Synthesis of building blocks for the development of the SUPRAPhos ligand library and examples of their application in catalysis

Article abstract of DOI:10.1002/ejoc.200800499

We have previously introduced the SUPRAPhos ligand library, which is based on components that are self-assembled through nitrogen-zinc interactions, and report here an extension of this library, which widens the scope for application in asymmetric homogeneous catalysis. For example, we report the synthesis of phosphorus amidite appended porphyrins and building blocks with stereogenic centers at the phosphorus. With the new building blocks described in this paper we can form a 450-membered SUPRAPhos library, which is based on 45 building blocks (30 pyridyl phosphorus ligands and 15 complementary porphyrin-appended phosphorus ligands). Examples of the use of members of the library in the rhodium-catalyzed asymmetric hydroformylation of styrene are included. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800499

FULL PAPER
DOI: 10.1002/ejoc.200800499
Synthesis of Building Blocks for the Development of the SUPRAPhos Ligand
Library and Examples of Their Application in Catalysis
P. Elsbeth Goudriaan,[a] Xiao-Bin Jang,[a] Mark Kuil,[a] Renske Lemmens,[a]
Piet W. N. M. Van Leeuwen,[a] and Joost N. H. Reek*[a]
Keywords: Bidentate ligands / Supramolecular chemistry / Ligand libraries / Phosphorus / Asymmetric catalysis
We have previously introduced the SUPRAPhos ligand li-
brary, which is based on components that are self-assembled
through nitrogen–zinc interactions, and report here an exten-
sion of this library, which widens the scope for application in
asymmetric homogeneous catalysis. For example, we report
the synthesis of phosphorus amidite appended porphyrins
and building blocks with stereogenic centers at the phospho-
rus. With the new building blocks described in this paper we
can form a 450-membered SUPRAPhos library, which is
based on 45 building blocks (30 pyridyl phosphorus ligands
and 15 complementary porphyrin-appended phosphorus li-
gands). Examples of the use of members of the library in the
rhodium-catalyzed asymmetric hydroformylation of styrene
are included.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
of libraries of monodentate ligands have been reported.[4]
For example, Lefort and co-workers reported the robotic
synthesis of 96 monodentate phosphoramidites (instant li-
gand libraries) and the robotic screening for asymmetric hy-
drogenation, which was accomplished in just 2 days, dem-
onstrating the value of simple ligand structures.[5] The prep-
aration of ligand libraries based on bidentate phosphorus
ligands is far more difficult and as such these are scarce.[6,7]
A new approach, introduced both by us[8,9] and others,[10]
is the preparation of bidentate ligands using noncovalent
interactions. The supramolecular approach is ideally suited
to the development of ligand libraries because 1) the
number of bidentate ligands grows exponentially with the
number of building blocks prepared, 2) the synthesis of li-
gand building blocks is generally (not always) easier than
that of (hetero)bidentate ligands, 3) a diverse ligand library
becomes accessible if building blocks with different phos-
phorus donor moieties are included, and 4) creation of a
sub-library related to a promising ligand structure is much
easier. Various supramolecular interactions, such as hydro-
gen bonds, metal–ligand interactions, and ionic interac-
tions, have been used to bring two ligand building blocks
together to provide a supramolecular bidentate ligand. This
can be achieved by the assembly of two monodentate ligand
building blocks on a template that is functionalized with
two complementary binding sites (Scheme 1, left) or by
using two monodentate ligand building blocks equipped
with complementary binding sites (Scheme 1, right). As
these supramolecular bidentate ligands are formed from
smaller building blocks, the synthesis is intrinsically less
complex than the synthesis of covalent (hetero)bidentate li-
gands. More importantly, only a small number of building
blocks are required for the construction of a large library.
Introduction
Asymmetric catalysis is an indispensable tool in modern
synthetic chemistry as it offers new routes to the efficient
preparation of single enantiomers of compounds, which is
clearly far more atom-efficient than racemic synthesis com-
bined with resolution. Although asymmetric catalysis is ap-
plied to industrial processes,[1] its use in the synthesis of
enantiopure products is still limited compared with, for in-
stance, the resolution of enantiomers.[2] One reason for this
is the high substrate- and reaction-specificity of the avail-
able chiral catalysts. As the selectivity of a catalyst for a
certain conversion can hardly be predicted by theoretical
models, current strategies for finding selective catalysts rely
on the screening of catalyst libraries.[3] Generally this in-
volves the in situ preparation of transition-metal complexes
using libraries of ligands. As the time-to-market is a decisive
parameter, not much time is available for the screening and
identification of catalysts. Hence the rapid search for a suit-
able catalyst for a certain conversion depends largely on the
availability of ligand libraries. Phosphorus-based ligands
comprise an important class of ligands that are used in
many different transition-metal-catalyzed reactions, and the
availability of diverse libraries is highly desirable. Chiral
monodentate ligands are intrinsically easier to prepare than
bidentate ligands, and several strategies for the preparation
[a] Homogeneous and Supramolecular Catalysis, Van’t Hoff Insti-
tute for Molecular Sciences,
Nieuwe Achtergracht 166, 1018 WV Amsterdam, The Nether-
lands
E-mail: reek@science.uva.nl
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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FULL PAPER
can form a large (450) and diverse library of bidentate li-
gands. Some of the ligands in the library were used to form
catalysts for the rhodium-catalyzed asymmetric hydrofor-
mylation of styrene.
Results and Discussion
The synthesized SUPRAPhos library can be divided into
two parts: The metalloporphyrin acceptor ligands and the
nitrogen donor ligands. The phosphite-porphyrinatozinc(II)
complexes (Scheme 3, III) were synthesized by reaction of
hydroxy-functionalized porphyrinatozinc(II) (Scheme 3, II)
with chlorophosphites according to the procedure pre-
viously developed in our laboratory.[9c] The required hy-
droxyporphyrins (Scheme 3, I) were prepared by condensa-
tion of benzaldehyde, hydroxybenzaldehyde, and pyrrole in
refluxing propionic acid.[11] After isolation the hydroxypor-
phyrins were metalated using zinc acetate in refluxing chlo-
roform/methanol and were purified by column chromatog-
raphy over basic alumina.
Scheme 1. Schematic representation of the formation of a supra-
molecular bidentate ligand by using a template (left) or directly
from complementary monodentate ligands (right).
We previously reported SUPRAPhos, a class of bidentate
ligands that is formed from porphyrinatozinc(II)···pyridyl
interactions. Initially we prepared a 48-membered bidentate
ligand library based on 14 building blocks. Six different
phosphite-porphyrinatozinc(II) compounds were used in
combination with eight nitrogen-donor-functionalized
phosphane or phosphite ligands (for an archetypical exam-
ple, see Scheme 2).[9c,9e]
Scheme 2. Formation of a supramolecular bidentate ligand.
The supramolecular ligand library was applied to palla-
dium-catalyzed allylic alkylation reactions, and the large
variation in the obtained enantiomeric excesses demon-
strated the proof of principle. After these initial results the
Scheme 3. Synthesis of phosphite-porphyrinatozinc(II) complexes
(for R see Scheme 5).
The phosphoramidite-appended porphyrins 11 and 12
SUPRAPhos library was extended to a 60-membered li- (Scheme 5) were prepared by using a similar strategy. The
brary, which was studied in the asymmetric rhodium-cata- free base aminoporphyrin was synthesized from the free
lyzed hydrogenation of trisubstituted cyclic N-(3,4-dihydro- base nitroporphyrin (Scheme 4, IV), which was synthesized
2-naphthalenyl)acetamide.[9g] This substrate is known to be by condensation of benzaldehyde, nitrobenzaldehyde, and
a difficult substrate for hydrogenation, and inherently no pyrrole under acidic conditions according to a literature
selective rhodium-based catalysts were known (70% ee). procedure (Adler method).[12] After purification by column
Parallel high-throughput screening of the library showed chromatography, the nitro group was reduced with tin(II)
that between 0 and 100% of the substrate was converted chloride under acidic conditions to provide the aminopor-
and that the ee of the product obtained varied between 12 % phyrin. To insert zinc(II) into these amino-appended por-
ee of one enantiomer and 94% ee of the other enantio- phyrins we initially used the same procedure as used for
mer. Importantly, the library produced only one hit, which the hydroxyporphyrins, that is, refluxing in a chloroform/
highlights the challenge involved. Part of the library was methanol mixture and subsequent washing with water to
also successfully used in the kinetic resolution of cyclohex- remove the excess zinc acetate followed by extraction, con-
enyl acetate.[9j] Stimulated by these successes we decided to centration, and column chromatography. This method
further expand the ligand library. Herein we report on the failed, however, as coordination of the amino group to the
synthesis of ligand building blocks for the SUPRAPhos li- zinc atom of another porphyrin gives rise to the formation
brary, including (new) porphyrin phosphites and phos- of higher order aggregates that hamper isolation and purifi-
phoramidites, pyridyl phosphoramidites, new pyridyl phos- cation. We therefore used a procedure that had previously
phites, and chiral pyridyl phosphanes. With these new been used for the metalation of the 4-analogue. This in-
building blocks and those previously reported,[9c–9e,9g,9h] we volved stirring a solution (dichloromethane/methanol) of
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Development of the SUPRAPhos Ligand Library
the free base porphyrin with 5 equiv. zinc acetate for 12 h
followed by precipitation of the product through evapora-
tion of the dichloromethane and the gradual addition of
methanol.[13] By using this procedure, compound
V
(Scheme 4) was isolated in almost quantitative yield in high
purity. The amidite ligand VI was formed after a straight-
forward reaction of the aminoporphyrin with a chlorophos-
phite (Scheme 4).
Scheme 4. Synthesis of ZnII porphyrin phosphoramidite ligands
[the functional group is either at the ortho or at the meta position
(11 and 12); for R, see Scheme 5].
Scheme 5. Acceptor-type building blocks that were prepared in or-
der to construct the Supraphos library.
phosphane boranes,[19] and the palladium-catalyzed cross-
coupling of organophosphorus compounds containing a P–
H bond with aryl of vinyl halides or triflates.[20]
Following these procedures, 15 phosphite-porphyrinato-
zinc(II) compounds and similar phosphoramidites
(Scheme 5) were synthesized from the corresponding hy-
droxy- and aminoporphyrins in yields varying from 40 to
50%.[14] All new porphyrin-appended ligands were charac-
Two routes for the preparation of P-stereogenic phos-
phanes equipped with nitrogen donor atoms were found to
be successful. We prepared the racemic synthon tert-bu-
tyl(phenyl)phosphane (J17; Scheme 6) by reaction of
dichloro(phenyl)phosphane with 1 equiv. of tert-butylmag-
nesium chloride at –78 °C followed (after stirring for 1 h at
room temperature) by the addition of 1 equiv. of lithium
aluminium hydride. Subsequent addition of the borane–
tetrahydrofuran complex resulted in immediate protection
of the phosphane, which was, after aqueous work up, puri-
fied by vacuum distillation, which provided in the first frac-
tion the unprotected phosphane J17 (25% yield) and in the
second fraction the protected phosphane J18 (59%
yield).[21] The secondary phosphane was further function-
alized both by enantioselective lithium–sparteine-mediated
synthesis and by palladium-catalyzed cross-coupling of the
organophosphorus compound with iodopyridine followed
by resolution (Scheme 7 and Scheme 8).
1
terized by H, 31P, and 13C NMR spectroscopy and by ele-
mental analysis or HRMS.
Three different types of nitrogen-donor-functionalized li-
gands were synthesized: Phosphanes [achiral (A) and chiral
(B)], phosphoramidites (C), and phosphites (D). These will
be described below.
The achiral pyridylphosphanes A1–A4 (see Scheme 12)
were prepared by lithiation of bromopyridine by using
nBuLi and TMEDA[15] in a 1:1:1 tetrahydrofuran/ethyl
ether/pentane solution at –115 °C followed by the addition
of diarylchlorophosphane at –70 °C.[16] The work up of
these compounds generally involved aqueous washing and
subsequent purification by column chromatography under
an inert atmosphere. Yields between 20 and 70% were ob-
tained.
The synthesis of chiral pyridyl-functionalized phos-
phanes (B) proved more challenging than anticipated. In
particular, the development of synthetic routes towards P-
stereogenic phosphanes was time-consuming. Chiral phos-
phanes can be prepared in an enantiopure form by either
enantioselective synthesis or optical resolution after the
preparation of the racemate.[17] For the enantioselective
synthesis there are several possibilities, such as the use of
heterobifunctional auxiliaries like, for instance, the
Scheme 6. Synthesis of a racemic secondary phosphane suitable for
the preparation of different P-stereogenic phosphane ligands.
3-[tert-Butyl(phenyl)phosphanyl]pyridine was prepared
ephedrine-based method developed by Jugé and co- by palladium-catalyzed P–C cross-coupling (Scheme 7).
workers,[18] the lithium–sparteine-mediated synthesis of The secondary phosphane J17 was coupled with 3-iodopyr-
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Most synthesized oxazolines known in the literature have a
substituent at the carbon next to the nitrogen.[24] When
amino alcohols with a substituent on the carbon next to the
oxygen were used, the reaction did proceed under standard
conditions, but not smoothly (2 equiv. of methanesulfonyl
chloride and 2 equiv. of base). In the presence of 5 equiv.
of methanesulfonyl chloride and 4.9 equiv. of base, the cy-
clized product was obtained in 86% yield. Subsequent de-
protection using the tetrafluoroboric acid–dimethyl ether
complex yielded pure B4 in almost quantitative yield after
column chromatography.
Scheme 7. Synthesis of (R)- and (S)-3-[tert-butyl(phenyl)phos-
Pyridyl-functionalized phospholane B1 was prepared fol-
lowing an eight-step process (Scheme 9) that was inspired
by a procedure developed by Guillen and Fiaud and co-
workers.[25] The phosphole ring was formed by the McCor-
mack cycloaddition of 1,4-diphenylbutadiene and an ami-
nophosphenium cation.[26] The cis-phospholene was hydro-
genated and isomerized to the trans-phospholane. After hy-
drolysis, the racemic mixture of this acid could easily be
resolved by crystallization with quinine from refluxing
methanol. The S,S isomer (J26) selectively crystallizes and
could be liberated from the quinine by treatment with a
basic solution. Reaction of the acid with oxalyl chloride
offered the reactive chlorophosphane oxide J27 in quantita-
tive yield. Reduction with lithium aluminium hydride fol-
lowed by aerobic work up provided the secondary phos-
phane oxide J28 in 90% yield. By palladium-catalyzed P–
phanyl]pyridine.
Scheme 8. Synthesis of oxazoline-functionalized phosphane li-
gands.
idine in DMF at 105 °C by using Pd(OAc)2/dppb as the C coupling, iodopyridine was coupled to the secondary
catalyst. Work up under aerobic conditions provided a race- phosphane, which resulted in the formation of the pyridyl-
mic mixture of (R)- and (S)-3-[tert-butyl(phenyl)phos- phosphane oxide J29. This phosphane oxide could sub-
phinoyl]pyridine in 62% yield after purification by column sequently be reduced by phenylsilane to yield the desired
chromatography. The enantiomers were resolved by separa- pyridyl-functionalized phospholane B1 in almost quantita-
tion on a chiral preparative HPLC column on a 300 mg tive yield.
scale. Subsequent reduction with phenylsilane yielded the
pure ligands B5 and B6 almost quantitatively.
The tert-butyl(phenyl)phosphane–borane building block
J18 was used to prepare phosphane-oxazoline ligands
(Scheme 8).[22] The secondary phosphane was transformed
into (R)-tert-butyl(phenyl)methylphosphane–borane J19 by
sparteine-mediated enantioselective lithiation. The product
was obtained in 93% enantiomeric excess and isolated in
enantiopure form after crystallization from ethyl acetate.[23]
Subsequent lithiation of the methyl group followed by the
addition of carbon dioxide yielded the corresponding phos-
phinic acid (J20) in 87% yield after crystallization from tol-
uene. To this acid many different amino alcohols can be
Scheme 9. Synthesis of pyridyl-functionalized phospholane ligand
B1.
coupled by using standard peptide coupling procedures,
The pyrrolidine-based phosphane B2 could be prepared
which yield protected phosphane-oxazoline ligands (J22) starting from -proline according to a published procedure
after a cyclization reaction. We used this methodology with (Scheme 10).[27] Boc-protected proline was reduced to pro-
an amino alcohol substituted at the carbon atom next to linol by the boron–THF complex to provide N-Boc-pro-
the oxygen functional group. A functional group next to the linol. The corresponding tosylate was formed by reaction
nitrogen might create too much steric hindrance for proper of the alcohol with tosyl chloride, after which the phos-
coordination to the porphyrinatozinc(II) and make the ox- phane could be formed by reaction with potassium di-
azoline, with a substituent on the carbon atom next to the phenylphosphide. Deprotection of the amine rendered
nitrogen, less suitable for the SUPRAPhos ligand library. phosphane B2.
Under standard conditions the cyclization reaction of non-
substituted amino alcohols failed. Apparently, substrate prepared by reacting hydroxy- and aminopyridines, respec-
preorganization is important for cyclization in these cases. tively, with the corresponding chlorophosphite
The phosphite and phosphoramidite ligands were easily
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Development of the SUPRAPhos Ligand Library
Scheme 11. General route for the synthesis of pyridyl phosphites
and phosphoramidites.
Scheme 10. Synthesis of pyrrolidine-based phosphane B2.
By using the above-mentioned methods, 27 different ni-
trogen-donor phosphorus ligands were prepared. The final
library of pyridyl-functionalized phosphorus ligands is de-
picted in Scheme 12.
(Scheme 11).[9a,9h] Purification of these type of compound
Based on these 30 nitrogen-donor phosphorus ligand
was accomplished by precipitation of impurities in a tolu- building blocks and 15 complementary porphyrin-ap-
ene/hexane mixture (usually 1:2 or 1:3) followed by fil- pended ligand building blocks we constructed a library of
tration. The yields were typically between 70 and 90%.
15ϫ30 = 450 bidentate phosphorus ligands. Of these 450
Scheme 12. Nitrogen-donor phosphorus ligands.
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J. N. H. Reek et al.
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bidentate ligands, 437 are chiral and hence applicable in
asymmetric catalysis. Table 1 presents an overview of the
types and numbers of (hetero)bidentate ligands that can be
formed with these building blocks. With these building
blocks we currently have the largest library of supramolec-
ular ligands in hand and we will further explore the proper-
ties of these ligands in various transition-metal-catalyzed
reactions.
Scheme 13. Rhodium-catalyzed hydroformylation of styrene.
Owing to the stability of the benzylic rhodium species
that is formed upon coordination of the alkene in a η3 fash-
ion, the branched 2-phenylpropionaldehyde is generally the
favored product.[29] Part of our SUPRAPhos library was
used in the asymmetric hydroformylation of styrene. We
chose representatives of all ligand classes in the first screen-
ing. This allowed the identification of suitable structures for
a second, more focused library. The screening experiments
were performed in autoclaves equipped with 8 or 14 mini
inner reactors (with magnetic stirrer bars) for parallel
screening and the temperature was controlled by using an
oil bath. [Rh(acac)(CO)2] was used as a metal precursor
and 5 equiv. of each monodentate ligand building block was
added. Syngas (20 bar, CO/H2, 1:1) was applied at various
temperatures. Some of the results of the first screening are
displayed in Table 2. The complete data set are given in the
Supporting Information.
Table 1. Overview of the library of supramolecular ligands.
Table 2. Selected results of the hydroformylation of styrene using
Rh(SUPRAPhos) complexes.[a]
Entry
Ligand T [°C] t [h] Conv.[b] [%] b/l[c]
ee [%]
1
2
3
4
5
6
7
8
1·A1
5·A1
1·B1
1·B1
5·B1
8·B1
9·B1
1·C1
5·C1
5·C2
6·C1
11·D1
11·D3
8·D1
8·D3
60
60
50
60
60
50
60
40
40
40
40
40
40
40
40
14
14
64
14
14
64
14
88
88
87
88
48
48
16
16
89
77
4.8
16
2.1
6.1
4.3
3.7
4.5
16
5.6
7.0
1.0
4.5
3.8
3.8
7.5
4.3
14
Ͻ2
2.4 (R)
17 (R)
9.0 (R)
8.4 (R)
12 (R)
3.8 (S)
27 (R)
76 (R)
5.6 (R)
46 (R)
57 (R)
Ͻ2
87
3.3
Ͼ99
11
9
1
10
11
12
13
14
15
4.1
1.8
1
36
3.7
Ͼ99
11 (S)
Ͻ2
16
17
18
19
20
21
22
23
24
1
8
50
40
60
40
60
60
60
40
40
16
16
14
48
14
12
12
87
16
20
Ͼ99
Ͼ99
5
Ͼ99
5.3
58
92
Ͼ99
3.8
15
6.7
5.6 (R)
5.1 (R)
Ͻ2
23 (R)
4.6 (S)
16 (R)
7.8 (R)
Ͻ2
9
11
Some of the ligands in this library have previously been
used in palladium-catalyzed allylic alkylation and rhodium-
catalyzed hydrogenation reactions. The results of the asym-
metric rhodium-catalyzed hydroformylation of styrene per-
formed by using some of these ligands is described below.
B1
C1[d]
C1[e]
C2
D3
5.1
5.3
6.9
8.9
14
–
[a] Conditions: [Rh(acac)(CO)2] = 1.00 m, [porphyrin phosphite]
= 5.00 m, [pyridyl phosphorus donor] = 5.00 m, [diisopropyle-
thylamine] = 50.5 m, substrate/Rh = 1000, p(CO/H2) = 20 bar. [b]
Percentage conversion of styrene to aldehydes. [c] b/l = branched/
linear ratio. [d] Rh/ligand ratio = 1:10. [e] Rh/ligand ratio = 1:5.
Asymmetric Hydroformylation of Styrene
Styrene hydroformylation gives access to valuable propi-
onic aldehydes, which are valuable intermediates in, for in-
The most active rhodium complexes were formed from
stance, the synthesis of pharmaceuticals like ibuprofen, ke- heterobidentate ligands containing either a phosphane or a
toprofen, and naproxen.[28] The hydroformylation of sty- bulky phosphite ligand (entries 1, 2, and 7). Unfortunately,
rene can produce two products: The achiral linear 3-phenyl- these ligands barely induced any enantioselectivity in the
propionaldehyde and the chiral 2-phenylpropionaldehyde reaction. Moderate-to-high enantioselectivities were ob-
(Scheme 13).
tained with rhodium complexes derived from a heterobiden-
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Development of the SUPRAPhos Ligand Library
ate ligand containing a phosphoramidite ligand. Unfortu- Table 3. Hydroformylation of styrene with SUPRAPhos phos-
phoramidite ligands under different conditions.[a]
nately, the complexes of these ligands led, without excep-
tion, to very low conversions of styrene. The screening re-
vealed the effects of small changes in the ligand system on
the outcome of the catalysis. For instance, 1·B1 gave 16%
conversion after 14 hours at 60 °C (entry 4), 5·B1 (entry 5)
showed 87% conversion under the same conditions. The
only difference between these ligands is the position of the
phosphite on the meso-phenyl ring of the porphyrin.
Steric bulk played an important role in the branched-to-
linear selectivity. Generally, bulky ligands gave rise to
higher branched-to-linear ratios. For instance, the catalyst
formed upon coordination of ligand 1·B1 resulted, at 50 °C,
in a b/l ratio of 4.3 (entry 3). The catalyst formed from the
more bulky 8·B1 provided, under the same conditions, a b/l 13
ratio of 16 (entry 6). Both ligands are derived from BINOL
phosphites; ligand 8, however, is considerably more bulky
because of the trimethylsilyl group at the ortho position of
the BINOL backbone. The difference in (enantio)selectivity
observed for the catalysts formed by coordination with 1·C1
and 5·C1 is also interesting. Both phosphites 1 and 5 are
(S)-BINOL phosphites, but are positioned, respectively, at
the ortho and meta positions of the meso-phenyl ring of the
porphyrin. The catalyst based on 1·C1 converted, with low
Entry Ligand
T
[°C]
p(CO/H2) Rh/LA/LD Conv.[b]
b/l[c]
ee[d]
[%]
[bar]
[%]
1
2
3
4
5
6
7
8
7·C1
7·C2
8·C1
8·C1
5·C1
5·C1
6·C1
6·C1
5·C1
5·C1
5·C1
5·C1
5·C1
40
40
40
40
60
60
60
60
40
40
40
40
40
10:10
10:10
10:10
10:10
10:10
10:10
10:10
10:10
10:10
10:20
10:20
10:20
20:10
1:5:5
1:5:5
9.7
47
1.0
Ͼ99
1.5
72
6.6
10
5.9
12
1.9
4.5
4.3
5.4
1.2
1.1
1.4
1.4
1.9
Ͻ2
Ͻ2
2.1
5.7
41
7.0
19
7.4
76
1:5:5
1:5:1[e]
1:5:5
1:2.5:2.5
1:5:5
1:2.5:2.5
1:5:5
1:5:5
1:5:5
6.5
80
9[f]
10
11[g]
12
Ͻ1
Ͻ1
Ͻ1
Ͻ1
1.0
71
N.d.
N.d.
47
1:4:4
1:5:5
[a] Conditions: [Rh(acac)(CO)2] = 1.00 m, [porphyrin phosphite]
= 5.00 m, [pyridyl phosphorus donor] = 5.00 m, [diisopropyl-
ethylamine] = 50.5 m, substrate/Rh = 1000, p(CO/H2) = 20 bar. [b]
Percentage conversion of styrene to aldehydes. [c] b/l = branched/
linear ratio. [d] In all cases the R enantiomer was obtained in excess.
[e] [porphyrin phosphite] = 5.00 m, [pyridyl phoshoramidite] =
1.0 m. [f] The styrene was added after 30 min incubation at 40 °C
and 20 bar syngas. [g] [Rh(acac)(CO)2] = 5.00 m.
activity, the styrene into phenylpropionaldehyde with a perature resulted in lower enantioselectivity, whereas the
branched-to-linear selectivity of 7.0 and 27% ee of the conversion increased to only 1.5%.[31] The same trend was
branched product (entry 8). The catalyst based on 5·C1 observed for the catalyst based on 6·C1 (entry 7). In both
formed equimolar amounts of the branched and linear experiments there was also an increase in selectivity for the
products, but the enantioselectivity was higher: 76% ee was branched product. Lowering the ligand-to-metal ratio re-
obtained although with a rather low conversion (entry 9).[30] sulted in a much higher conversion, but almost complete
The difference between 5·C1 and 5·C2 is also striking; loss of enantioselectivity was observed (cf. entry 5 with 6
whereas the former catalyzed the conversion of styrene with and entry 7 with 8). For the catalysts based on 5·C1 the
high enantioselectivity, only 5.6% ee was obtained with the selectivity for the branched product was significantly en-
latter ligand (entry 10). The only difference between these hanced. These results indicate that different rhodium spe-
two ligands is the presence of a secondary or tertiary amine cies, such as mono-phosphite and ligand-free rhodium com-
in the phosphoramidite ligand. These minor changes, which plexes, are formed under these conditions.
result in large differences in catalytic outcome, emphasize
the necessity of ligand library screening for identifying suit- ond, more focused library. Because high activity was ob-
able catalysts for a process. tained with phosphane-containing SUPRAPhos ligands
Based on the results obtained so far, we developed a sec-
Further experiments comprised parameter changes to and high enantioselectivity with (secondary) phosphor-
improve the activity of the catalyst based on 5·C1. We inves- amidite SUPRAPhos ligands, we used in situ formed rho-
tigated the influence of steric bulk at the ortho position of dium complexes of phosphoramidite porphyrins 11 and 12
the BINOL (ligands 7 and 8), the influence of temperature, with the phosphane donor ligands A1–A3 and B5 and B6
the metal-to-ligand ratio, and the (partial) CO/H2 pressure (Table 4).
(Table 3).
Interestingly, the activities of the catalysts based on the
The catalysts based on bulky ligand assemblies showed phosphane-phosphoramidite ligands were much higher
much higher activity than 5·C1, but the enantioselectivity than those based on phosphite-phosphoramidite, with con-
dropped dramatically. The highest ee obtained with the versions up to 39% in 20 hours (entry 6). Unfortunately, the
bulky ligands (5.7%; Table 3, entry 4) was reached when enantioselectivity was not so high, although in general it
5 equiv. of the bulky porphyrin phosphite and 1 equiv. of was higher than for the phosphane-phosphite bidentate li-
the pyridyl phosphoramidite were used. This avoids the for- gand systems shown in Table 2. The highest enantio-
mation of homo-phosphoramidite complexes, but the result selectivities were obtained for catalysts based on the SUP-
suggests that the catalysis is dominated by the mono-por- RAPhos ligands 11·A3 and 12·A3, 25 and 27%, respectively
phyrin phosphite rhodium complex (cf. Table 2, entry 17; (entries 3 and 8). The catalysts based on assemblies with
high conversion, low ee, b/l close to 15).
the P-stereogenic phosphanes B5 and B6 gave (very) low
When the rhodium catalyst based on 5·C1 was used at enantioselectivity (varying between 2.2 and 10; entries 4, 5,
60 instead of 40 °C, the ee of the product dropped to 41% 9 and 10). A large variation in regioselectivity was obtained
(compared with 76% at 40 °C). Thus the increase in tem- with these catalysts, from a b/l ratio of 8.3 for the catalyst
Eur. J. Org. Chem. 2008, 6079–6092
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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J. N. H. Reek et al.
FULL PAPER
Table 4. Hydroformylation of styrene using a small phosphane selectivity within one ligand class between closely related
phosphoramidite library.[a]
ligands. This stresses the importance of library screening in
homogeneous catalysis.
Entry
Ligand
Conv.[b] [%]
b/l[c]
ee [%] (config.)
1
2
3
4
5
6
7
8
9
10
11·A1
11·A2
11·A3
11·B5
11·B6
12·A1
12·A2
12·A3
12·B5
12·B6
16
8.8
13
8.8
5.9
39
16
1.9
11
8.3
2.5
0.8
7.9
7.5
5.3
6.6
0.5
2.9
3.4
16 (R)
22 (R)
25 (R)
2.2 (R)
4.0 (R)
7.3 (S)
Ͻ2
27 (R)
10 (R)
5.2 (R)
Experimental Section
General Remarks: All experiments were performed under a dry, in-
ert atmosphere of nitrogen using standard Schlenk techniques un-
less stated otherwise. Solvents were dried and distilled under nitro-
gen prior to use. Toluene was distilled from sodium, ethyl ether and
tetrahydrofuran from sodium/benzophenone, and hexanes from so-
dium/benzophenone/triethylene glycol dimethyl ether (‘triglyme’).
Dichloromethane, ethyl acetate, and acetonitrile were distilled from
CaH2. Dimethylformamide was distilled from CaSO4. NMR spec-
tra were recorded with a Varian Mercury 300 or a Varian Inova
500 spectrometer. 31P and 13C NMR spectra were measured with
1H decoupled. CDCl3 was used as the solvent; shifts are given rela-
tive to TMS (1H, 13C) and 85% H3PO4 (31P). Optical rotations
were measured with a Perkin-Elmer 241 polarimeter using a so-
dium lamp (289 nm) unless stated otherwise. Elemental analyses
were performed at the H. Kolbe Mikroanalytisches Laboratorium
in Mülheim (Germany). HRMS were recorded at the Department
of Mass Spectrometry at the University of Amsterdam with a
JEOL JMS SX/SX102A four-sector mass spectrometer using FAB+
ionization with 3-nitrobenzyl alcohol as the matrix. UV/Vis ti-
tration experiments were performed with a HP 8453 UV/Vis Sys-
tem. Gas chromatographic analyses for Conversions and regioselec-
tivities were determined by GC with a Shimadzu GC-17A appara-
tus [split/splitless, equipped with a FID detector and a BPX35 col-
umn (internal diameter 0.22 mm, film thickness 0.25 µm, carrier
gas 70 kPa He)]. Chiral gas chromatographic analyses were per-
formed with an Interscience Trace GC Ultra instrument (FID de-
tector) equipped with a ph Megadex column (internal diameter
0.1 mm, 5 m column, film thickness 0.1 µm).
13
[a] Conditions: [Rh(acac)(CO)2] = 1.00 m, [porphyrin phos-
phoramidite] = 5.00 m, [pyridylphosphane] = 5.00 m, [diisopro-
pylethylamine] = 50.5 m, substrate/Rh = 1000, p(CO/H2) =
20 bar, T = 40 °C, 20 h. [b] Percentage conversion of styrene to
aldehydes. [c] b/l = branched/linear ratio.
based on 11·A1 (entry 1) to 0.5 for the catalyst based on
12·A3 (entry 8), the latter implying the formation of mainly
the linear aldehyde.[32] In particular, in the case of the chiral
phosphanes B5 and B6, a clear influence of the position of
the amidite on the porphyrin on the regioselectivity of the
reaction was observed. For example, the catalyst based on
11·B5 (2-amidite porphyrin) gave a b/l ratio of 7.9 (entry 4),
whereas the catalyst based on the 3-analogue, 12·B5, gave
the aldehydes with a b/l ratio of 2.9 (entry 9).
Conclusions
Supramolecular chemistry provides efficient tools for
making new ligands that are particularly suited to the con-
struction of large ligand libraries. Previously we introduced
SUPRAPhos as an example of such a new class of ligands.
In this article we have elaborated the synthesis of building
blocks that can be used for the formation of supramolecular
bidentate ligands (SUPRAPhos), and with the building
blocks currently available a 450-membered library of biden-
tate phosphorus ligands is accessible of which 437 members
are chiral. The library contains a large number of diverse
ligands: Phosphane-phosphite, phosphane-phosphoramid-
ite, phosphite-phosphite, and phosphite-phosphoramidite
heterobidentate ligands. In this library building blocks are
available to form 70 heterobidentate phosphorus ligands
containing a P-stereogenic phosphorus center, ligands that
are difficult to prepare by classical synthesis.
Materials: Chemicals were purchased from commercial suppliers
and, unless stated otherwise, used without further purification. Tri-
ethylamine and diisopropylethylamine were distilled from CaH2
prior to use. The following compounds were prepared according to
literature procedures: The chlorophosphite of (S)-2,2Ј-binaph-
thol,[33] the phosphorochloridite of (S)-(–)-3,3Ј-bis(trimethylsilyl)-
2,2Ј-binaphthol,[34] (1S,7S)-4-chloro-9,9-dimethyl-2,2,6,6-tetrakis-
(3,5-dimethylphenyl)-3,5,8,10-tetraoxa-4-phosphabicyclo[5.3.0]dec-
ane,[35] ligands 1–10,[9c,9g] B2,[27] C1–3[9h] and D1–6, and 9–
14.[9c,9g,9h,9o]
Synthesis of (R)-[3,3Ј-Bis(trimethylsilyl)-1,1Ј-binaphthyl-2,2Ј-diyl]
[5-(Phenyl-3-yl)-10,15,20-triphenylporphyrinyl-κ4N21,N22,N-zinc(II)]
Phosphite (8): A solution of (R)-3,3Ј-bis(trimethylsilyl)-2,2Ј-binaph-
thol phosphorus chloridite (1.30 g, 2.62 mmol) in CH2Cl2 (10 mL)
was added to a mixture of 5-(3-hydroxyphenyl)-10,15,20-triphenyl-
porphyrinatozinc(II) (1.86 g, 2.68 mmol), azeotropically dried with
Application of part of the library in the asymmetric hy-
droformylation of styrene reveals a catalytic performance toluene (3ϫ10 mL) and DIPEA (4.80 mL, 27.6 mmol) in CH2Cl2
(100 mL) was added dropwise at –78 °C. After addition of the PCl
compound, the mixture was stirred for 15 min at –78 °C and 3 h at
room temperature. The solvent was evaporated and the crude prod-
uct dissolved in a minimum amount of CH2Cl2 and purified over
a short column (ca. 3 cm) of basic alumina. After evaporation of
the solvent, the product was obtained as a purple solid. Yield 1.66 g
(55%). 1H NMR (300 MHz, CDCl3): δ = 9.00–8.97 (m, 4 H), 8.90–
8.80 (m, 3 H), 8.32–8.22 (m, 5 H), 8.08 (br. s, 1 H), 7.97 (d, J =
7.80 Hz, 1 H), 7.87 (d, J = 8.10 Hz, 1 H), 7.80–7.71 (m, 9 H), 7.65–
7.63 (m, 4 H), 7.55–7.53 (m, 1 H), 7.32 (t, J = 6.90 Hz, 1 H), 7.24–
that is strongly dependent on the ligand class used. Cata-
lysts formed from phosphane-containing or bulky phos-
phite ligands generally show high activity in the hydrofor-
mylation reactions. However, the product enantioselectivi-
ties obtained with these catalysts were often very low. In
contrast, reactions performed with catalysts formed from a
SUPRAPhos ligand containing a phosphoramidite ligand
result in relatively high enantioselectivities and low activi-
ties. Besides the differences between ligand classes, some-
times large variations were also observed in activity and 7.19 (m, 1 H), 7.14–7.06 (m, 1 H), 6.97 (d, J = 8.70 Hz, 1 H), 6.77
6086
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Eur. J. Org. Chem. 2008, 6079–6092

Development of the SUPRAPhos Ligand Library
(d, J = 8.70 Hz, 1 H), 6.64 (d, J = 7.50 Hz, 1 H), 6.37 (t, J = wise. The mixture was stirred overnight and at the same time al-
7.50 Hz, 1 H), 5.92 (t, J = 7.20 Hz, 1 H), 0.54 (s, 9 H), 0.43 (9
lowed to warm up to room temperature. The solvent was evapo-
rated and the product dissolved in CH2Cl2 (5 mL) and filtered
through a short column of basic alumina (4 cm) using dichloro-
methane as eluent. Evaporation of the solvent yielded the ligand as
a purple solid. Yield 213 mg (45%). 1H NMR (300 MHz, CDCl3): δ
= 9.07–9.05 (m, 2 H), 9.01–8.96 (m, 6 H), 8.28–8.21 (m, 6 H), 7.95
(d, J = 5.40 Hz, 1 H), 7.91 (d, J = 8.00 Hz, 1 H), 7.87 (d, J =
7.50 Hz, 1 H) 7.85–7.83 (m, 2 H), 7.79–7.74 (m, 7 H), 7.67 (d, J =
8.00 Hz, 1 H), 7.61 (t, J = 8.00 Hz, 1 H), 7.54 (d, J = 7.50 Hz, 1
H), 7.45–7.40 (m, 4 H), 7.35 (d, J = 9.00 Hz, 1 H), 7.31 (d, J =
8.50 Hz, 1 H), 7.27–7.24 (m, 2 H), 7.13 (t, J = 7.50 Hz, 1 H), 7.07
(t, J = 7.50 Hz, 1 H), 5.44 (s, 1 H) ppm. 13C NMR (300 MHz,
CDCl3): δ = 150.5, 150.4, 150.3, 149.0, 147.3, 144.4, 143.2, 139.7
(d, J = 16.2 Hz), 134.7 (d, J = 24.9 Hz), 133.8, 132.9 (J = 16.2 Hz),
132.2, 131.8, 131.3, 130.7 (d, J = 30.0 Hz), 130.1 (d, J = 28.3 Hz),
129.0, 128.7, 128.5, 128.3, 127.8, 127.6, 127.1, 126.9, 126.6, 125.3,
125.1, 124.9, 124.4, 123.9, 122.5, 121.8, 121.7, 121.4, 121.3, 120.7,
117.3 ppm. 31P NMR (300 MHz, CDCl3): δ = 147.8 ppm. MS
(FAB): calcd. for C64H40N5O2PZn 1007.2368; found 1007.2396.
H) ppm. 31P NMR (121.3 MHz, CDCl3): δ = 139.0 ppm.
The other enantiomeric form (7) was prepared in an identical way
and has identical spectroscopic data.
Synthesis of 5-(3-Aminophenyl)-10,15,20-triphenylporphyrinyl-
κ4N21,N22,N23,N24-zinc(II)
A solution of meso-(3-aminophenyl)triphenylporphyrin (387 mg,
0.61 mmol) and Zn(OAc)2·2H2O (337 mg, 1.54 mmol) in a CH2Cl2/
MeOH mixture was stirred for 16 h at room temperature, after
which part of the solvent was evaporated. During evaporation of
the CH2Cl2, methanol was added gradually in order to precipitate
the product. After leaving the product to precipitate overnight, it
was filtered and washed with methanol. The product was used
without further purification. Yield 326 mg (77 %). 1H NMR
(300 MHz, CDCl3 + 2 drops CD3CN): δ = 8.78–8.70 (m, 4 H), 8.52
(d, J = 4.20 Hz, 1 H), 8.23–8.15 (m, 4 H), 8.09–8.02 (m, 3 H), 7.94
(d, J = 7.50 Hz, 1 H), 7.65–7.44 (m, 13 H), 7.14 (d, J = 7.20 Hz, 1
H) ppm.
Synthesis of (S)-(1,1Ј-Binaphthyl-2,2Ј-diyl) [5-(Phenyl-2-yl)-
10,15,20-triphenylporphyrinyl-κ4N21,N22,N23,N24-zinc(II)]phosphor-
amidite (12): 5-(2-Aminophenyl)-10,15,20-triphenylporphyrinato-
zinc(II) (0.40 mmol, 278 mg) was azeotropically dried with toluene
(3 ϫ 2 mL). After dissolving in THF (30 mL), it was cooled to
–50 °C, after which DIPEA (4.01 mmol, 0.70 mL) was added.
Freshly prepared (S)-2,2Ј-binaphthol phosphorus chloridite
(0.40 mmol, 141 mg), dissolved in THF (10 mL), was added drop-
wise. The mixture was stirred overnight and at the same time al-
lowed to warm up to room temperature. The solvent was evapo-
rated and the product dissolved in CH2Cl2 (5 mL) and filtered
through a very short column of basic alumina (5 cm) using dichlo-
romethane as eluent. Evaporation of the solvent yielded the ligand
as a purple solid. Yield 169 mg (42 %). 1H NMR (300 MHz,
CDCl3): δ = 8.97–8.83 (m, 8 H), 8.25–8.02 (m, 6 H), 7.88–7.66 (m,
14 H), 7.41–7.36 (m, 1 H), 7.19 (d, J = 6.90 Hz, 1 H), 7.14 (d, J =
8.70 Hz, 1 H), 6.97 (d, J = 6.60 Hz, 1 H), 6.87 (d, J = 8.40 Hz, 1
H), 6.58–6.53 (m, 3 H), 6.07 (d, J = 8.10 Hz, 1 H), 5.97 (d, J =
8.70 Hz, 1 H), 4.79 (s, 1 H) ppm. 13C NMR (300 MHz, CDCl3): δ
= 150.54, 150.46, 150.3, 150.11, 150.06, 148.3, 146.3, 143.2, 143.0,
142.6 [d, J(C,P) = 17.1 Hz], 135.2, 134.7, 132.9, 132.8, 132.5, 132.2,
131.7, 131.5, 131.4, 130.2, 129.8, 129.6, 128.4, 128.3, 127.8, 127.7,
127.6, 127.3, 126.8, 126.0 [d, J(C,P) = 20.8 Hz], 125.2 [d, J(C,P) =
26.9 Hz], 124.0, 122.6, 121.7, 121.4, 121.2 [d, J(C,P) = 6.12 Hz],
120.4, 116.6 [d, J(C,P) = 22.0 Hz], 114.7 ppm. 31P NMR
(300 MHz, CDCl3): δ = 146.4 ppm.
Synthesis of 5-(2-Aminophenyl)-10,15,20-triphenylporphyrinyl-
κ4N21,N22,N23,N24-zinc(II)
A solution of meso-(2-aminophenyl)triphenylporphyrin (388 mg,
0.62 mmol) and Zn(OAc)2·2H2O (780 mg, 3.55 mmol) in a CH2Cl2/
MeOH solvent mixture (2:1, 40 mL) was stirred for 16 h at room
temperature, after which part of the solvent was evaporated. Dur-
ing evaporation of the CH2Cl2, methanol was added gradually in
order to precipitate the product. After precipitation overnight, the
product was isolated by filtration and washed with methanol. The
product was used without further purification. Yield 278 mg (65%).
1H NMR (300 MHz, CDCl3): δ = 9.03 (d, J = 4.50 Hz, 2 H), 8.90
(d, J = 5.10 Hz, 2 H), 8.57 (d, J = 4.20 Hz, 2 H), 8.49 (br. d, J =
6.00 Hz, 1 H), 8.33 (br. d, J = 6.90 Hz, 1 H), 8.24 (br. s, 2 H), 7.97
(d, J = 7.20 Hz, 2 H), 7.87–7.62 (m, 12 H), 7.37–7.34 (m, 1 H),
6.89–6.87 (m, 2 H), 4.04 (br. s, 2 H) ppm. 13C NMR (300 MHz,
CDCl3): δ = 150.6, 150.4, 149.9, 148.7, 143.6, 143.3, 140.7, 134.9,
134.7, 134.6, 134.4, 132.7, 132.2, 130.4, 129.9, 127.8, 127.7 127.5,
126.9, 126.8, 126.7, 126.6, 121.5, 121.2, 121.0, 119.7, 116.6,
112.9 ppm. C44H29N5Zn (693.14) + 2.5 equiv. H2O: calcd. C 71.59,
H 4.64, N 9.49; found C 71.93, H 4.39, N 8.36.
Synthesis of (R)-(+)-3,3Ј-Dimethyl-2,2Ј-binaphthol Phosphorus
Chloridite: (R)-(+)-3,3Ј-Dimethyl-1,1Ј-bi-2-naphthol (3.42 g,
10.9 mmol) was azeotropically dried with toluene (3ϫ3 mL), dis-
solved in CH2Cl2 (30 mL) and added dropwise to a solution of PCl3
(9.48 mL, 109 mmol) and Et3N (3.02 mL, 21.7 mmol) in CH2Cl2
(80 mL) at –60 °C. When the addition of (R)-3,3Ј-dimethyl-1,1Ј-bi-
2-naphthol was complete, the cooling bath was removed and the
mixture was stirred for 3 h at room temperature. The reaction mix-
Synthesis of (S)-(1,1Ј-Binaphthyl-2,2Ј-diyl) [5-(Phenyl-3-yl)- ture was concentrated in vacuo, redissolved in toluene (30 mL), af-
10,15,20-triphenylporphyrinyl-κ4N21,N22,N23,N24-zinc(II)]phosphor- ter which hexanes (60 mL) were added. The precipitated salts were
amidite (11): 5-(3-Aminophenyl)-10,15,20-triphenylporphyrin zinc-
(II) (0.47 mmol, 326 mg) was azeotropically dried with toluene
(3 ϫ 2 mL). After dissolving in THF (30 mL), it was cooled to
removed by filtration under nitrogen. After evaporation of the sol-
vent, the product was obtained as a white-yellowish foam in quanti-
tative yield. 1H NMR (300 MHz, CDCl3): δ = 7.91 (br. s, 2 H),
–50 °C, after which DIPEA (4.70 mmol, 0.82 mL) was added. 7.89 (br. s, 2 H), 7.51–7.43 (m, 2 H), 7.35–7.30 (m, 2 H), 7.27–7.22
Freshly prepared (S)-2,2Ј-binaphthol phosphorus chloridite (m, 2 H), 2.66 (s, 6 H) ppm. 31P NMR (300 MHz, CDCl3): δ =
(0.47 mmol, 165 mg), dissolved in THF (10 mL), was added drop-
175.3 ppm.
Eur. J. Org. Chem. 2008, 6079–6092
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6087

J. N. H. Reek et al.
Synthesis of (R)-(3,3Ј-Dimethyl-1,1Ј-binaphthyl-2,2Ј-diyl) [5-(Phen- at room temperature. After cooling to –70 °C, a THF/Et2O/pentane
FULL PAPER
yl-2-yl)-10,15,20-triphenylporphyrinyl-κ4N21,N22,N23,N24-zinc(II)]
Phosphite (13): A solution of (R)-3,3Ј-dimethyl-2,2Ј-binaphthol
phosphorus chloridite in CH2Cl2 (3 mL) was added dropwise to a
mixture of 5-(2-hydroxyphenyl)-10,15,20-triphenylporphyrin zin-
c(II) (319 mg, 0.46 mmol), azeotropically dried with toluene
(3ϫ2 mL), and DIPEA (0.80 mL, 4.60 mmol) in CH2Cl2 (20 mL)
at –78 °C. After addition of the PCl compound, the mixture was
stirred for 15 min at –78 °C and 3 h at room temperature. The sol-
vent was evaporated and the crude product dissolved in a minimum
amount of CH2Cl2 and purified through a short column (Ϯ3 cm)
of basic alumina. After evaporation of the solvent, the product was
obtained as a purple solid. Yield 224 mg (47 %). 1H NMR
(300 MHz, CDCl3): δ = 9.00–8.93 (m, 4 H), 8.89 (d, J = 9.00 Hz,
1 H), 8.87 (d, J = 9.00 Hz, 1 H), 8.75 (d, J = 4.80 Hz, 1 H), 8.67
solution (50 mL, 1:1:1) was added. The mixture was cooled to
–120 °C and 3-bromopyridine (1.60 mL, 2.61 g, 16.5 mmol), dis-
solved in a 1:1:1 mixture of THF/Et2O/pentane (10 mL), was added
slowly. The mixture was stirred for 10 min at –120 °C, after which
bis(2,6-dimethylphenyl)chlorophosphane (prepared according to a
literature procedure[36]), dissolved in THF, was added dropwise.
The resulting reaction mixture was stirred overnight and warmed
to room temperature. The orange solution was washed once with
brine, dried with MgSO4, and filtered (all under nitrogen). After
adding some silica, the mixture was concentrated in vacuo (and
simultaneously impregnated on silica). The product was purified by
column chromatography using PE 40–65 with 10% Et3N as eluent.
The product was further purified by chromatographic separation
with a Chromatotron® using CH2Cl2 as eluent. When the impurity
(d, J = 4.50 Hz, 1 H), 8.35–8.34 (br. m, 2 H), 8.25–8.17 (m, 3 H), was removed, 1% MeOH was added to the eluent (Rf on silica with
8.04 (d, J = 7.20 Hz, 1 H), 7.86–7.50 (m, 14 H), 7.23–7.11 (m, 2
1% MeOH/CH2Cl2: 0.37). Yield 1.2 g (23%). 1H NMR (300 MHz,
H), 6.67 (t, J = 7.65 Hz, 1 H), 6.45 (d, J = 8.40 Hz, 1 H), 5.93– CDCl3): δ = 8.60 (br. s, 1 H), 8.50 (dd, J = 4.65, J = 1.65 Hz, 1
5.83 (m, 3 H), 5.76 (br. s, 2 H), 2.18 (s, 6 H) ppm. 13C NMR
(125.7 MHz, CDCl3): δ = 151.5 (d, J = 3.52 Hz), 150.7, 150.33,
H), 7.59 (br. t, J = 6.30 Hz, 1 H), 7.20–7.14 (m, 3 H), 7.03–6.99
(m, 4 H), 2.13 (s, 12 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ =
150.30 (d, J = 2.39 Hz), 150.25 (d, J = 2.39 Hz), 150.0 (d, J = 154.7 [d, J(C,P) = 28.1 Hz], 149.1 (s), 142.9 [d, J(C,P) = 15.9 Hz],
8.04 Hz), 146.8 (d, J = 5.78 Hz), 145.8 (d, J = 3.52 Hz), 143.3 (d,
J = 6.40 Hz), 143.1, 136.3, 135.7, 134.8, 134.7, 134.6, 132.4, 132.1,
141.0 [d, J(C,P) = 18.3 Hz], 133.9 [d, J(C,P) = 17.0 Hz], 132.6 [d,
J(C,P) = 19.6 Hz], 129.6 (s) 129.3 (d, J = 34.1 Hz), 123.4 [d, J(C,P)
132.0, 131.7, 131.4, 131.2, 129.9, 129.54, 129.49, 129.3, 129.2, = 3.70 Hz], 23.6 [d, J(C,P) = 15.9 Hz] ppm. 31P NMR (121.5 MHz,
128.9, 128.5, 127.7 (d, J = 2.89 Hz), 127.5, 127.4, 126.8, 126.7 (d, CDCl3): δ = –26.4 ppm. C21H22NP (319.38): calcd. C 78.97, H 6.94,
J = 4.02 Hz), 126.6, 125.5, 125.1 (d, J = 9.30 Hz), 124.9 (d, J =
6.28 Hz), 123.9 (d, J = 5.15 Hz), 123.4, 123.1 (d, J = 5.15 Hz),
121.5, 121.4 (d, J = 2.89 Hz), 121.1, 121.0, 119.8 (d, J =
10.4 Hz) ppm. 31P NMR (121.3 MHz, CDCl3): δ = 143.7 ppm. MS
(FAB): calcd. for C66H43N4O3PZn 1036.2521; found 1036.2526.
C66H43N4O3PZn (1036.46) + 1 equiv. H2O: calcd. C 75.18, H 4.30,
N 5.31; found C 74.77, H 4.65, N 5.39.
N 4.39; found C 78.74, H 6.87, N 4.46.
Synthesis of (R,R)-2,5-Diphenylphospholane 1-Oxide: (R,R)-1-Oxo-
2,5-diphenyl-1λ5-phospholan-1-ol (1.22 g, 4.51 mmol), prepared
according to a literature procedure,[25] was three times azeo-
tropically dried with toluene and suspended in THF. After cooling
to 0 °C, Oxalyl chloride (1.55 mL, 2.29 g, 18.1 mmol) was added.
After 5 min stirring at 0 °C, the cooling bath was removed and the
Synthesis of (R)-(3,3Ј-Dimethyl-1,1Ј-binaphthyl-2,2Ј-diyl) [5-(Phen- mixture stirred for 2 h at room temperature. The solvent and excess
yl-3-yl)-10,15,20-triphenylporphyrinyl-κ4N21,N22,N23,N24-zinc(II)]
Phosphite (14): A solution of (R)-3,3Ј-dimethyl-2,2Ј-binaphthol
phosphorus chloridite in CH2Cl2 (3 mL) was added dropwise to a
mixture of 5-(3-hydroxyphenyl)-10,15,20-triphenylporphyrin zin-
c(II) (319 mg, 0.46 mmol), azeotropically dried with toluene
(3ϫ2 mL), and DIPEA (0.80 mL, 4.60 mmol) in CH2Cl2 (20 mL)
at –78 °C. After addition of the PCl compound, the mixture was
stirred for 15 min at –78 °C and 3 h at room temperature. The sol-
vent was evaporated and the crude product dissolved in a minimum
amount of CH2Cl2 and purified through a short column (Ϯ3 cm)
of basic alumina. After evaporation of the solvent, the product was
obtained as a purple solid. Yield 229 mg (48 %). 1H NMR
oxalyl chloride were removed by evaporation and the product was
dissolved in Et2O. After 5 min sonification in the ultrasound bath,
LiAlH4 (0.17 g, 4.51 mmol) was added in portions at 0 °C. After
stirring overnight, all the phosphinic acid was reduced to the hy-
dride, as judged by 31P NMR (singlet, –19 ppm). The work up was
performed under air, thereby oxidizing the product. A 1.0  aq.
HCl solution was added, followed by separation of the layers. The
aqueous layer was once extracted with EtOAc. Afterwards, the
combined organic layers were twice washed with a sat. aq. K2CO3
solution and once with a sat. NaCl solution. The organic layer was
dried with MgSO4, filtered, and concentrated in vacuo. The white
solid was crystallized from EtOAc and immediately used in the next
(300 MHz, CDCl3): δ = 9.00–8.93 (m, 7 H), 8.28–8.08 (m, 5 H), step. Yield 1.06 g (92%)
8.08–8.03 (m, 2 H), 7.82–7.68 (m, 13 H), 7.64–7.61 (m, 2 H), 7.40–
Synthesis of 3-(1-Oxo-2,5-diphenylphospholan-1-yl)pyridine (Both
7.35 (m, 2 H), 7.30–7.25 (m, 2 H), 7.22–7.14 (m, 3 H), 7.08–7.03
(m, 1 H), 2.65 [d. J(H,P) = 11.1 Hz] ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 150.56 (s), 150.49 (s), 150.16 (s), 147.86 (s), 147.79 (s),
146.48 (s), 146.45 (s), 145.00 (s), 143.09 (s), 134.72 (s), 132.43 (s),
132.33 (s), 132.28 (s), 132.01 (s), 131.92 (s), 131.76 (s), 131.59 (s),
131.37 (s), 130.84 (s), 130.29 (s), 130.0 (s), 127.99 (s), 127.77 (s),
127.62 (s), 127.16 [d, J(C,P) = 3.70 Hz], 126.81 (s), 126.37 [d, J(C,P)
= 8.61 Hz], 125.62 (s), 125.44 (s), 125.37 (s), 125.05 (s), 124.94 (s),
124.86 (s), 123.03 (s), 121.60 (s), 121.48 (s), 119.84 (s), 119.22 [d,
J(C,P) = 8.53 Hz] ppm. 31P NMR (121.3 MHz, CDCl3): δ =
142.5 ppm. MS (FAB): calcd. for C66H43N4O3PZn 1036.2521;
found 1036.2526. C66H43N4O3PZn (1036.46): calcd. C 76.48, H
4.18, N 5.41; found C 76.55, H 4.10, N 5.40.
Enantiomers): Pd(OAc)2 (43.6 mg, 0.19 mmol) and 1,3-bis(diphen-
ylphosphanyl)propane (dppp) (88.2 mg, 0.21 mmol) were placed in
a dry, degassed Schlenk tube and degassed by three vacuum/nitro-
gen cycles. The catalyst precursor was dissolved in DMF (10 mL)
and stirred for 15 min at room temperature. 3-Iodopyridine
(478 mg, 2.33 mmol) was added and the mixture was stirred for an
additional 15 min. A solution of (R,R)-2,5-diphenylphospholane 1-
oxide (498 mg, 1.94 mmol), three times azeotropically dried with
toluene, and DIPEA in DMF (5 mL) was added to the catalyst
solution. The resulting dark-red solution was stirred for 16 h at
105 °C. After cooling to room temperature, the DMF was evapo-
rated. The crude product was redissolved in dichloromethane,
washed twice with 5% aq. NaHCO3 and once with brine. The or-
ganic layer was dried with MgSO4, filtered, and the solvents evapo-
rated. After a very fast purification over a small layer of silica to
remove the main impurities, the product was purified by means of
Synthesis of 3-[Bis(2,6-dimethylphenyl)phosphanyl]pyridine (A4): n-
Butyllithium (5.28 mL of a 2.5  solution in hexanes; 13.2 mmol)
and TMEDA (1.99 mL, 1.53 g, 13.2 mmol) were stirred for 15 min
6088
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 6079–6092

Development of the SUPRAPhos Ligand Library
chromatographic separation with a Chromatotron® using EtOAC/
PE (3:1) as the eluent.
water with 37% aq. HCl (a few mL). The layers were separated
and the aqueous layer was twice extracted with chloroform. A 0.5 
aq. Na2CO3 solution (100 mL) was added to the combined organic
layers, which resulted in deprotonation of the product. As a conse-
quence, the deprotonated acid moves to the aqueous layer. The
layers were separated, after which 4  aq. HCl (100 mL) and
CHCl3 (200 mL) were added to the aqueous layer. The protonated
product immediately moved to the organic layer, which was col-
lected. The aqueous layer was three times extracted with CHCl3.
The combined organic layers were dried with Na2SO4, filtered, and
concentrated in vacuo. The product was crystallized from toluene
to yield 1.0 g (87%) of the acid as a white solid. [α]D = +50.1 (c =
0.974, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 10.33 (br. s, 1 H),
7.78–7.71 (m, 2 H), 7.53–7.41 (m, 3 H), 3.23 [t, J(P,H) = 13.2 Hz, 1
H], 3.00 [dd, J(P,H) = 13.2, J(H,H) = 9.3 Hz, 1 H], 1.12 [d, J(P,H)
= 14.4 Hz, 9 H], 0.8–0.2 (br. s, 3 H) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 173.3 (s), 133.6 [d, J(C,P) = 8.53 Hz], 131.9 [d, J(C,P)
= 2.49 Hz], 128.6 [d, J(C,P) = 9.82 Hz], 125.1 [d, J(C,P) = 48.8 Hz],
30.3 [d, J(C,P) = 31.8 Hz], 27.6 [d, J(C,P) = 25.7 Hz], 25.5 [d,
J(C,P) = 2.42 Hz] ppm. 31P NMR (121.5 MHz, CDCl3): δ = 33.4
(d, JP,B = 61.2 Hz) ppm. C12H20BO2P (238.07): calcd. C 60.54, H
8.47; found C 60.42, H 8.42.
Analytical Data for the S,S Enantiomer: 1H NMR (300 MHz,
CDCl3): δ = 8.63 (br. s, 1 H), 8.54 (br. s, 1 H), 7.82–7.76 (m, 1 H),
7.31–7.25 (m, 5 H), 7.12–7.02 (m, 6 H), 4.01–3.88 (m, 1 H), 3.57–
3.74 (m, 1 H), 2.80–2.52 (m, 3 H), 2.33–2.23 (m, 1 H) ppm. 13C
NMR (75.5 MHz, CDCl3): δ = 151.7 (s), 150.6 (s), 150.5 (s), 140.4
(br. s), 135.5 (s), 135.2 (s), 129.0 (br. s), 127.6 (s), 127.3 [d, J(C,P)
= 4.76 Hz], 127.1 (s), 123.6 [d, J(C,P) = 7.32 Hz], 51.1 [d, J(C,P) =
62.5 Hz], 47.3 [d, J(C,P) = 62.3 Hz], 31.9 [d, J(C,P) = 7.40 Hz],
27.7 [d, J(C,P) = 8.53 Hz] ppm. 31P NMR (121.5 MHz, CDCl3): δ
= 52.9 ppm. C21H20NOP (333.36): calcd. C 75.66, H 6.05, N 4.20;
found C 75.75, H 6.08, N 4.04.
Analysis Data for the R,R Enantiomer: 1H NMR (300 MHz,
CDCl3): δ = 8.61 (d, J = 3.30 Hz), 8.51 (dd, J = 4.65, J = 2.25 Hz,
1 H), 7.80–7.73 (m, 1 H), 7.31–7.17 (m, 5 H), 7.12–7.02 (m, 6 H),
3.96–3.85 (m, 1 H), 3.53–3.46 (m, 1 H), 2.71–2.52 (m, 3 H), 2.32–
2.23 (m, 1 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 152.4 (s),
151.3 (s), 151.2 (s), 139.8 (s), 135.4 [d, J(C,P) = 3.77 Hz], 135.1 [d,
J(C,P) = 6.03 Hz], 129.1 [d, J(C,P) = 5.28 Hz], 129.0 [d, J(C,P) =
1.51 Hz], 128.9 (br. s), 127.6 [d, J(C,P) = 2.26 Hz], 127.3 [d, J(C,P)
= 4.52 Hz], 127.1 [d, J(C,P) = 3.02 Hz], 123.3 [d, J(C,P) = 7.32 Hz],
51.1 [d, J(C,P) = 62.3 Hz], 47.3 [d, J(C,P) = 62.3 Hz], 31.9 [d,
J(C,P) = 7.32 Hz], 27.7 [d, J(C,P) = 9.74 Hz] ppm. 31P NMR
(121.5 MHz, CDCl3): δ = 52.6 ppm.
Synthesis of 2-[(R)-Boronato(tert-butyl)(phenyl)phosphanyl]-N-[(S)-
2-hydroxypropyl]acetamide: tert-Butyl(phenyl)(carboxymethyl)-
phosphane–borane (250 mg, 1.11 mmol) was azeotropically dried
(2ϫ, toluene), dissolved in THF (15 mL), and cooled to 0 °C. 1-
Hydroxybenzotriazole (HOBt) (301 mg, 2.23 mmol) and 1-(3-di-
methylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI)
(256 mg, 1.34 mmol) were added and the resulting mixture was
stirred for 30 min at room temperature. After cooling to 0 °C, (S)-
(+)-1-amino-2-propanol (100 mg, 1.34 mmol) was added and the
mixture was stirred overnight at room temperature. 1  aq. HCl
Synthesis of (R,R)-3-(2,5-Diphenylphospholan-1-yl)pyridine (B1):
(R,R)-3-(1-Oxo-2,5-diphenylphospholan-1-yl)pyridine (300 mg,
0.90 mmol) was azeotropically dried with toluene (3 ϫ 2 mL).
PhSiH3 (ca. 4 mL) was added, the mixture was heated at reflux
with stirring for 16 h. After evaporation, the product was dissolved
in CH2Cl2 and purified using a Chromatotron® with CH2Cl2 as
eluent. Yield 234 mg (84%). 1H NMR (300 MHz, CDCl3): δ = 8.40 solution (10 mL) was added to the reaction mixture, followed by
(d, J = 4.80 Hz, 2 H), 7.43–7.21 (m, 6 H), 7.12–6.91 (m, 6 H), 4.11– CHCl3 ( 50 mL). The layers were separated and the aqueous layer
4.03 (m, 1 H), 3.97–3.85 (m, 1 H), 2.82–2.75 (m, 1 H), 2.47–2.38
(m, 1 H), 2.36–2.25 (m, 1 H), 2.17–2.05 (m, 1 H) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 153.4 (d, J = 17.1 Hz), 149.6, 144.1 (d, J
was twice extracted with chloroform. The combined organic layers
were washed once with sat. aq. NaHCO3 and once with brine. After
drying with Na2SO4, the solution was filtered and concentrated in
= 18.3 Hz), 141.1 (d, J = 19.6 Hz), 138.1, 132.3 (d, J = 34.2 Hz), vacuo. Column chromatography (silica, eluent: pure EtOAc, Rf =
129.0, 128.4, 128.1 (d, J = 9.74 Hz), 127.8 (d, J = 3.70 Hz), 126.5 0.32) yielded 219 mg (67%) of the product as a white solid. [α]D
=
(d, J = 2.42 Hz), 126.2 (d, J = 2.42 Hz), 122.9 (d, J = 6.12 Hz),
48.6 (d, J = 17.1 Hz), 46.8 (d, J = 15.9 Hz), 37.1, 32.9 (d, J =
+70.4 (c = 0.100, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.77–
7.71 (m, 2 H), 7.53–7.41 (m, 3 H), 6.74 (br. s, 1 H), 3.65–3.59 (m,
3.62 Hz) ppm. 31P NMR (121.5 MHz, CDCl3): δ = 15.9 ppm. 1 H), 3.37–3.29 (m, 1 H), 3.15 (t, J = 14.3 Hz, 1 H), 3.02–2.97 (m,
C21H20NP (317.36): calcd. C 78.16, H 6.25, N 4.34; found C 78.37,
H 6.28, N 3.95 (33% oxide present in sample during elemental
analysis).
1 H), 2.88–2.79 (m, 1 H), 2.65 (br. s, 1 H), 1.10 [d, J(P,H) = 14.7 Hz,
9 H], 0.95 (d, J = 6.30 Hz, 3 H), 0.90–0.20 (br., 3 H, BH3) ppm.
13C APT NMR (75.5 MHz, CDCl3): δ = 166.8 (s), 133.7 (d, J =
8.61 Hz), 132.0 (s), 128.6 (d, J = 9.74 Hz), 124.7 (d, J = 51.3 Hz),
66.7 (s), 47.6 (s), 30.1 (d, J = 30.6 Hz), 28.9 (d, J = 25.7 Hz), 25.3
(s), 20.5 (s) ppm. 31P NMR (121.5 MHz, CDCl3): δ = 30.2 [br. d,
J(P,B) = 66.3 Hz] ppm. C15H27BNO2P (295.17): calcd. C 61.04, H
9.22, N 4.75; found C 61.18, H 8.78, N 4.71.
tert-Butyl(phenyl)phosphane–Borane: The complex was prepared
according to a literature procedure.[37]
(R)-tert-Butyl(methyl)phenylphosphane–Borane: The complex was
prepared according to a literature procedure.[23]
Synthesis of (R)-{[Boronato(tert-butyl)(phenyl)]phosphanyl}acetic Synthesis of 2-{(R)-[Boronato(tert-butyl)(phenyl)phosphinyl]methyl}-
Acid: (R)-tert-Butyl(methyl)phenylphosphane–borane (1.00 g,
5.15 mmol) was dried azeotropically (3ϫ4 mL) and dissolved in
Et2O (40 mL). tert-Buthyllithium (4.47 mL, a 1.5  solution in pen-
tane, 6.70 mmol) was added at –78 °C. After 1 h stirring at this
temperature, CO2 gas was bubbled through the solution. For that
purpose, a round-bottomed flask was filled with CO2 (s) and con-
nected to a column with Sicapent® in order to dry the released gas.
The gas was transferred to the flask through a polyflow® tube. The
CO2 was bubbled through for 1 h at –78 °C, and for 1 h at room
temperature Et2O (40 mL) was added to keep the solvent level con-
stant. CO2 bubbling was stopped and the mixture was stirred at
room temperature for 16 h. Then the mixture was poured into ice–
(5S)-5-methyl-2-oxazoline: 2-[(R)-Boronatophenyl(tert-butyl)phos-
phanyl]-N-[(S)-2-hydroxypropyl]acetamide (0.82 g, 2.77 mmol) was
azeotropically dried with toluene (3 ϫ 3 mL) and dissolved in
CH2Cl2 ( 50 mL). The reaction mixture was cooled to 0 °C and
Et3N (1.9 mL, 13.6 mmol, 4.9 equiv.) and methanesulfonyl chloride
(1.1 mL, 13.8 mmol, 5 equiv.) were added. After 30 min stirring,
the ice bath was removed and the reaction mixture was stirred for
13 h at room temperature. The reaction was quenched by the ad-
dition of sat. aq. NaHCO3, diluted with CHCl3, and the layers were
separated. The aqueous layer was twice extracted with CHCl3. The
combined organic layers were washed with brine and dried with
Na2SO4. After filtration, the solvent was evaporated under reduced
Eur. J. Org. Chem. 2008, 6079–6092
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6089

J. N. H. Reek et al.
pressure, after which the product was purified by column in PhSiH3 (5 mL) and heated at reflux with stirring for 40 h. Then
FULL PAPER
chromatography over basic alumina. Eluent: petroleum ether/ethyl
acetate (1:1), with gradient to pure ethyl acetate. Rf = 0.34; yield
664 mg (86 %). [α]D = +35.1 (c = 0.480, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 7.80 (t, J = 8.4 Hz, 2 H), 7.54–7.42 (m, 3
H), 4.63–4.55 (m, 1 H), 3.89–3.80 (m, 1 H), 3.27–3.18 (m, 2 H),
3.05–2.95 (m, 1 H), 1.14 (d, J = 13.8 Hz, 9 H), 1.02 (d, J = 3 H,
6.60 Hz), 0.82–0.20 (br., 3 H) ppm. 13C NMR (75.5 MHz, CDCl3):
δ = 161.8, 133.9 (d, J = 8.67 Hz), 131.7 (d, J = 2.39 Hz), 128.4 (d,
J = 9.30 Hz), 125.7 (d, J = 48.4 Hz), 61.4, 30.2 (d, J = 30.7 Hz),
25.6, 21.3 (d, J = 29.4 Hz), 21.0 ppm. 31P NMR (121.5 MHz,
CDCl3): δ = 33.5 (br. d, J = 60.0 Hz) ppm. C15H25BNOP (277.15):
calcd. C 65.00, H 9.09, N 5.05; found C 64.77, H 8.98, N 5.02.
the solvent was removed in vacuo and the product was purified
over a short silica column (Ϯ5 cm) using EtOAc/PE (1:1) as eluent.
1
Analytical Data for Enantiomer 1: H NMR (300 MHz, CDCl3): δ
= 8.77 (br. s, 1 H), 8.56 (d, J = 5.10 Hz, 1 H), 7.83–7.81 (m, 1 H),
7.58–7.53 (m, 2 H), 7.38–7.35 (m, 3 H), 7.29–7.25 (m, 1 H), 1.19
(d, J = 12.9 Hz, 9 H) ppm. 31P NMR (300 MHz, CDCl3): δ =
12.8 ppm. C15H18NO2P + H2O: calcd. C 64.97, H 7.27, N 5.05;
found C 65.18, H 6.75, N 4.82.
1
Analytical Data for Enantiomer 2: H NMR (300 MHz, CDCl3): δ
= 8.78 (br. s, 1 H), 8.57 (d, J = 4.80 Hz, 1 H), 7.87–7.82 (m, 1 H),
7.62–7.52 (m, 2 H), 7.44–7.26 (m, 4 H), 1.20 (d, J = 12.9 Hz, 9
H) ppm. 13C NMR (125.7 MHz, CDCl3): δ = 154.1, 153.8 (d, J =
9.81 Hz), 149.8, 148.8, 142.5, 136.2, 134.6 (d, J = 37.9 Hz), 129.5
(d, J = 29.4 Hz), 128.4, 123.5, 31.1, 28.8 (d, J = 14.7 Hz) ppm. 31P
NMR (300 MHz, CDCl3): δ = 12.8 ppm.
Synthesis of 2-[(R)-(tert-Butyl)(phenyl)phosphanylmethyl]-(5S)-5-
methyl-2-oxazoline (B4): (5S)-2-{(R)-[Boronatophenyl(tert-butyl)-
phosphanyl]methyl}-5-methyl-2-oxazoline (155.2 mg, 0.59 mmol)
was azeotropically dried with toluene (3ϫ2 mL) and dissolved in
CH2Cl2 (10 mL). The solution was cooled to –20 °C, after which
tetrafluoroboric acid–dimethyl ether complex (0.61 mL,
5.90 mmol) was added. The mixture was stirred for 16 h at room
temperature. A degassed sat. aq. NaHCO3 solution was added and
the mixture was stirred for an additional hour. The layers were
separated and the aqueous layer was three times extracted with
Et2O. The combined organic layers were dried with Na2SO4, fil-
tered, and concentrated in vacuo. The crude product was purified
over a small column of basic alumina (ca. 5 cm), using Et2O as
eluent. 31P NMR (121.5 MHz, CDCl3): δ = 47.5 ppm.
Synthesis of (S,S)-3-[4,4,8,8-Tetrakis(3,5-dimethylphenyl)-2,2-di-
methyl-3a,4,8,8a-tetrahydro-2H-[1,3]dioxolo[4,5-e][1,3,2]dioxaphos-
phepin-6-yloxy]pyridine
(D7):
3-Hydroxypyridine
(0.58 g,
6.13 mmol), azeotropically dried with toluene (3ϫ5 mL), and tri-
ethylamine (0.94 mL, 6.74 mmol) were dissolved in dichlorometh-
ane (20 mL) and the solution was cooled to –50 °C. Freshly pre-
pared
(1S,7S)-4-chloro-9,9-dimethyl-2,2,6,6-tetrakis(3,5-dimeth-
ylphenyl)-3,5,8,10-tetraoxa-4-phosphabicyclo[5.3.0]decane (3.94 g,
6.13 mmol) dissolved in dichloromethane (20 mL) was added drop-
wise. The cooling bath was removed, the solution was warmed to
room temperature, and stirring was continued for 2 h. The solvent
was evaporated after which the product was extracted with a mix-
ture of toluene (20 mL) and hexanes (60 mL). After filtration the
solvent was removed in vacuo to give D7 (3.31 g, 4.72 mmol, 77%)
(rac)-3-[(tert-Butyl)(phenyl)phosphinoyl]pyridine: In a dry, degassed
Schlenk tube, Pd(OAc)2 (135 mg, 0.60 mmol) and dppb (282 mg,
0.66 mmol) were dissolved in freshly distilled DMF (15 mL). After
5 min stirring, 3-iodopyridine (1.48 g, 7.22 mmol) was added, after
which the mixture was stirred for 10 min at room temperature. tert-
Butyl(phenyl)phosphane (1.0 g, 6.02 mmol) and DIPEA (4.2 mL,
3.11 g, 24.1 mmol) dissolved in DMF (5 mL) were added, after
which the mixture was stirred at 105 °C for 16 h. The solution was
cooled to room temperature and the DMF evaporated. The re-
sulting brown-red oil was dissolved in chloroform, washed twice
with 5% aq. NaHCO3 and once with brine (under air; oxidation
of phosphane). The organic layer was dried with MgSO4, filtered,
and concentrated in vacuo. The crude product (oxide) was purified
by means of chromatographic separation with a Chromatotron®
equipped with a silica plate using EtOAc/CH2Cl2 (1:1) with 1%
1
as a white foam: H NMR (CDCl3, 300 MHz): δ = 8.26 (dd, J =
4.65, 1.50 Hz, 1 H), 7.90 (br. d, J = 2.70 Hz, 1 H), 7.28–7.26 (m, 1
H), 7.21–7.15 (m, 5 H), 7.10–7.02 (m, 5 H), 6.97–6.91 (m, 3 H),
6.84 (br. d, J = 9.60 Hz, 2 H), 5.45 (d, J = 7.80 Hz, 1 H), 5.06 (dd,
J = 8.25, 0.60 Hz, 1 H), 2.32 (d, J = 11.4 Hz, 15 H), 2.24 (s, 9 H),
0.85 (s, 3 H), 0.73 (s, 3 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ
= 149.9, 149.2, 149.1, 145.9, 144.3, 142.5, 142.4, 141.1, 141.0, 137.6,
137.4, 136.7, 136.6, 129.7, 129.3, 129.2, 129.1, 128.5, 127.1, 127.0,
126.9, 126.7, 125.6, 125.2, 125.1, 123.5, 113.2, 86.9, 86.8, 85.9, 85.8,
82.6, 82.5, 80.1, 27.0, 26.7, 21.9, 21.8 ppm. 31P NMR (121.5 MHz,
CDCl3): δ = 126.45 ppm. C44H48NO5P (701.83): calcd. C 75.30, H
6.89, N 2.00; found C 75.18, H 6.77, N 1.96.
1
Et3N as eluent. Yield 0.97 g (62%) of an off-white solid. H NMR
(300 MHz, CDCl3): δ = 9.12 (m, 1 H), 8.73 (m, 1 H), 8.31 (m, 1
H), 7.92 (m, 2 H), 7.49 (m, 4 H), 1.25 [d, J(H,P) = 15.3 Hz, 9
H] ppm. 13C NMR (125.7 MHz, CDCl3): δ = 152.2 [d, J(C,P) =
1.76 Hz], 152.1 [d, J(C,P) = 9.80 Hz], 140.8 [d, J(C,P) = 5.78 Hz],
132.2 [d, J(C,P) = 8.67 Hz], 132.2 [d, J(C,P) = 2.89 Hz], 130.4 [d,
J(C,P) = 92.4 Hz], 128.8 [d, J(C,P) = 10.9 Hz], 128.3 [d, J(C,P) =
85.5 Hz], 123.8 [d, J(C,P) = 7.54 Hz], 34.3 [d, J(C,P) = 71.6 Hz],
25.2 ppm. 3 1 P NMR (300 MHz, CDCl3 ): δ = 38.2 ppm.
C15H18NOP (259.28): calcd. C 69.48, H 7.00, N 5.40; found C
69.58, H 8.44, N 5.20.
General Procedure for the Hydroformylation of Styrene: The experi-
ments were performed in a stainless steel autoclave (volume
150 mL) charged with an inset suitable for 14 reaction vials (includ-
ing Teflon® stirring bars) to conduct parallel reactions. The vessels
(GC vials) were oven-dried, cooled under vacuum, and filled under
nitrogen. The substrate styrene was freshly filtered through neutral
alumina before use to remove possible peroxide impurities. In a
typical experiment, the vials were filled with [Rh(acac)(CO)2]
(0.50 µmol), acceptor-type phosphorus ligand (porphyrin phos-
phite; 2.50 µmol), donor-type phosphorus ligand (e.g., pyridyl
phosphane; 2.50 µmol), N,N-diisopropylethylamine (4.4 µL), sty-
rene (57.3 µL), and decane (28.7 µL; as internal standard) in tolu-
ene (0.50 mL). The vials were closed and a needle was inserted to
ensure gas-uptake. The autoclave was closed and four times purged
with 15 bar of syngas (H2/CO, 1:1), pressurized to 20 bar syngas,
and subsequently the reactions were stirred (see main text in for
details of temperature and reaction time). After the required time,
the autoclave was cooled to 0 °C, after which the pressure was re-
duced to 1 bar. Two drops of tri-n-butyl phosphite were added to
all the reaction vials to prevent any further reaction. From each
The enantiomers were separated at DSM by preparative HPLC
equipped with an AD column [l = 25 cm, eluent: n-heptane/tert-
butyl alcohol (72.5:27.5), 1 mL/min]. t1 = 15.5 min (enantiomeric
purity: 98.5Ϯ0.5%), t2 = 20.3 min (enantiomeric purity: 97.6%).
Elemental analysis after separation of the enantiomers: Enantiomer
1: C15H18NOP (259.28): calcd. C 69.48, H 7.00, N 5.40; found C
69.33, H 6.93, N 5.32. Enantiomer 2: C15H18NOP (259.28): calcd.
C 69.48, H 7.00, N 5.40; found C 69.34, H 6.96, N 5.30.
3-[(tert-Butyl)(phenyl)phosphanyl]pyridine (Both Enantiomers B5
and B6): The phosphane oxide (120 mg, 0.46 mmol) was dissolved
6090
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Eur. J. Org. Chem. 2008, 6079–6092

Development of the SUPRAPhos Ligand Library
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vial two samples were taken and diluted with dichloromethane for
GC and chiral GC analysis. The samples for chiral GC analysis
were filtered through a plug of silica; the samples for normal GC
analysis were not filtered because retention of the aldehydes on
silica causes inaccuracies in the determination of the conversion
and branched-to-linear selectivity. The enantiomeric purity was de-
termined by chiral GC [ph Megadex column, internal diameter
0.1 mm, 5 m column, film thickness 0.1 µm; initial temperature =
40 °C and ∆T = 25 °C min–1; tR (R) = 5.65 min and tR (S) =
5.73 min]. All reactions were performed in duplicate.
[5]
[6]
[7]
Supporting Information (see also the footnote on the first page of
this article): Data of all the ligands that are applied in the initial
screening hydroformylation of styrene.
[8]
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Acknowledgments
Ilse Maes and Dr. André H. M. de Vries from DSM are kindly ac-
knowledged for the preparative HPLC resolution of phosphanes
B5 and B6. Dr. A. H. M. de Vries is also gratefully acknowledged
for the donation of (R)-(+)-3,3Ј-dimethyl-2,2Ј-binaphthol and Dr.
P. H. M. Budzelaar (Koninklijke/Shell Laboratorium Amsterdam)
is gratefully acknowledged for the donation of pyridyl phosphorus
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Received: May 22, 2008
Published Online: November 10, 2008
6092
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Eur. J. Org. Chem. 2008, 6079–6092