3, entries 4 and 5). This be-
havior is similar to that observed in the hydrogena-
tion of Z-trisubstituted olefins. However, for disubsti-
tuted S20, the presence of an enantiopure bulky (R)-
biaryl phosphite moiety is crucial if the enantioselec-
tivities of the ligand series are to be at their highest.
Figure 3. Selected hydrogenation results of trisubstituted olefins that bear a neighboring
polar group by using [Ir(cod)(L1–L2a–e)]BArF catalyst precursors. Reaction conditions:
0.5 mol% catalyst precursor, CH2Cl2 as solvent, 50 bar H2, RT, 2 h. Full conversions were
achieved in all cases.
gands[6b] (i.e., 99% ee for S15 using Ir-L3c) can be maintained
Table 3. Ir-catalyzed hydrogenation of S20 using L1–L2a–e.[a]
with the phosphite–thiazoline analogues. Ir-L1c, therefore, pro-
vided enantioselectivities up to 99%. For a,b-unsaturated ke-
tones, the enantioselectivities are highly independent of the
electronic nature of the substrate phenyl ring and the substitu-
ent in the ester function, which allows the successful asymmet-
ric reduction of a wide range of a,b-unsaturated esters.
High enantioselectivities (up to 99% ee) were also obtained
in the hydrogenation of vinylsilane S19 by using Ir-L1e. Com-
parison with related phosphite–oxazoline catalytic systems
again showed that the introduction of a thiazoline group led
to higher enantioselectivities (ee improved from 94% using Ir-
L3 to 99%).[12]
Entry
Ligand
Conversion [%][b]
ee [%][c]
1
2
3
4
5
6
7
L1a
L1b
L1c
L1d
L1e
L2a
L3a
100
100
100
100
100
100
100
94 (S)
92 (S)
95 (S)
78 (S)
99 (S)
94 (R)
91 (S)
[a] Reactions performed using 0.5 mmol of S20 and 0.25 mol% of Ir cata-
lyst precursor at 1 bar of H2. [b] Conversion measured by GC after 2 h.
[c] ee Values determined by chiral GC.
To sum up, this is one of the few catalytic systems that can
hydrogenate a wide range of trisubstituted olefins, including
those with a neighboring polar group, with high activities and
enantioselectivities.[2]
This finding contrasts with the positive effect on enantioselec-
tivity observed if an (S)-binaphthylphosphite moiety was used
in the related phosphite–oxazoline ligands.[6c] Again, the re-
placement of the oxazoline moiety by a thiazoline group is
beneficial in terms of enantioselectivity (Table 3, entries 1 vs.
7).
Asymmetric hydrogenation of 1,1-disubstituted terminal
olefins
To further study the potential of L1–L2a–e, we tested them in
the asymmetric hydrogenation of more demanding terminal
olefins.[13] The enantioselectivity obtained with 1,1-disubstitut-
ed terminal olefins is lower than that with trisubstituted olefins
largely because of the isomerization of the terminal double
bond to the more stable internal trans-alkene, which usually
leads to the predominant formation of the opposite enantio-
mer of the hydrogenated product and/or to difficulty in con-
trolling face selectivity.[2d,e] Few known catalytic systems pro-
Next, we evaluated L1–L2a–e in the asymmetric hydrogena-
tion of other 1,1-disubstituted substrates, which include those
that contain an heteroaromatic ring and a neighboring polar
group, and notable results are shown in Table 4. The results
followed the same trend as for the hydrogenation of S20.
Again, the catalyst precursor that contained L1e provided the
best enantioselectivities.
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properties of the alkyl substituent. Therefore, several para-sub-
stituted 2-phenylbut-2-enes (S20–S22; Table 3, entry 5 and
Table 4, entries 1 and 2) and several a-alkyl styrenes (S23–S28;
Table 4, entries 3–8) were hydrogenated, and excellent enantio-
selectivities were achieved (ee values from 91–99%). Although
these results are comparable to those obtained with related
chiral phosphite–oxazoline ligands,[6c] it should be noted that
for S23–S25 the presence of a thiazoline group led to higher
enantioselectivities (i.e., for S23, the ee increased from 94 to
98%).[6c] As heterocycles are of interest to industry and as the
heterocyclic part can be further modified after hydrogenation,
we investigated whether phosphite–thiazoline ligands can also
be used in the hydrogenation of 1,1-heteroaromatic terminal
olefins (Table 4, entries 9–11). We were pleased to find that sev-
eral pyridine- and thiophene-containing substrates S29–S31
were also readily hydrogenated in high enantioselectivities
using Ir-L1e (ee up to 99%).
Finally, we also examined the hydrogenation of several 1,1-
disubstitued terminal olefins that contain a neighboring polar
group, which give rise to important intermediates for the syn-
thesis of high-value products (e.g., derivatives of the hydro-
genated product 2-phenylpropanol are frequently used in the
fragrance industry).[15] Allylic alcohol S32, allylic acetate S33,
and allylic silane S34 were hydrogenated with similar high effi-
ciencies (ee values from 91–94%; Table 4, entries 12–14). Ir-L1e
clearly outperforms complexes of related phosphite–oxazoline
ligands in the asymmetric hydrogenation of trifluoromethyl
olefin S35 (99% ee using Ir-L1e vs. 75% ee using related Ir
phosphite–oxazoline catalysts).[6c] In addition, this result com-
pares favorably with the best reported in the literature and
opens up the possibility of using Ir hydrogenation catalysts to
develop chiral organofluorine drug intermediates.[16]
Table 4. Selected results for the Ir-catalyzed hydrogenation of minimally
functionalized 1,1-disubstituted terminal olefins using L1–L2a–e.[a]
Entry
1
Substrate
Ligand
ee [%][b]
99 (S)
L1e
2
L1e
98 (S)
3
4
5
L1e
L1e
L1e
98 (S)
97 (S)
93 (S)
6
L1e
L1e
L1e
L1e
L1e
L1e
91 (S)
94 (S)
99 (S)
98 (+)
99 (+)
95 (À)
7
8
9
10
11
Conclusion
We have replaced the oxazoline group with a thiazoline
moiety in one of the most successful phosphite–oxazoline
ligand families (LP-Ox, Figure 1) for the Ir-catalyzed hydrogena-
tion of minimally functionalized olefins. A small but structurally
important library of Ir phosphite–thiazoline precatalysts (Ir-L1–
L2a–e) has been developed by changing the substituents/con-
figurations at the biaryl phosphite group. By tuning these
ligand parameters appropriately, we achieved excellent enan-
tioselectivities in the hydrogenation of a wide range of E- and
Z-trisubstituted and 1,1-disubstituted terminal olefins, which
included examples with neighboring polar groups. We have
found that replacing the oxazoline with a thiazoline moiety in
the ligand design is beneficial in terms of the substrate scope.
Thus, the range of substrates that can be hydrogenated with
excellent enantioselectivities with the new Ir phosphite–thiazo-
line catalysts has been extended because more challenging Z-
trisubstituted olefins, a,b-unsaturated ketones, and trifluoro-
methyl olefins have been included. These results open up
a new class of ligands for the highly enantioselective Ir-cata-
lyzed hydrogenation of a wide range of substrates, which com-
pares favorably with the best reported in the literature.
12[c]
13[c]
14[c]
15
L1e
L1e
L1e
L1e
94 (R)
91 (R)
93 (S)
99 (À)
[a] Reactions performed using 0.5 mmol of substrate and 0.25 mol% of Ir
catalyst precursor at 1 bar of H2. Full conversion were achieved after 2 h.
[b] ee Values determined by chiral GC. [c] Reaction performed under
50 bar of H2.
Our results with several 1,1-disubstituted aryl alkyl substrates
(S20–S28) indicated that enantioselectivity is relatively insensi-
tive to the electronic effects in the aryl ring and to the steric
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Preparation of [Ir(cod)(L)]BArF
Experimental Section
General procedure: The appropriate ligand (0.074 mmol) was dis-
solved in CH2Cl2 (2 mL), and [Ir(m-Cl)cod]2 (25 mg, 0.037 mmol) was
added. The reaction was heated to reflux at 508C for 1 h. After
5 min at RT, NaBArF (77.1 mg, 0.082 mmol) and water (2 mL) were
added, and the reaction mixture was stirred vigorously for 30 min
at RT. The phases were separated, and the aqueous phase was ex-
tracted twice with CH2Cl2. The combined organic phases were fil-
tered through a Celite plug, dried with MgSO4, and the solvent
was evaporated to give the product as an orange solid.
General
All reactions were performed by using standard Schlenk tech-
niques under Ar. Solvents were purified and dried by standard pro-
cedures. Phosphorochloridites were prepared easily in one step
from the corresponding biaryls.[17] L1a–c,[7] L2a,[7] and [Ir-
were prepared as reported previously. H, 13C{1H},
[6b,c]
1
(cod)(L3)]BArF
and 31P{1H} NMR spectra were recorded by using a 400 MHz spec-
trometer. Chemical shifts are reported relative to that of SiMe4 (1H
and 13C) as an internal standard or H3PO4 (31P) as an external stan-
1
dard. H, 13C and 31P NMR assignments were made on the basis of
[Ir(cod)(L1a)]BArF: Yield: 124 mg (92%); 31P NMR (CDCl3): d=
99.7 ppm (s); 1H NMR (CDCl3): d=1.11 (s, 3H, CH3), 1.34 (s, 3H,
CH3), 1.46 (s, 9H, CH3, tBu), 1.56 (s, 9H, CH3, tBu), 1.64 (s, 9H, CH3,
tBu), 1.72 (s, 9H, CH3, tBu), 2.1–2.3 (b, 5H, CH2, cod), 2.32 (b, 1H,
CH2, cod), 2.39 (b, 2H, CH2, cod), 3.25 (m, 1H, CH2ÀS), 3.72 (m, 1H,
CH2ÀS), 4.32 (m, 1H, CH=cod), 4.54 (m, 1H, CH=cod), 5.09 (m, 1H,
CH=cod), 5.13 (m, 1H, CHÀN), 6.6–8.4 ppm (m, 21H, CH=); 13C NMR
(CDCl3): d=24.5 (CH3), 27.5 (CH2 cod), 27.7 (CH2 cod), 28.4 (CH3),
30.4 (CH3), 30.6 (CH3, tBu), 30.8 (CH3, tBu), 31.0 (CH2 cod), 32.2 (CH3,
tBu), 33.3 (CH2ÀS), 35.1 (C, tBu), 35.3 (C, tBu), 35.5 (C, tBu), 35.7 (C,
1H-1H gradient COSY (gCOSY), H-13C gHSQC, and H-31P gHMBC ex-
1
1
periments. All catalytic experiments were performed three times.
Preparation of the phosphite–thiazoline ligands
General procedure: The appropriate phosphorochloridite
(3.0 mmol) produced in situ was dissolved in toluene (12.5 mL),
and pyridine (1.14 mL, 14 mmol) was added. The corresponding
hydroxylthiazoline (2.8 mmol) was dried azeotropically with tolu-
ene (3ꢃ2 mL) and then dissolved in toluene (12.5 mL) to which
pyridine (1.14 mL, 14 mmol) was added. This solution was trans-
ferred slowly at 08C to the solution of phosphorochloridite. The re-
action mixture was stirred overnight at 808C, and the pyridine salts
were removed by filtration. Evaporation of the solvent gave
a white foam, which was purified by flash chromatography on alu-
mina to produce the corresponding ligand as a white solid.
tBu), 67.5 (CH=cod), 69.9 (CH=cod), 84.2 (CHÀN), 85.5 (d, C, JCÀP
=
=
4.2 Hz), 96.7 (d, CH=cod, JCÀP =16.4 Hz), 104.6 (d, CH=cod, JCÀP
12.0 Hz), 117.4 (b, CH=, BArF), 120–132 (aromatic carbon atoms),
134.7 (b, CH=, BArF), 135.8–157 (aromatic carbon atoms), 161.9 (q,
CÀB, BArF, 1JCÀB =49 Hz), 179.9 ppm (s, C=N); elemental analysis
calcd (%) for C80H78BF24IrNO3PS (1823.51): C 52.69, H 4.31, N 0.77, S
1.76; found: C 52.73, H 4.33, N 0.75, S 1.72.
[Ir(cod)(L1b)]BArF: Yield: 122 mg (93%); 31P NMR (CDCl3): d=
96.3 ppm (s); 1H NMR (CDCl3): d=1.11 (s, 3H, CH3), 1.34 (s, 3H,
CH3), 1.46 (s, 9H, CH3, tBu), 1.56 (s, 9H, CH3, tBu), 2.1–2.3 (b, 5H,
CH2, cod), 2.29 (b, 1H, CH2, cod), 2.39 (b, 2H, CH2, cod), 3.23 (m,
1H, CH2ÀS), 3.68 (m, 2H, CH2ÀS and CH=cod), 3.76 (s, 3H, CH3ÀO),
3.77 (s, 3H, CH3ÀO), 4.29 (m, 1H, CH=cod), 4.51 (m, 1H, CH=cod),
5.17 (m, 1H, CH=cod), 5.22 (m, 1H, CHÀN), 6.6–8.4 ppm (m, 21H,
CH=); 13C NMR (CDCl3): d=24.5 (CH3), 27.5 (CH2 cod), 27.7 (CH2
cod), 28.4 (CH3), 30.4 (CH2 cod), 30.6 (CH3, tBu), 30.8 (CH3, tBu), 31.0
(CH2 cod), 33.1 (CH2ÀS), 35.1 (C, tBu), 35.5 (C, tBu), 55.6 (CH3ÀO),
L1d: Yield: 428 mg (71%); 31P NMR (400 MHz, C6D6): d=150.6 ppm
(s); H NMR (C6D6): d=1.48 (s, 9H, CH3, tBu), 1.55 (s, 9H, CH3, tBu),
1
1.60 (s, 3H, CH3), 1.62 (s, 3H, CH3), 1.73 (s, 3H, CH3), 1.80 (s, 3H,
2
CH3), 2.01 (s, 3H, CH3), 2.07 (s, 3H, CH3), 2.57 (dd, 1H, JHÀH
=
=
3
2
3
12.0 Hz, JHÀH =8.8 Hz, CH2ÀS), 2.83 (dd, 1H, JHÀH =12.0 Hz, JHÀH
10 Hz, CH2ÀS), 4.53 (m, 1H, CHÀN), 6.7–8.2 ppm (m, 7H, CH=);
13C NMR (C6D6): d=16.9 (CH3ÀAr), 17.1 (CH3ÀAr), 19.2 (CH3ÀAr),
20.1 (CH3ÀAr), 23.6 (CH3), 28.1 (d, CH3, JCÀP =7.8 Hz), 31.4 (CH3, tBu),
32.1 (CH3, tBu), 33.7 (CH2ÀS), 82.1 (C), 87.3 (CHÀN), 123.8 (CH=),
128.3 (CH=), 127.0 (C), 127.3 (C), 128.9 (CH=), 132.2 (CH=), 132.7
(CH=), 133.0 (C), 137.3 (C), 144.9 (C), 146.1 (C), 146.7 (C), 148.8 (C),
149.1, 167.4 ppm (C=N); elemental analysis calcd (%) for
C36H46NO3PS (603.29): C 71.61, H 7.68, N 2.32, S 5.31; found: C
71.67, H 7.70, N 2.29, S 5.27.
67.2 (CH=cod), 69.8 (CH=cod), 83.6 (CHÀN), 85.7 (d, C, JCÀP
=
=
5.4 Hz), 95.8 (d, CH=cod, JCÀP =18.7 Hz), 105.8 (d, CH=cod, JCÀP
12.2 Hz), 113.2 (CH=), 114.5 (CH=), 114.8 (CH=), 117.4 (b, CH=, BArF),
120–132 (aromatic carbon atoms), 134.7 (b, CH=, BArF), 135.8–157
(aromatic carbon atoms), 161.9 (q, CÀB, BArF, 1JCÀB =49 Hz),
182.9 ppm (s, C=N); elemental analysis calcd (%) for
C74H66BF24IrNO5PS (1771.37): C 50.18, H 3.76, N 0.79, S 1.81; found:
C 50.24, H 3.73, N 0.76, S 1.78.
L1e: Yield: 380 mg (63%); 31P NMR (400 MHz, C6D6): d=152.1 ppm
1
(s); H NMR (C6D6): d=1.46 (s, 9H, CH3, tBu), 1.54 (s, 9H, CH3, tBu),
1.58 (s, 3H, CH3), 1.64 (s, 3H, CH3), 1.75 (s, 3H, CH3), 1.89 (s, 3H,
2
CH3), 2.01 (s, 3H, CH3), 2.05 (s, 3H, CH3), 2.61 (dd, 1H, JHÀH
=
=
[Ir(cod)(L1c)]BArF: Yield: 116 mg (90%); 31P NMR (CDCl3): d=
3
2
3
12.0 Hz, JHÀH =7.2 Hz, CH2ÀS), 2.81 (dd, 1H, JHÀH =12.0 Hz, JHÀH
1
96.3 ppm (s); H NMR (CDCl3): d=0.36 (s, 9H, CH3ÀSi), 0.84 (s, 9H,
10 Hz, CH2ÀS), 4.58 (m, 1H, CHÀN), 6.7–8.2 ppm (m, 7H, CH=);
13C NMR (C6D6): d=16.8 (CH3ÀAr), 17.1 (CH3ÀAr), 19.8 (CH3ÀAr),
20.0 (CH3ÀAr), 23.5 (CH3), 28.2 (d, CH3, JCÀP =7.8 Hz), 31.5 (CH3, tBu),
31.7 (CH3, tBu), 33.4 (CH2ÀS), 82.0 (C), 87.3 (CHÀN), 123.9 (CH=),
128.5 (CH=), 126.8 (C), 127.0 (C), 128.5 (CH=), 129.7 (CH=), 132.1
(CH=), 132.8 (CH=), 133.1 (C), 136.8 (C), 145.1 (C), 146.4 (C), 146.6
(C), 148.9 (C), 149.1, 167.2 ppm (C=N); elemental analysis calcd (%)
for C36H46NO3PS (603.29): C 71.61, H 7.68, N 2.32, S 5.31; found: C
71.64, H 7.70, N 2.30, S 5.29.
CH3ÀSi), 1.26 (s, 3H, CH3), 1.42 (s, 3H, CH3), 2.0–2.4 (b, 6H, CH2,
cod), 2.44 (b, 2H, CH2, cod), 3.22 (m, 1H, CH2ÀS), 3.59 (m, 2H, CH2À
S and CH=cod), 4.11 (m, 1H, CH=cod), 4.34 (m, 1H, CH=cod), 5.01
(m, 1H, CH=cod), 5.14 (m, 1H, CHÀN), 6.6–8.4 ppm (m, 23H, CH=);
13C NMR (CDCl3): d=0.2 (d, CH3ÀSi, JCÀP =6.2 Hz), 1.2 (CH3ÀSi), 24.2
(CH3), 27.7 (CH2 cod), 27.9 (CH3), 28.2 (CH2 cod), 30.3 (CH2 cod),
33.7 (CH2ÀS), 68.3 (CH=cod), 70.3 (CH=cod), 83.7 (CHÀN), 85.1 (C),
97.2 (d, CH=cod, JCÀP =12.6 Hz), 104.2 (d, CH=cod, JCÀP =12.6 Hz),
117.4 (b, CH=, BArF), 120–132 (aromatic carbon atoms), 134.7 (b,
CH=, BArF), 135.8–157 (aromatic carbon atoms), 161.9 (q, CÀB, BArF,
1JCÀB =49 Hz), 181.1 ppm (s, C=N); elemental analysis calcd (%) for
C70H62BF24IrNO3PSSi2 (1743.31): C 48.22, H 3.58, N 0.80, S 1.84;
found: C 48.26, H 3.61, N 0.79, S 1.81.
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[Ir(cod)(L1d)]BArF: Yield: 124 mg (95%); 31P NMR (CDCl3): d=
99.1 ppm (s); 1H NMR (CDCl3): d=1.19 (s, 3H, CH3), 1.28 (s, 3H,
CH3), 1.43 (s, 9H, CH3, tBu), 1.49 (s, 9H, CH3, tBu), 1.85 (s, 3H, CH3),
1.92 (s, 3H, CH3), 2.04 (s, 3H, CH3), 2.12 (s, 3H, CH3ÀSi), 2.1–2.5 (b,
8H, CH2, cod), 3.19 (m, 1H, CH2ÀS), 3.57 (m, 1H, CH=cod), 3.62 (m,
1H, CH2ÀS), 3.99 (m, 1H, CH=cod), 4.39 (m, 1H, CH=cod), 5.04 (m,
1H, CH=cod), 5.26 (m, 1H, CHÀN), 6.6–8.4 ppm (m, 19H, CH=);
13C NMR (CDCl3): d=16.4 (CH3ÀAr), 16.9 (CH3ÀAr), 19.9 (CH3ÀAr),
20.4 (CH3ÀAr), 24.1 (CH3), 27.2 (CH2 cod), 27.4 (CH2 cod), 27.9 (CH3),
30.4 (CH2 cod), 31.2 (CH3, tBu), 31.4 (CH3, tBu), 31.5 (CH2 cod), 33.7
(CH2ÀS), 35.1 (C, tBu), 35.3 (C, tBu), 71.1 (CH=cod), 73.2 (CH=cod),
evaporation. The residue was dissolved in Et2O (1.5 mL) and filtered
through a short Celite plug. The ee was determined by chiral GC or
1
chiral HPLC and the conversion was determined by H NMR spec-
troscopy. The ee values of the hydrogenated products of S1,[4d]
S2,[6e] S3,[18a] S4–S5,[4d] S6,[17a] S7,[4d] S8–S12,[4p] S13–S15,[4d] S16–
S18,[4q] S19,[17b] S20,[12a] S21,[4d] S22,[12a] S23–S24,[17c] S25,[6c] S26,[4d]
S27,[17c] S28–S30,[4d] S31,[6c] S32,[17d] S33,[4d] S34,[17b] and S35[6c] were
determined using the conditions described previously.
Acknowledgements
82.9 (CHÀN), 84.9 (d, C, JCÀP =4.8 Hz), 97.1 (d, CH=cod, JCÀP
=
19.2 Hz), 103.9 (d, CH=cod, JCÀP =11.4 Hz), 117.4 (b, CH=, BArF),
120–132 (aromatic carbon atoms), 134.7 (b, CH=, BArF), 135.8–157
(aromatic carbon atoms), 161.9 (q, CÀB, BArF, 1JCÀB =49 Hz),
182.4 ppm (s, C=N); elemental analysis calcd (%) for
C76H70BF24IrNO3PS (1767.42): C 51.65, H 3.99, N 0.79, S 1.81; found:
C 51.71, H 4.03, N 0.76, S 1.79.
We would like to thank the Spanish Government for providing
grant CTQ2010-15835, the Catalan Government for grant
2009SGR116, and the ICREA Foundation for providing M.D. and
O.P. with financial support through the ICREA Academia awards.
Keywords: asymmetric catalysis
design · iridium · N,P-ligands
· hydrogenation · ligand
[Ir(cod)(L1e)]BArF: Yield: 119 mg (91%); 31P NMR (CDCl3): d=
98.4 ppm (s); 1H NMR (CDCl3): d=1.22 (s, 3H, CH3), 1.27 (s, 3H,
CH3), 1.47 (s, 9H, CH3, tBu), 1.63 (s, 9H, CH3, tBu), 1.85 (s, 3H, CH3),
1.97 (s, 3H, CH3), 2.01 (s, 3H, CH3), 2.05 (s, 3H, CH3ÀSi), 2.1–2.5 (b,
8H, CH2, cod), 3.21 (m, 1H, CH2ÀS), 3.49 (m, 1H, CH=cod), 3.53 (m,
1H, CH2ÀS), 4.03 (m, 1H, CH=cod), 4.78 (m, 1H, CH=cod), 5.01 (m,
1H, CH=cod), 5.14 (m, 1H, CHÀN), 6.6–8.4 ppm (m, 19H, CH=);
13C NMR (CDCl3): d=16.5 (CH3ÀAr), 17.1 (CH3ÀAr), 20.1 (CH3ÀAr),
20.3 (CH3ÀAr), 24.4 (CH3), 27.2 (CH2 cod), 27.4 (CH2 cod), 28.1 (CH3),
30.0 (CH2 cod), 31.4 (CH3, tBu), 31.7 (CH3, tBu), 32.3 (CH2 cod), 33.2
(CH2ÀS), 35.1 (C, tBu), 35.3 (C, tBu), 72.9 (CH=cod), 75.8 (CH=cod),
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83.9 (CHÀN), 84.2 (d, C, JCÀP =2.4 Hz), 97.9 (d, CH=cod, JCÀP
=
20.4 Hz), 105.2 (d, CH=cod, JCÀP =10.4 Hz), 117.4 (b, CH=, BArF),
120–132 (aromatic carbon atoms), 134.7 (b, CH=, BArF), 135.8–157
(aromatic carbon atoms), 161.9 (q, CÀB, BArF, 1JCÀB =49 Hz),
182.3 ppm (s, C=N); elemental analysis calcd (%) for
C76H70BF24IrNO3PS (1767.42): C 51.65, H 3.99, N 0.79, S 1.81; found:
C 51.68, H 4.02, N 0.76, S 1.79.
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[Ir(cod)(L2a)]BArF: Yield: 124 mg (92%); 31P NMR (CDCl3): d=
99.7 ppm (s); 1H NMR (CDCl3): d=1.17 (s, 3H, CH3), 1.32 (s, 3H,
CH3), 1.49 (s, 9H, CH3, tBu), 1.54 (s, 9H, CH3, tBu), 1.69 (s, 9H, CH3,
tBu), 1.71 (s, 9H, CH3, tBu), 2.1–2.3 (b, 5H, CH2, cod), 2.34 (b, 1H,
CH2, cod), 2.43 (b, 2H, CH2, cod), 3.21 (m, 1H, CH2ÀS), 3.79 (m, 1H,
CH2ÀS), 4.39 (m, 1H, CH=cod), 4.63 (m, 1H, CH=cod), 5.12 (m, 1H,
CH=cod), 5.24 (m, 1H, CHÀN), 6.6–8.4 ppm (m, 21H, CH=); 13C NMR
(CDCl3): d=24.7 (CH3), 27.6 (CH2 cod), 27.7 (CH2 cod), 28.9 (CH3),
30.3 (CH3), 30.9 (CH3, tBu), 31.2 (CH3, tBu), 31.6 (CH2 cod), 32.2 (CH3,
tBu), 32.5 (CH3, tBu), 33.3 (CH2ÀS), 35.1 (C, tBu), 35.3 (C, tBu), 35.5
(C, tBu), 35.7 (C, tBu), 68.9 (CH=cod), 71.3 (CH=cod), 84.1 (CHÀN),
85.2 (d, C, JCÀP =4.2 Hz), 96.9 (d, CH=cod, JCÀP =14.4 Hz), 105.1 (d,
CH=cod, JCÀP =9.6 Hz), 117.4 (b, CH=, BArF), 120–132 (aromatic
carbon atoms), 134.7 (b, CH=, BArF), 135.8–157 (aromatic carbon
1
atoms), 161.9 (q, CÀB, BArF, JCÀB =49 Hz), 179.9 ppm (s, C=N); ele-
mental analysis calcd (%) for C80H78BF24IrNO3PS (1823.51): C 52.69,
H 4.31, N 0.77, S 1.76; found: C 52.71, H 4.32, N 0.75, S 1.73.
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Hydrogenation of olefins
General procedure: The alkene (0.5 mmol) and Ir complex
(0.25 mol%) were dissolved in CH2Cl2 (2 mL) in a high-pressure au-
toclave, which was purged four times with H2. Then, it was pressur-
ized at the desired pressure. After the desired reaction time, the
autoclave was depressurized, and the solvent was removed by
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3890; c) J. Mazuela, J. J. Verendel, M. Coll, B. Schꢄffner, A. Bçrner, P. G.
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[13] In contrast to the hydrogenation of trisubstituted olefins, the enantio-
selectivity in the reduction of terminal alkenes is highly pressure depen-
dent. Therefore, hydrogenation at an atmospheric pressure of H2 gave,
in general, significantly higher ee values than at higher pressures. See:
a) S. McIntyre, E. Hçrmann, F. Menges, S. P. Smidt, A. Pfaltz, Adv. Synth.
Catal. 2005, 347, 282–288; b) Ref. [4b].
[14] For the successful application of Sm, Ru, and Rh complexes, see: a) V. P.
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[7] L1a–c and L2a have recently been successfully used in the Pd-cata-
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[11] Unpublished results: the hydrogenation of S8 using the Ir complex of
L3a afforded 100% conversion and 93% ee at 50 bar of H2 using
0.5 mol% of catalyst.
[17] G. J. H. Buisman, P. C. J. Kamer, P. W. N. M. van Leeuwen, Tetrahedron:
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[12] Unpublished results: the hydrogenation of S19 using the Ir complex of
L3c afforded 100% conversion and 94% ee at 50 bar of H2 using
0.5 mol% of catalyst.
Received: March 15, 2013
Published online on May 27, 2013
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