Iridium-catalyzed enantioselective hydrogenation of alkenylboronic esters

Article abstract of DOI:10.1002/chem.201200246

Choose the right ligand: An iridium complex derived from a phosphino-imidazoline ligand is a highly efficient catalyst for the asymmetric hydrogenation of terminal vinyl boronic esters (see scheme). On the other hand, trisubstituted alkenyl-boronates can

Full text of DOI:10.1002/chem.201200246

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DOI: 10.1002/chem.201200246
Iridium-Catalyzed Enantioselective Hydrogenation of Alkenylboronic Esters
Adnan Ganic´ and Andreas Pfaltz*[a]
Chiral boronates represent highly versatile building
blocks in organic synthesis,[1] since carbon–boron bonds can
originally developed by Matteson[3] and further investigated
by Aggarwal,[4] yields chiral secondary boron compounds di-
rectly from a-haloboronic esters or primary alcohols. Al-
though these approaches have proved very useful in com-
plex molecule synthesis, it was desirable to develop catalytic
methods that do not require stoichiometric quantities of
chiral reagents. The discovery of Mꢀnnig and Nçth that rho-
dium complexes catalyze the addition of catecholborane to
alkenes paved the way toward enantioselective catalytic hy-
droboration.[5] Subsequently, rhodium,[6] and to a lesser
extent other transition-metal complexes with chiral ligands
have been successfully used as catalysts to prepare chiral or-
ganoboranes in high enantiomeric purity.[7,8] However, the
substrate scope of these reactions is still limited. With few
exceptions, high enantio- and regioselectivities are only ob-
tained with aryl-substituted alkenes.
À
À
À
be readily converted into C O, C N, and C C bonds in
a stereospecific manner.[2] Therefore, enantioselective routes
to these compounds are of great value. The most widely
used method for the synthesis of enantioenriched chiral bor-
onic esters is the hydroboration of C=C bonds with chiral
hydroboranes pioneered by Brown (Scheme 1a). The
method works particularly well with 1,2-disubstituted cis
olefins, whereas the corresponding trans isomers and trisub-
stituted olefins usually react with much lower enantioselecti-
vity.[2a–c] On the other hand, the homologation reaction in-
volving a stereoselective migration–displacement process,
In this respect, asymmetric hydrogenation of alkenylbor-
onic esters offers an attractive alternative, because it avoids
the regioselectivity problems often encountered in catalytic
and stoichiometric hydroborations. Moreover, asymmetric
hydrogenation is one of the best established reactions in or-
ganic synthesis with a wide range of potential catalysts avail-
able. Morken and co-workers reported the first successful
enantioselective hydrogenations of 1,2-bis(boronates)[9] and
alkenylboronates,[10] using
a
Rh-Walphos[11] complex
(Scheme 1c; R2 =H or B(OR)2). In this way chiral secon-
dary boronates that are not accessible by hydroboration
were obtained in high enantiomeric purity. However, rela-
tively high catalyst loadings of 5 mol% and long reaction
times were required. More recently, Andersson and co-
workers found that iridium complexes with chiral N,P-li-
gands are more active catalysts in reactions of this type,
giving full conversion with only 0.5 mol% catalyst loading.
With certain alkenylboronates with an aryl group at the C=
C bond, excellent enantioselectivities were achieved, where-
as analogous alkyl-substituted substrates gave unsatisfactory
enantiomeric excess (ee) values.[12] Overall, the scope of
these Rh- and Ir-catalyzed hydrogenations is still limited, so
the search for other catalysts that enhance the application
range will continue. Herein, we report two efficient Ir cata-
lysts for the enantioselective hydrogenation of a wide range
of pinacol-derived alkenylboronic esters.
Scheme 1. Enantioselective routes to chiral secondary alkyl boronates.
´
[a] A. Ganic, Prof. Dr. A. Pfaltz
Department of Chemistry
University of Basel
St. Johanns-Ring 19, 4056 Basel (Switzerland)
Fax : (+41)61-267-1103
E-mail: andreas.pfaltz@unibas.ch
The hydrogenation of the aliphatic boronate 1a, which so
far had given unsatisfactory results with Ir catalysts,[12a]
served as a starting point for our study. In a series of chiral
N,P-ligand complexes that we screened in this reaction,[13]
complex 3a derived from an imidazoline–phosphinite
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200246.
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Table 1. Catalyst screening for the hydrogenation of boronic ester 1a.
Table 2. Ligand optimization performed in the hydrogenation of vinyl
boronate 1a.
Entry
N
R
R’
tBu Ph
iPr Ph
tBu o-Tol
tBu p-F3C-Ph
R’’
conv. [%][a] ee [%][b]
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
>99
>99
>99
>99
86
46
79
80
59
81
91
77
tBu 3,5-(MeO)2-Ph >99
o-Tol tBu Ph
Cy
tBu
>99
>99
>99
tBu Ph
tBu Ph
[a] Determined by GC analysis of the reaction mixture after removal of
the catalyst (see the Supporting Information for details). [b] Determined
by GC analysis on a chiral stationary phase (see the Supporting Informa-
tion for details).
enantioselectivity (Table 2, entry 6), whereas the more elec-
tron-donating dicyclohexylphosphino group improved the ee
value to 91% (Table 2, entry 7). The sterically more de-
manding di-tert-butylphosphino group, on the other hand,
caused a decrease of the ee value to 77% (Table 2, entry 8).
Thus, catalyst 3g that seemed to have an optimal balance
between the electronic and steric properties was selected for
further studies.
[a] Determined by GC analysis of the reaction mixture after removal of
the catalyst (see the Supporting Information for details). [b] Determined
by GC analysis on a chiral stationary phase (see the Supporting Informa-
tion for details).
The enantioselectivity of catalyst 3g could be further im-
proved by lowering the temperature. The best result was
achieved at À208C with an ee value of 96%, while still
maintaining full conversion (Table 3). A series of experi-
ments at this temperature with different catalyst loadings
and a reaction time of 4 h demonstrated that a 0.1 mol%
ligand[14] stood out as the most promising catalyst, providing
an ee value of 68% at 50 bar hydrogen pressure (Table 1).
By lowering the hydrogen pressure to 2 bar the ee value in-
creased to 86%.[15] We also investigated the solvent influ-
ence, since hydrogenation with rhodium complexes showed
a remarkably high solvent dependence for substrates of this
type.[10] However, in our case the solvent influence proved
to be weak. In dichloromethane, dichloroethane, toluene,
and chlorobenzene an ee value of 86% was obtained, where-
as only slightly lower enantioselectivities were recorded in
more polar solvents like cyclopentyl methyl ether (83% ee),
ethyl acetate (81% ee), or trifluoroethanol (78% ee). We
also found that no special precautions are necessary to ex-
clude oxygen and moisture when setting up the hydrogena-
tion, so the reaction solutions can be conveniently prepared
in the laboratory atmosphere without rigorous purification
of the solvents.
Next we studied the steric and electronic effects of the
substituents at the stereogenic center, at the nitrogen atom
in the imidazoline ring and at the phosphorus atom. As
shown in Table 2 the sterically demanding tert-butyl group
on the imidazole ring is necessary for achieving high enan-
tioselectivity (Table 2, entries 1 and 2). Introduction of elec-
tron donor or acceptor substituents in the N-phenyl group
led to lower ee values (Table 2, entries 3–6). Replacement of
the P-phenyl groups by ortho-tolyl groups also lowered the
Table 3. Optimization of reaction parameters (temperature, time, catalyst
loading).
Entry
T [8C]
Ir-cat.
[mol%]
t [hours]
Conv. [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
9
25
40
0
À20
À20
À20
À20
À20
À20
1.00
1.00
1.00
1.00
1.00
0.50
0.25
0.10
0.05
12
12
12
12
4
4
4
4
4
>99
>99
>99
>99
>99
>99
>99
>99
58
91
77
95
96
96
96
96
96
96
[a] Determined by GC analysis of the reaction mixture after removal of
the catalyst (see the Supporting Information for details). [b] Determined
by GC analysis on a chiral stationary phase (see the Supporting Informa-
tion for details).
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Iridium-Catalyzed Enantioselective Hydrogenation
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catalyst loading is sufficient to achieve full conversion and
retain the ee value at 96%. Lower catalyst loadings led to
incomplete conversion although the enantioselectivity was
not affected (Table 3, entry 9).
strongly differed from Anderssonꢂs Ir catalysts that gave
enantioselectivities of up to 89% ee with substrate 1g, but
only 18% ee with 1a.[12a]
The next substrates targeted were bisboronic esters 4a–d
(Table 5). However, for this substrate class the phosphinite–
For the di-tert-butylphosphino-imidazoline ligand complex
3h the temperature had a similar effect with an increase in
ee value from 68% at 408C to 81% at À208C. Remarkably,
the di-ortho-tolyl analogue 3 f showed strikingly different
behavior. In this case, the enantioselectivity dropped from
81 to 15% ee when the temperature was lowered from 25 to
À208C. The enantioselectivity of the corresponding catalyst
3a with a diphenylphosphino group, on the other hand, re-
mained in a narrow range of 80 to 85% ee between À20 and
408C (for details, see the Supporting Information).
Table 5. Substrate scope of trisubstituted pinacol derived boronic esters.
Having established the optimal conditions for substrate
1a, the scope of catalyst 3g in the hydrogenation of boronic
esters with a terminal C=C bond was investigated (Table 4).
Table 4. Substrate scope of the hydrogenation of terminal boronic esters.
[a] Determined by GC analysis of the reaction mixture after removal of
the catalyst (see the Supporting Information for details). [b] Determined
by GC analysis on a chiral stationary phase (see the Supporting Informa-
tion for details). [c] Reaction time 12 h.
[a] Determined by GC analysis of the reaction mixture after removal of
the catalyst (see the Supporting Information for details); [b] Determined
by GC or HPLC analysis on chiral stationary phase (see the Supporting
Information for details).
All substrates that have a CH2 group next to the double
bond were well tolerated. Excellent activity and enantiose-
lectivity were obtained for a variety of different substrates
with additional functional groups (chloride 1c, protected al-
lylic alcohol 1d, or phenyl groups 1e–f). Sterically more de-
manding substituents next to the C=C bond (1g–i) required
higher catalyst loadings (1 mol%) and longer reaction times
(>12 h) to achieve full conversion, and a dramatic drop in
enantioselectivity was observed. In this respect, catalyst 3g
imidazoline ligand complex 3g gave poor enantioselectivi-
ties (only 13% ee for substrate 4a). In a brief catalyst
screening including the complexes shown in Table 1 (for de-
tails, see the Supporting Information) the pyridine–phos-
phinite complex 6[16] emerged as the most promising catalyst
for substrates of this type. Subsequently, a series of different
bisboronic esters was hydrogenated with catalyst 6 without
further optimization of the reaction conditions. Various sub-
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´
A. Pfaltz and A. Ganic
nert for help during the preparation of this manuscript and for fruitful
discussions.
stituents (cyclohexyl, n-hexyl, tert-butyl, and phenyl) at the
C=C bond were tolerated, giving high conversions for all
substrates. The cyclohexyl- and phenyl-substituted bisboro-
nates 4a and 4d reacted with excellent enantioselectivities
of 95 and 98% ee, whereas the sterically less demanding n-
hexyl derivative gave 72% ee.
Keywords: asymmetric catalysis · boron · hydrogenation ·
iridium · N,P ligands
Bisboronic esters 4a–d are versatile precursors for the
preparation of alkenyl-monoboronic esters with a trisubsti-
tuted C=C bond by Suzuki–Miyaura coupling occurring se-
lectively at the more reactive terminal boronate group.[17] In
this way a series of alkenylboronates 4e–n were prepared,
in which the terminal boron substituent had been replaced
by different groups. Hydrogenation of these substrates led
to the corresponding secondary alkylboronic esters with ex-
cellent enantioselectivities from 95 up to >99% ee. With
the exception of the sterically demanding tert-butyl deriva-
tive 4g, all other substrates gave >97% conversion. Elec-
tron donor or acceptor groups at the aryl substituent had no
significant effect on the ee value and conversion. Aryl sub-
stituents at the C=C bond are not essential for achieving
high enantioselectivity, as shown by hydrogenation of the
merely alkyl-substituted substrates 4m and 4n. Substrate
4o[18] with a boronic ester residue at the less-substituted ole-
finic C atom reacted with lower, but still very good enantio-
selectivity to give the corresponding primary alkylboronate
with full conversion and 90% ee.
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hydrogenation of pinacol-derived boronic esters. Whereas
a phosphinoimidazoline ligand was identified as highly effi-
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Experimental Section
Procedure for the iridium-catalyzed asymmetric hydrogenation: A solu-
tion of the substrate 1a (303 mg, 1.27 mmol, 1.0 equiv) and the iridium
complex 3g (2.07 mg, 1.28 mmol, 0.1 mol-%) in dichloromethane (6 mL)
was placed in an autoclave. The equipment was pressurized with nitrogen
(1 bar) and cooled to À208C for 1 hour. The autoclave was then pressur-
ized five times with hydrogen (up to 10 bar) and released. The reaction
was performed under 2 bar H2 atmosphere over 4 h at À208C. After re-
leasing the hydrogen pressure the reaction mixture was allowed to reach
RT and the solvent was removed under reduced pressure. The crude
product was taken up in n-heptane (3 mL) and purified over a plug of
silica gel (0.5 cmꢃ2 cm n-heptane/tert-butyl methyl ether (TBME) 10:1)
to give analytically pure hydrogenation product 2a (297 mg, 1.24 mmol,
97%) suitable for analysis.
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Acknowledgements
Financial support from the Swiss National Science Foundation and the
University of Basel is gratefully acknowledged. We thank Dr. Renꢄ Tan-
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Iridium-Catalyzed Enantioselective Hydrogenation
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´
´
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Received: January 23, 2012
Published online: && &&, 2012
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A. Pfaltz and A. Ganic
Asymmetric Synthesis
´
A. Ganic, A. Pfaltz* ......... &&&& — &&&&
Iridium-Catalyzed Enantioselective
Hydrogenation of Alkenylboronic
Esters
Choose the right ligand: An iridium
complex derived from a phosphino–
imidazoline ligand is a highly efficient
catalyst for the asymmetric hydrogena-
tion of terminal vinyl boronic esters
(see scheme). On the other hand, tri-
substituted alkenyl-boronates can be
reduced with high activity and good to
excellent enantioselectivity employing
a pyridine-phosphinite ligand.
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