A library approach to the development of BenzaPhos: Highly efficient chiral supramolecular ligands for asymmetric hydrogenation

Article abstract of DOI:10.1002/chem.201201032

A library of chiral supramolecular ligands, named BenzaPhos, of straightforward preparation (two steps from commercially or readily available starting materials) and modular structure, was designed and synthesized. The ligands were screened in the search for new rhodium catalysts for the enantioselective hydrogenation of several benchmark and industrially relevant substrates. Once a series of hits were identified, structural modifications were introduced on three of the best ligands and a small second-generation library was created. Members of the latter library showed outstanding levels of activity and enantioselectivity in the hydrogenation of challenging olefins, such as enamide S4 and β-dehydroamino ester S5 (>99 % ee: best value ever reported in both cases). A series of control experiments were undertaken to clarify the role of hydrogen bonding in determining the catalytic properties of the new ligands. The results of these experiments, together with those of computational studies carried out on four dihydride complexes involved in the catalytic hydrogenation of substrate S4, strongly suggest that a substrate orientation takes place in the catalytic cycle by formation of a hydrogen bond between the ligand amide oxygen atom and the substrate amide NH atom. As simple as selective: BenzaPhos ligands, benzamide-containing chiral monophosphites of modular structure and trivial synthesis, have been screened in the Rh-catalyzed hydrogenation of olefins (see scheme), giving excellent enantioselectivities with three benchmark and two industrially relevant substrates. Control experiments and computational studies suggest an important role of ligand-substrate hydrogen bonding in the stereodiscriminating step of the catalytic cycle. Copyright

Full text of DOI:10.1002/chem.201201032

FULL PAPER
DOI: 10.1002/chem.201201032
A Library Approach to the Development of BenzaPhos: Highly Efficient
Chiral Supramolecular Ligands for Asymmetric Hydrogenation
Luca Pignataro,*[a] Chiara Bovio,[a] Monica Civera,[a] Umberto Piarulli,*[b] and
Cesare Gennari*[a]
Abstract: A library of chiral supra-
molecular ligands, named BenzaPhos,
of straightforward preparation (two
steps from commercially or readily
available starting materials) and modu-
lar structure, was designed and synthe-
sized. The ligands were screened in the
search for new rhodium catalysts for
the enantioselective hydrogenation of
several benchmark and industrially rel-
evant substrates. Once a series of hits
were identified, structural modifica-
tions were introduced on three of the
best ligands and a small second-genera-
tion library was created. Members of
the latter library showed outstanding
levels of activity and enantioselectivity
in the hydrogenation of challenging
olefins, such as enamide S4 and b-de-
hydroamino ester S5 (>99% ee: best
value ever reported in both cases). A
series of control experiments were un-
dertaken to clarify the role of hydrogen
bonding in determining the catalytic
properties of the new ligands. The re-
sults of these experiments, together
with those of computational studies
carried out on four dihydride com-
plexes involved in the catalytic hydro-
genation of substrate S4, strongly sug-
gest that a substrate orientation takes
place in the catalytic cycle by forma-
tion of a hydrogen bond between the
ligand amide oxygen atom and the sub-
strate amide NH atom.
Keywords: asymmetric catalysis
combinatorial catalysis · hydrogen
bonds substrate orientation
supramolecular chemistry
·
·
·
Introduction
ACHTUNGTRENoNUNG ns for this paradoxical situation are 1) the strong time-to-
market pressure present in the pharmaceutical industry,
which does not allow sufficient time for the development of
a catalytic process and 2) the high cost of the chiral catalysts
employed. A combinatorial approach to catalysis[3] may
tackle both of these issues by allowing libraries of ligands/
catalysts to be quickly tested (by high-throughput screening)
to identify efficient enantioselective catalysts for a selected
substrate. A fundamental requisite for this is that the lig-
During its fifty-year-long history, asymmetric homogeneous
catalysis has progressed enormously, and highly enantiose-
lective catalysts have been discovered for many important
organic transformations.[1] The fast-growing social demand
for enantiopure compounds—especially in the manufacture
of pharmaceutical products—has certainly been a potent
stimulus for such development, catalytic methodologies
being in principle the most direct and atom-economical way
to perform an enantioselective reaction. Despite this, asym-
metric catalysis has not yet established itself as the method-
ology of choice for the industrial preparation of enantiopure
compounds, most of which are still obtained from the classi-
cal resolution of diastereomeric salts.[2] Two important reas-
AHCTUNGTREGaNNUN nds/catalysts can be readily accessed and are of low cost, so
that relatively large libraries can be prepared and screened
in a short time. Chiral monodentate P ligands, the rediscov-
ery of which started some fifteen years ago,[4] are excellent
candidates for combinatorial screening strategies in asym-
metric transition-metal catalysis, because of the following
general features: 1) they are simpler to prepare than biden-
tate ligands, while securing in many cases similar or even
better levels of stereocontrol; 2) they often have a modular
structure, which facilitates the introduction of structural di-
versity into the library; and 3) the use of binary mixtures of
monodentate ligands in the presence of a transition-metal
source allows further expansion of the combinatorial space,
the complexes obtained from ligand combinations often
being more enantioselective than the complex of each sepa-
rate ligand.[5]
[a] Dr. L. Pignataro, C. Bovio, Dr. M. Civera, Prof. Dr. C. Gennari
Universitꢀ degli Studi di Milano
Dipartimento di Chimica Organica e Industriale
Istituto di Scienze e Tecnologie Molecolari (ISTM) del CNR
Via G. Venezian, 21, 20133, Milano (Italy)
Fax : (+39)02-50314072
E-mail: luca.pignataro@unimi.it
cesare.gennari@unimi.it
[b] Prof. Dr. U. Piarulli
Universitꢀ degli Studi dellꢁInsubria
Dipartimento di Scienza e Alta Tecnologia
Via Valleggio, 11, 22100, Como (Italy)
Fax : (+39)031-2386449
Alongside a renewed interest in chiral monodentate lig-
AHCTUNGTRENNUNG
E-mail: umberto.piarulli@uninsubria.it
AHCTUNGTRENNUNG
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201032.
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Scheme 1. Conception of BenzaPhos (B) from PhthalaPhos ligands (A). Curved arrows indicate possible points of diversification.
ty capable of either ligand–ligand or ligand–substrate nonco-
valent interactions. These supramolecular constructs display
improved catalytic performances (i.e., activity and regio-
and/or stereoselectivity) compared to those obtained with
simple monodentate ligands. Unfortunately, in many cases
the penalty for installing a second functional group capable
of noncovalent interactions consists of increasing the struc-
tural complexity of the ligands and, consequently, the syn-
thetic effort required for their preparation. Therefore, the
creation of new classes of chiral ligands with simple struc-
tures and very easy methods of preparation is the condition
for supramolecular catalysis to become of practical industrial
use.
Results and Discussion
Ligand design: As shown in Scheme 1, the BenzaPhos lig-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
group that is not connected to the phosphite residue) has
been removed. This modification has two important conse-
quences: 1) as discussed in more detail below, the ligand
synthesis is significantly shortened, the BenzaPhos ligands
being simple benzoic acid derivatives that are prepared in
only two steps from an aminoalcohol; and 2) the BenzaPhos
ligands have only one functional group capable of forming
Our research group has a longstanding interest in catalytic
enantioselective methodologies based on both simple mono-
dentate[7] and supramolecular ligands,[8] and has recently de-
veloped a new class of highly efficient chiral ligands, called
PhthalaPhos ligands, for the Rh-catalyzed asymmetric hy-
drogenation of olefins.[9] The PhthalaPhos ligands are 1,1’-
bi-2-naphthol (BINOL)-derived phosphites capable of exert-
ing a substrate-orientating effect by hydrogen bonding,[9b]
which makes them significantly more enantioselective than
structurally related monofunctional ligands. Although
PhthalaPhos ligands have simpler structures and are easier
to prepare than other supramolecular ligands[6] (they can be
synthesized in four steps from inexpensive commercial prod-
ucts), we sought to further simplify their structure while pre-
serving the ability to orientate the reaction substrate in the
hydrogenation process.
Scheme 2. Substrate orientation by hydrogen bonding proposed for the
PhthalaPhos ligands.[9b]
Herein, we describe our efforts in this direction, which re-
sulted in the creation of a new class of chiral supramolecular
BINOL-derived phosphites, called BenzaPhos, prepared in
only two linear steps from readily available or commercial
starting materials and are therefore well-suited for a library
approach to the discovery of effective catalysts. The new lig-
ACHTUNGTRENNUNGands were screened in the Rh-catalyzed asymmetric hydro-
genation of olefins, and optimized by taking advantage of
their modular structure. Control experiments and computa-
tional studies were carried out to assess whether the role of
the amide group also consists of a substrate-orientating
effect in this case.
Scheme 3. Synthesis of BenzaPhos ligands. Procedure A for N-benzoyl-
AHCTUNGERTGaNNUN tion: a) benzoyl chloride, 4-(trifluoromethyl)benzoyl chloride, or
4-(methoxy)benzoyl chloride (1 equiv), triethylamine (TEA), 08C to RT,
45–92%. Procedure B for N-benzoylation: b) benzoyl chloride (3 equiv),
TEA, THF, RT; c) LiOH·H2O, 4:1 THF/H2O, RT, 39–83% (two steps).
Formation of the BINOL phosphite: d) (S)-BINOL-PCl, TEA, THF, RT,
41–80%.
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The Development of BenzaPhos Ligands
FULL PAPER
strong hydrogen bonds and, remarkably, they lack the very
amide group that—according to our studies[9b]—is involved
in substrate orientation in the case of the PhthalaPhos lig-
pattern was performed with the aim of optimizing the re-
sults (the second-generation library). We decided not to vary
the BINOL substitution because our previous data showed
that the presence of substituents at the 3,3’ position is detri-
mental to the catalytic activity in the hydrogenation pro-
cess.[9]
ACHTUNGTRENNUNG
combinatorial search for new catalysts, a library of (S)-
BINOL-derived phosphite ligands was prepared, containing
an unsubstituted benzamide group (R’=H, see Scheme 1B)
and differing only in the linker (the first-generation library).
Once a few hits were identified in the asymmetric Rh-cata-
lyzed hydrogenation, variation of the benzamide substitution
Preparation of the BenzaPhos ligand library: The ligands
(1a–s, Scheme 3) were prepared in two steps from simple
aminoalcohols, which were N-benzoylated (39–83% yield)
and then reacted with (S)-BINOL-derived chlorophos-
Figure 1. The first-generation BenzaPhos ligand library.
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L. Pignataro, U. Piarulli, C. Gennari et al.
phite[10] (41–80% yield). Some
of the aminoalcohols are com-
mercially available, whereas the
others were easily prepared ac-
cording to known methods.[9b]
The aminoalcohols were N-
benzoylated by using two differ-
ent procedures, depending on
the
strength of the amino and
hydroxy functionalities
relative
nucleophilic
(Scheme 3). Substrates possess-
ing an aliphatic OH group were
selectively N-benzoylated (with
one exception) in the presence
of benzoyl chloride [or 4-(tri-
fluoromethyl)benzoyl chloride
or 4-(methoxy)benzoyl chlo-
ride; 1 equiv] to yield alcohols
2 (procedure A). Amino alco-
hols possessing a phenolic OH
group could not be selectively
N-benzoylated and yielded mix-
Figure 3. Diagram representing the full set of results from the BenzaPhos ligand screening with substrates
S1–S6.
tures of N-benzoylated, O-benzoylated, and bis(benzoyl-
ated) products. Consequently, these aminoalcohols were
bis(benzoylated) in the presence of benzoyl chloride
(3 equiv), and the ester group in the resulting crude ami-
doesters was selectively saponified to yield the correspond-
ing alcohols (procedure B).
obtained with each substrate are shown in Tables 1–6. The
full set of results is graphically represented in Figure 3, and
tabulated in the Supporting Information.
ACHTUNGTRENNUNG
The library screening in the hydrogenation of methyl 2-
acetamidoacrylate S1 (Table 1 and Figure 3) gave encourag-
ing results, with six ligands affording >94% ee, three of
which afforded >97% ee. The importance of a properly
positioned benzamide group is revealed by the following ob-
servations: 1) the length and geometry of the linker group
of ligands 1 proved crucial for obtaining a high level of
stereocontrol (see the Supporting Information for the com-
Catalytic screening of the first-generation library: The first-
generation ligand library, shown in Figure 1 (1a–m), was
screened in the rhodium-catalyzed enantioselective
hydrogenACHTUNGTRENNUNGation of six prochiral olefins: three classical bench-
mark substrates, that is, methyl 2-acetamidoacrylate (S1),
methyl (Z)-2-acetamidocinnamate (S2), and N-(1-
phenylvinyl)acetACHTUNGTRENNUNGamide (S3), and three challenging, industri-
Table 1. Selected results of the screening of the first-generation Benza-
Phos library in the enantioselective hydrogenation of methyl 2-acetami-
doacrylate S1.[a]
ally relevant[11] substrates, that is, cyclic enamide S4 [N-(3,4-
dihydronaphthalen-1-yl)acetamide], b2-dehydro aminoester
S5 [(E)-methyl 2-(acetamidomethyl)-3-phenylacrylate], and
the Roche ester precursor S6 [methyl 2-(hydroxymethyl)-
ACHTUNGTRENNUNG
acrylate]. Phenyl phosphite 3a[12] and benzyl phosphite 3b[13]
Conv. [%][b]
ee [%],[b]
(Figure 2)—two simple monodentate BINOL-phosphites
Ligand
abs. conf.[c]
1
2
3
4
5
6
7
8
1b
1c
1e
1i
100
100
100
100
100
100
100
100
99, R
99, R
98, R
97, R
97, R
96, R
84, R
90, R
1j
1k
3a
3b
Figure 2. Monodentate phosphites employed as reference compounds in
the catalytic screening.
[a] Reaction conditions: substrate/ligand/[RhACHTUNTGRNEUNG(cod)2BF4]=100:2.2:1, sol-
vent=CH2Cl2, c0 (S1)=0.048m, T=258C. [b] Determined by GC with
a chiral capillary column (MEGADEX DACTBSb, diacetyl-tert-butylsil-
yl-b-cyclodextrin; Conv.=conversion). [c] Assignment based on the GC
retention times, by comparison with the results obtained with 3a, the
stereochemical preference of which is known (abs. conf.=absolute con-
figuration).[12]
that are structurally related to the BenzaPhos ligands, but
devoid of functional groups capable of supramolecular inter-
actions—were also screened with the same substrates to pro-
vide a reference for evaluating the effect of the benzamide
group on the catalytic behavior of ligands 1. The best results
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The Development of BenzaPhos Ligands
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plete set of data), and 2) reference ligands 3a and 3b gave
lower ee values (84 and 90% ee, respectively).
The effect of the linker is also evident in the hydrogen-
AHCTUNGTRENNUNG
Very good results were also obtained in the screening of
benchmark substrates S2 and S3. With the former alkene
(best results shown in Table 2), six ligands gave >94% ee,
one of which ligand gave >99% ee,[14] whereas the reference
phosphites 3a and 3b afforded only 70 and 83% ee, respec-
tively. With enamide S3 (best results shown in Table 3),
eight ligands gave >94% ee, three of which gave >97% ee,
whereas the reference ligands 3a and 3b gave 90 and
94% ee, respectively. Therefore, also in this case the pres-
ence of the benzamide group enhances the stereocontrol,
provided that the linker is suitable.
AHCTUNGTREGaNNNU nds gave very good stereocontrol in the hydrogenation of
substrate S4 (under 20 bar hydrogen pressure), equaling in
two cases (Table 4, entries 2 and 3) the best ee value
(98% ee) reported in the literature for employing a mono-
dentate (at ꢀ208C)[16] or bidentate ligand (at RT).[17] Also in
this case, the reference ligands 3a and 3b proved less enan-
tioselective than the best members of our library, although
a respectable 96% ee was obtained with 3b.
The screening of the ligand library with olefin S5
(Table 5)[18] required a hydrogen pressure of 50 bar, due to
the poor reactivity of this substrate. Both ee and conversion
values ranged widely, but appeared to be correlated, the
Table 2. Selected results of the screening of the first-generation Benza-
Phos library in the enantioselective hydrogenation of methyl (Z)-2-acet-
amidocinnamate S2.[a]
Table 4. Selected results of the screening of the first-generation Benza-
Phos library in the enantioselective hydrogenation of N-(3,4-dihydro-
naphthalen-1-yl)acetamide S4.[a]
Ligand
Conv. [%][b]
ee [%],[b]
abs. conf.[c]
1
2
3
4
5
6
7
8
1b
1c
1e
1h
1i
1k
3a
3b
100
100
100
100
100
100
100
100
97, R
96, R
97, R
95, R
>99, R
96, R
70, R
83, R
Ligand
Conv. [%][b]
ee [%],[b]
abs. conf.[c]
1
2
3
4
5
6
7
8
1b
1c
1e
1 f
1g
1h
3a
3b
100
100
100
95
93
100
30
97, R
98, R
98, R
92, R
94, R
96, R
53, R
96, R
[a] Reaction conditions: substrate/ligand/[RhACHTUNTGRNEUNG(cod)2BF4]=100:2.2:1, sol-
vent=CH2Cl2, c0 (S2)=0.048m, P=1 bar, T=258C. [b] Conversion deter-
mined by H NMR spectroscopy on the crude reaction mixture; ee deter-
mined by HPLC with a chiral column (Daicel Chiralpak AD-H). [c] As-
signed by comparison of the sign of the optical rotation with literature
data.[14]
1
100
[a] Reaction conditions: substrate/ligand/[RhACHTUNTGRNEUNG(cod)2BF4]=100:2.2:1, sol-
vent=CH2Cl2, c0 (S4)=0.024m, P=20 bar, T=258C. [b] Determined by
GC with a chiral capillary column (MEGADEX DACTBSb, diacetyl-tert-
butylsilyl-b-cyclodextrin). [c] Assigned by comparison of the sign of the
optical rotation with literature data.[15]
Table 3. Selected results of the screening of the first-generation Benza-
Phos library in the enantioselective hydrogenation of N-(1-phenylvinyl)-
ACHTUNGTRENNUNG
acetamide S3.[a]
Table 5. Selected results of the screening of the first-generation Benza-
Phos library in the enantioselective hydrogenation of (E)-methyl 2-(acet-
amidomethyl)-3-phenylacrylate S5.[a]
Ligand
Conv. [%][b]
ee [%],[b]
abs. conf.[c]
1
2
3
4
5
6
7
8
9
1b
1c
1e
1 f
1g
1i
100
100
100
100
100
100
100
100
100
100
99, R
>99, R
97, R
95, R
99, R
97, R
97, R
96, R
90, R
94, R
Ligand
Conv. [%][b]
ee [%],[b]
abs. conf.[c]
1
2
3
4
5
6
7
1b
1c
1e
1g
1h
3a
3b
35
62
30
94
43
6
93, R
>99, R
86, R
>99, R
>99, R
32, R
1j
1k
3a
3b
10
37
90, R
[a] Reaction conditions: substrate/ligand/[RhACHTUNTGRNEUNG(cod)2BF4]=100:2.2:1, sol-
vent=CH2Cl2, c0 (S3)=0.024m, P=5 bar, T=258C. [b] Determined by
GC with a chiral capillary column (MEGADEX DACTBSb, diacetyl-tert-
butylsilyl-b-cyclodextrin). [c] Assignment based on the GC retention
times, by comparison with the results obtained with 3a, the stereochemi-
cal preference of which is known.[12,13]
[a] Reaction conditions: substrate/ligand/[RhACHTGUNETRN(NUG cod)2BF4]=100:2.2:1, sol-
vent=CH2Cl2, c0 (S5)=0.024m, P=50 bar, T=258C. [b] Determined by
GC with a chiral capillary column (MEGADEX DACTBSb, diacetyl-tert-
butylsilyl-b-cyclodextrin). [c] Assigned by comparison of the sign of the
optical rotation with literature data.[18]
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L. Pignataro, U. Piarulli, C. Gennari et al.
most stereoselective ligands giving higher conversions. Lig-
ACHTUNGTRENNUNGands 1c, 1g, and 1h (Table 5, entries 2, 4, and 5) gave very
proach. In particular, the nature of the linker appears to
strongly affect the catalytic behavior of the ligands.
4) The ligands featuring rigid linker groups (1a, 1l, and
1m) behave poorly in all cases, showing lower levels of
activity and stereoselectivity.
high ee values (>99%), comparable with the best results
obtained with the PhthalaPhos ligands (i.e., the highest
enantiomeric excess ever reported for substrate S5).[9] Un-
fortunately, the conversion was never complete. Lower ee
values and conversions were again obtained with the refer-
ence ligands 3a and 3b (Table 5, entries 6 and 7), the latter
being more enantioselective than the former.
On the basis of the screening described above, we select-
ed three highly effective ligands (1b, 1c, and 1g) for further
optimization by varying the benzamide group.
Finally, the library was screened in the hydrogenation of
the Roche ester precursor S6 under 50 bar hydrogen pres-
sure. As with the other substrates, conversion and ee values
with S6 ranged widely depending on the ligand used (see
the Supporting Information for the complete set of data). In
several cases (see Table 6), full conversion and good ee
values[19] were obtained, although these never exceeded
87% ee (Table 6, entry 4). The reference ligands 3a and 3b
gave 64 and 85% ee (Table 6, entry 6 and 7), respectively.
Second-generation ligands: Six second-generation ligands
(1n–s, Figure 4) were designed by replacing the benzamide
residue of ligands 1b, 1c, and 1g with a 4-(trifluoromethyl)-
benzamide and a 4-(methoxy)benzamide group. The synthe-
sis of the new ligands was carried out by following the two-
step protocol shown in Scheme 3 (procedure A), replacing
benzoyl chloride with commercially available 4-(trifluoro-
methyl)benzoyl chloride and 4-(methoxy)benzoyl chloride
(yield of the N-benzoylation=60–92%; yield of the phos-
phite synthesis=48–74%).
Table 6. Selected results of the screening of the first-generation Benza-
Phos library in the enantioselective hydrogenation of methyl 2-(hydroxy-
methyl)acrylate S6 (the Roche ester precursor).[a]
Ligand
Conv. [%][b]
ee [%],[b]
abs. conf.[c]
1
2
3
4
5
6
7
1b
1c
1e
1g
1h
3a
3b
100
100
100
100
100
100
100
85, S
84, S
76, S
87, S
86, S
64, S
85, S
[a] Reaction conditions: substrate/ligand/[RhACHTUNTGRNEUNG(cod)2BF4]=100:2.2:1, sol-
vent=CH2Cl2, c0 (S6)=0.024m, P=50 bar, T=258C. [b] Conversion
determined by 1H NMR spectroscopy on the crude reaction mixture; ee
determined on the 4-nitrobenzoic acid ester derivative by HPLC with
a chiral column (Daicel Chiralpak AD-H). [c] Assigned by comparison
of the sign of the optical rotation with literature data.[19]
The full set of results for the catalytic screening with sub-
strates S1–S6 is graphically depicted in Figure 3. From this
synopsis, the following comments can be made:
Figure 4. Second-generation BenzaPhos ligands (featuring a 4-substituted
benzamide group).
1) For all substrates, the use of BenzaPhos ligands leads to
a remarkable improvement, in terms of activity and
stereocontrol, compared with that observed with simple
monodentate phosphites. Although always present, such
an improvement is generally more evident with reference
to 3a than 3b.
The second-generation ligands 1n–s were screened in the
hydrogenation of substrates S1–S6. From the results of the
screening, shown in Table 7, the following comments can be
made:
2) There is a larger number of highly effective ligands for
the hydrogenation of benchmark substrates (S1, S2, and
S3) than for challenging olefins (S4, S5, and S6).
3) The best performing ligands are not the same for all sub-
strates, which underlines the value of the library ap-
1) The presence of a substituted benzamide group led to
a significant improvement in the stereoselectivity (com-
pared to the parent ligands 1b, 1c, and 1g, featuring the
same linker) in the hydrogenation of substrates S2, S4,
and S6. In the first case, both ligand 1p (99% ee) and 1q
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The Development of BenzaPhos Ligands
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Table 7. Second-generation ligand (1n–s) screening in the hydrogenation of substrates S1–S6.[a]
Parent ligand
Ligand used
S1[b,c]
ee [%],
abs. conf.
S2[b,c]
ee [%],
abs. conf.
S3[b,c]
ee [%],
abs. conf.
S4[b]
Conv.
[%]
S5[b]
Conv.
[%]
S6[b,c]
ee [%],
abs. conf.
ee [%],
abs. conf.
ee [%],
abs. conf.
1n
1o
98, R
97, R
89, R
96, R
98, R
99, R
92
57
91, R
84, R
27
57
55, R
76, R
87, S
87, S
1b
1c
1g
1p
1q
97, R
97, R
99, R
98, R
99, R
>99, R
100
100
>99, R
99, R
28
44
90, R
92, R
85, S
88, S
1r
1s
91, R
91, R
82, R
82, R
98, R
97, R
100
83
97, R
96, R
70
100
82, R
>99, R
86, S
86, S
[a] Improvements compared with the parent (first-generation) ligands (i.e., featuring the same linker) are highlighted with boldface characters. [b] For re-
action and ee determination conditions in the hydrogenation of S1, S2, S3, S4, S5, and S6, see the footnotes of Tables 1, 2, 3, 4, 5, and 6, respectively.
[c] Conversion=100% in all cases.
(98% ee) proved more enantioselective than the parent
ligand 1c. In the hydrogenation of S4, ligand 1p afforded
>99% ee, which is the highest ee value ever reported for
this cyclic enamide.[9,16,17] Furthermore, ligands 1q, 1r,
and 1s proved more enantioselective than their first-gen-
eration counterparts (1c and 1g). In the case of S6,
ligand 1q afforded the highest ee value of the entire
BenzaPhos library (88% ee), although still not compara-
ble with the best literature precedents.[11] In the
hydrogenACHTUNGTRENNUNGation of S5, ligand 1s allowed full conversion
with virtually perfect stereocontrol, thus improving on
the result obtained by using its parent ligand 1g. Togeth-
er with that obtained with the PhthalaPhos ligands,[9] this
is the best result ever reported for the hydrogenation of
substrate S5, for which only one highly enantioselective
example had been described previously.[11]
Figure 5. 31P NMR spectrum of a 2:1 mixture of ligand 1p and [Rh-
AHCTUNTGRENGUN(N cod)2BF4] after 1 min at 208C (A) and after 10 min at 358C (B).
2) No improvement was achieved by using second-genera-
tion ligands in the hydrogenation of substrates S1 and
S3, which can be explained considering the already high
level of stereocontrol obtained with the parent ligands
1b, 1c, and 1g.
3) Trifluoromethyl- and methoxy-substituted ligands featur-
ing the same linker gave very similar ee values, which
suggests that the electronic effects of the benzamide
group are rather unimportant for stereoinduction. There-
fore, the effect on the reaction of the para-substituent on
the benzamide ring (compared with the unsubstituted
ring) cannot be easily rationalized.
ature is returned to 208C, the d1 doublet does not reappear.
From this observation, we concluded that doublet d1 corre-
sponds to a kinetic complex that is gradually converted into
the thermodynamically more stable complex responsible for
the d2 signal. Signal d2 was confidently assigned to complex
[RhACHTNUGRTENNUG(1p)2ACHTUNGTREN(NUNG cod)BF4] with cis-phosphite ligands because the
chemical shift and the JP,Rh value are very close to those pre-
viously reported for the precatalytic complexes of the
PhthalaPhos ligands.[9a]
High-resolution MS (ESI) analysis confirmed this assign-
ment, showing a molecular peak at m/z=1457.289 that cor-
responds to the cationic complex [Rh
d1 was tentatively assigned to the complex [RhCAHTUNGTRENNNUG
ACHUTGTNERN(NUG 1p)2ACHTUNGTRENNUNG
(cod)]+. Doublet
(1p)4BF4] for
Spectroscopic studies on a precatalytic complex: A rather
puzzling scenario emerged from the 31P NMR analysis of the
the following reasons: 1) the observed multiplicity is consis-
tent with a complex featuring chemically equivalent phos-
phorus atoms; 2) the singlet signal of excess free ligand 1p
is not present in the 31P NMR spectrum featuring d1 and d2
(Figure 5A), as would be expected if d1 belonged to the
precatalytic complex formed by reaction of [RhACTHNUTRGNE(UNG cod)2BF4]
(cod=1,5-cyclooctadiene) with a representative ligand of
the BenzaPhos library (1p). When this ligand and [Rh-
ACHTUNGTRENNUNG(cod)2BF4], in a 2:1 ratio, are dissolved in CD2Cl2 at 208C,
two doublet signals d1 (d=142.7 ppm, JP, Rh =189.5 ppm) and
d2 (d=122.3 ppm, JP, Rh =258.7 ppm) in a 44:56 ratio are ini-
tially visible (Figure 5A). We found that the intensity of the
d1 signal slowly decreases with time, and its decrement is ac-
celerated when the temperature is increased to 358C. After
10 min at this temperature, d2 is the only visible signal (Fig-
ure 5B) that remains. Remarkably, when the sample temper-
monophosphite complex [RhACTHNGUTERNNU(G 1p)ACHTGNUTREN(NUNG cod)BF4]; and 3) the d1
signal is not present in the 31P NMR spectrum of mixtures
with lower ligand/[Rh] ratio (1:1 and 1:2), for which only
doublet d2 is detected. As additional support for our hy-
pothesis, in the 31P NMR spectrum of a 4:1 mixture of 1p
and [Rh
ACHTNUGTERN(NUNG cod)2BF4] in CD2Cl2 only the d1 signal is present.
MS (ESI) analysis of the latter mixture (in CH2Cl2) showed
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L. Pignataro, U. Piarulli, C. Gennari et al.
a molecular peak with m/z=2595.500, corresponding to the
cationic complex [Rh
(1p)4]+.
AHCTUNGTRENNUNG
Control experiments The superiority discussed above—in
terms of catalytic activity and enantioselectivity—of the
BenzaPhos ligands over the reference BINOL-phosphites
3a and 3b strongly suggests that their amide group affects
the catalytic behavior by virtue of its hydrogen-bonding
properties. The effect of hydrogen-bonding groups on the
catalytic performance of monodentate P ligands has been in-
terpreted previously in terms of the formation of rigid and
stereodefined “supramolecular bidentate ligands” by ligand–
ligand interactions,[6h,11,20] or as a result of substrate orienta-
tion due to ligand–substrate interactions taking place in the
catalytic cycle.[6h,9b,21] Both of these approaches, which have
also been applied simultaneously within the same catalytic
system,[20s,21b] result in an improvement of the activity and/or
regio- and stereoselectivity of the ligands compared with
structurally related, simple monodentate ligands. To further
prove the influence of hydrogen bonding on the catalytic
properties of BenzaPhos ligands, and to gain insight into its
actual role, we carried out a series of control experiments,
which are described in this section.
The secondary amide group in BenzaPhos ligands 1a–
s possesses both a hydrogen-bond donor site (the amide NH
hydrogen atom ) and a hydrogen bond acceptor group (the
amide CO oxygen atom). For this reason, BenzaPhos ligands
are, in principle, able to form both ligand–ligand and
ligand–substrate hydrogen bonds. To ascertain whether the
former or the latter interactions are responsible for the cata-
lytic properties of the ligands, phosphite 1p-Me (Figure 6),
an N-methylated version of ligand 1p, was synthesized as
described in the Supporting Information.
Figure 6. Phosphite 1p-Me, a N-methylated version of ligand 1p.
Table 8. The use of N-methylated ligand 1p-Me in the enantioselective
hydrogenation of N-(3,4-dihydronaphthalen-1-yl)acetamide S4 and
methyl (E)-2-(acetamidomethyl)-3-phenylacrylate S5.[a]
Substrate
Ligand
Conv. [%]
ee [%],
abs. conf.
1
2
3
4
S4
S4
S5
S5
1p
1p-Me
1p
100
100
28
>99, R
>99, R
90, R
1p-Me
46
96, R
[a] For reaction and ee determination conditions for S4, see the footnotes
of Table 4, and for S5, see the footnotes of Table 5.
Me. The experiments were set up in parallel by using a Parr
multireactor, and the conversion values were calculated
from the hydrogen uptake. The typical pseudo-first-order ki-
netic profiles obtained are shown in Figure 7, together with
that of the rhodium complex of reference ligand 3b.[9b]
Unlike the other members of the BenzaPhos library (1a–
s), ligand 1p-Me is devoid of a hydrogen-bond donor group,
and thus is unable to self-assemble into a “supramolecular
bidentate ligand” by means of
interACHTUNGTRENNUNGliACHTUNGTRENNUNGgand hydrogen bonding.
We thus screened ligand 1p-Me
in the hydrogenation of chal-
lenging substrates S4 and S5,
obtaining the results shown in
Table 8. With substrate S4
(Table 8, entries 1 and 2),
ligand 1p-Me gave full conver-
sion and the same outstanding
level of stereocontrol as the
parent ligand 1p. In the hydro-
genation of substrate S5
(Table 8, entries 3 and 4), 1p-
Me gave improved conversion
and ee with respect to the
parent ligand 1p.
We also carried out kinetic
studies on the hydrogenation of
S4, to compare the catalytic ac-
Figure 7. Kinetics of hydrogenation of substrate S4 catalyzed by the rhodium complex of ligand 1p (&), 1p-
^
Me (D) and reference ligand 3b ( ), respectively. Solvent=CH2Cl2; c0 (S4)=0.331m; Phydrogen =60 bar; T=
tivities of ligands 1p and 1p- 258C; catalyst loading=1 mol%; c (cat.)=3.31 mm.
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The Development of BenzaPhos Ligands
FULL PAPER
Table 9. Kinetic parameters of the hydrogenation of N-(3,4-dihydronaph-
thalen-1-yl)acetamide S4 catalyzed by the 1p–, 1p-Me–, and 3b–rhodium
complexes, respectively.[a]
Table 10. Solvent screening in the hydrogenation of substrates S4 and S5
with ligands 1p, 1s, 1p-Me, and 3b.[a]
[b]
[b]
[c]
kapp [minꢀ1
]
t1/2 [min]
k [Lmolꢀ1 minꢀ1
]
TOF [hꢀ1
]
1p
1p-Me
3b
0.051
0.049
0.028
13.7
14.1
24.4
15.3
14.8
8.6
244
235
180
[a] Solvent=CH2Cl2; c0 (S4)=0.331m;
Phydrogen =60 bar; catalyst load-
ing=1 mol%; c (cat.)=3.31 mm. [b] kapp =kꢀc (cat.). [c] Determined at
t=15 min.
Substrate Ligand Solvent
Conv. ee [%],
[%]
abs. conf.
These kinetic profiles and the calculated parameters (first-
order kapp, second-order k, half-life t1/2, and turnover fre-
quency (TOF)) given in Table 9, show that the complexes of
1p and 1p-Me have very similar catalytic activities, which
are significantly higher than that of the complex of refer-
ence ligand 3b (devoid of the amide group).
The results of the control experiments described above
suggest that the amide NH group in ligands 1a–s is not in-
volved in hydrogen-bonding interactions relevant for the
catalytic properties. Hydrogen bonds between ligands coor-
dinated to rhodium—although possibly present for ligands
1a–s in the precatalyst or at some stage of the catalytic
cycle—are not responsible for the outstanding catalytic
properties of BenzaPhos ligands. Hydrogen bonding is
therefore likely to occur between the amide oxygen of the
ligand and a hydrogen-bond donor group of the substrate,
and results in a substrate-orientating effect during the cata-
lytic cycle.
To further prove the influence of hydrogen bonding on
the catalytic properties of BenzaPhos ligands, we decided to
perform the hydrogenation of S4 and S5 in a solvent more
polar than CH2Cl2 because solvent polarity is expected to
disrupt ligand–substrate hydrogen bonds, and thus to erode
both catalytic activity and enantioselectivity. However, it is
known that polar and protic solvents lead to a dramatic
drop in enantioselectivity in the hydrogenations catalyzed
by rhodium complexes of monophosphite ligands,[9b,22] and
thus experiments run in solvents such as AcOEt, THF, or
iPrOH would not provide any useful information on the
role of hydrogen bonding.
For this reason, we decided to perform the experiments in
CF3CH2OH, a protic solvent that we have found not to sig-
nificantly erode the catalytic performance of simple
BINOL-based monophosphites, such as 3a and 3b.[9b] For
each substrate, we screened reference phosphite 3b, the
best-performing ligand of the library (1p for S4 and 1s for
S5), and the N-methylated ligand 1p-Me, obtaining the re-
sults given in Table 10. Although fluorinated alcohols, which
are highly polar solvents but poor hydrogen-bond acceptors,
were reported not to disturb the hydrogen bonds of self-
assembled rhodium–phosphine complexes,[23] we observed
a substantial drop in conversion and ee value when the hy-
drogenations promoted by BenzaPhos–rhodium complexes
were carried out in 7:1 CF3CH2OH/CH2Cl2 (Table 10, en-
tries 4 vs. 3, 6 vs. 5, 10 vs. 9, and 12 vs. 11). On the other
hand, the rhodium complex of reference monophosphite 3b
1
2
3
4
5
6
7
8
9
S4
S4
S4
S4
S4
S4
S5
S5
S5
3b
3b
1p
1p
CH2Cl2
100
96, R
93, R
>99, R
38, R
>99, R
61, R
90, R
93, R
>99, R
89, R
96, R
64, R
CF3CH2OH/CH2Cl2 (7:1) 100
CH2Cl2
CF3CH2OH/CH2Cl2 (7:1)
100
44
100
78
37
45
100
57
46
1p-Me CH2Cl2
1p-Me CF3CH2OH/CH2Cl2 (7:1)
3b
3b
1s
1s
CH2Cl2
CF3CH2OH/CH2Cl2 (7:1)
CH2Cl2
10 S5
11 S5
12 S5
CF3CH2OH/CH2Cl2 (7:1)
1p-Me CH2Cl2
1p-Me CF3CH2OH/CH2Cl2 (7:1)
44
[a] For reaction and ee determination conditions for S4, see the footnotes
of Table 4, and for S5, see the footnotes of Table 5.
maintained essentially the same level of conversion and
stereoselectivity when switching from CH2Cl2 to 7:1
CF3CH2OH/CH2Cl2 (Table 10, entries 2 vs. 1 and 8 vs. 7).
Therefore, this experiment confirms that hydrogen-bonding
interactions play an important role in determining the cata-
lytic behavior of the BenzaPhos ligands.
With the aim of further investigating the role of hydrogen
bonding between the BenzaPhos ligand amide oxygen atom
and the substrate hydrogen-bond donor group during the
catalytic cycle, we performed the hydrogenation of sub-
strates structurally related to S4 and S5, but lacking the
amide NH hydrogen atom: the N-methyl analogues S4-Me
and S5-Me, and the esters S4-O and S5-O (Figure 8).[24] Al-
though the modifications introduced in the substrates proba-
bly affect their stereoelectronic properties well beyond the
simple loss of hydrogen-bond donor ability, we believe that
these experiments may usefully support or contradict our
hypotheses on the ligand–substrate interactions. For each
series of analogues (Table 11 and Table 12, respectively) the
rhodium complexes of 1p-Me and of the BenzaPhos ligand
Figure 8. A) N-methylated substrates S4-Me and S5-Me. B) ester sub-
strates S4-O and S5-O.
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L. Pignataro, U. Piarulli, C. Gennari et al.
Table 11. Hydrogenation of substrate S4 and its analogues (S4-Me and
S4-O) by using ligands 1p and 1p-Me.[a]
Table 12. Hydrogenation of substrate S5 and its analogues (S5-Me and
S5-O) by using ligands 1s and 1p-Me.[a]
Substrate
Ligand
P
Conv.
[%]
ee [%],
abs. conf. or [a]D sign
[bar]
Substrate
Ligand
P
Conv.
[%]
ee [%],
abs. conf. or [a]D sign
1
2
3
4
5
6
7
8
S5[b]
1s
1p-Me
3a
1s
1p-Me
3a
50
50
50
50
50
50
100
46
6
15
28
4
>99, R
96, R
32, R
91, (+)
92, (+)
91, (+)
–
A
S5[b]
1
2
3
4
5
6
S4[b]
1p
1p-Me
1p
1p-Me
1p
1p-Me
20
20
20
20
110
110
100
100
2
13
11
33
>99, R
>99, R
68, (+)
87, (+)
17, R
S5[b]
S4[b]
S5-Me[c]
S5-Me[c]
S5-Me[c]
S5-O[d]
S5-O[d]
S4-Me[c]
S4-Me[c]
S4-O[d]
S4-O[d]
1s
1p-Me
110
110
0
0
49, R
–
[a] Reaction conditions: substrate/ligand/[RhACHTUNTGRNEUNG(cod)2BF4]=100:2.2:1, sol-
vent=CH2Cl2, c0 (substrate)=0.024m, T=258C. [b] Conversion and ee
determined as specified in the footnotes of Table 4. [c] Conversion and ee
[a] Reaction conditions: substrate/ligand/[RhACHTUNTGRNEUNG(cod)2BF4]=100:2.2:1, sol-
vent=CH2Cl2, c0 (substrate)=0.024m, T=258C. [b] Conversion and ee
determined as specified in the footnotes of Table 5. [c] Conversion deter-
mined by H NMR spectroscopy on the crude reaction mixture; ee deter-
mined by HPLC with a chiral column (Phenomenex Lux Cellulose 2).
[d] Conversion determined by 1H NMR spectroscopy on the crude reac-
tion mixture; ee determined by HPLC with a chiral column (Daicel Chi-
determined by GC with
a chiral capillary column (MEGADEX
1
DACTBSb, diacetyl-tert-butylsilyl-b-cyclodextrin); correlation of [a]D
sign with the absolute configuration still not established. [d] Conversion
determined by 1H NMR spectroscopy on the crude reaction mixture; ee
determined by HPLC with a chiral column (Phenomenex Lux Cellulose
3); absolute configuration assigned by comparison of the sign of the opti-
cal rotation with literature data.[25]
AHCTUNGTREGUNrNN alcel OD-H).
drogenation of substrate S5-O did not lead to any product
even under forcing conditions (Table 12, entries 7 and 8).
On the whole, the control experiments demonstrate that
hydrogen-bonding interactions significantly affect the cata-
lytic behavior of BenzaPhos ligands, allowing them to access
higher conversion and ee values than the related BINOL-
monophosphites devoid of amide groups. Moreover, the ex-
perimental results strongly suggest that the hydrogen bond
responsible for the outstanding performances of the ligands
should form—in the hydrogenation catalytic cycle—between
the ligand amide carbonyl oxygen atom and the substrate
hydrogen-bond donor group.
that performs best with the parent olefin (1p for S4 and 1s
for S5) were employed.
As shown in Table 11, the hydrogenation of S4-Me gave
poor conversions and significantly depleted ee values (com-
pared with those obtained with the parent substrate S4),
with both 1p (Table 11, entry 3 vs. 1) and 1p-Me (Table 11,
entry 4 vs. 2) as the chiral ligand. The enol ester S4-O dis-
played very poor reactivity in the presence of ligands 1p
and 1p-Me, and forcing conditions (110 bar hydrogen pres-
sure) were required to achieve meaningful conversions. Low
ee values (absolute configuration of the product assigned by
comparison of the sign of the optical rotation with literature
data[25]) were obtained with both ligand 1p and 1p-Me
(Table 11, entries 5 and 6). Although other stereoelectronic
factors may contribute to the observed outcome, these re-
sults can also be justified by the lack of an amide NH hydro-
gen-bond donor in the substrate, which prevents the interac-
tion with the carbonyl oxygen in the BenzaPhos ligand from
occurring.
In addition, the results obtained for the hydrogenation of
the S5 analogues (Table 12) are consistent with our interpre-
tation of the catalytic behavior of the BenzaPhos ligands:
both ligands 1s and 1p-Me proved remarkably less active
and slightly less enantioselective with substrate S5-Me than
with the parent compound S5 (Table 12, entries 4 vs. 1 and 5
vs. 2). The drop in enantioselectivity is relatively small be-
cause the hydrogenation of S5-Me occurs with rather high
ee independent of the ligand employed: even the reference
phosphite 3a, unable to form hydrogen bonds and perform-
ing poorly with the parent substrate S5 (Table 12, entry 3),
afforded a respectable 91% ee (Table 12, entry 6). The hy-
Computational studies: As a complement to the experimen-
tal evidence derived from the aforementioned experiments,
we set out to develop a computational model of a hydrogen-
AHCTUNGTREGaNNUN tion intermediate for which the ligand–substrate hydrogen
bond could be visualized. Since this hydrogen bond is influ-
ential on the stereocontrol, we decided to focus on an inter-
mediate in the catalytic cycle located as close as possible to
the stereodiscriminating step of the process. According to
most of the literature concerning the mechanism of rhodi-
um-catalyzed asymmetric hydrogenation,[26] stereoselection
takes place during the formation of chelate octahedral dihy-
dride rhodium complexes. In particular, recent studies car-
ried out by Gridnev, Imamoto and co-workers[26h–i] describe
the hydrogenation process as a sequence of reversible steps,
the stereoselectivity of which is determined at the reversible
stage of association of the double bond in the rapidly inter-
converting dihydrides A and A’ to give the chelate dihy-
drides B and B’ (Scheme 4).
Consequently, the stereochemical outcome should depend
on which enantioface of the substrate is coordinated to rho-
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The Development of BenzaPhos Ligands
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Scheme 4. The stereodiscriminating step of the rhodium-catalyzed hydro-
genation according to recent literature contributions.[26h–i]
Figure 9. A) Pro-R chelate dihydride complexes (Si face of the substrate
coordinated to Rh). B) Pro-S chelate dihydride complexes (Re face of
the substrate coordinated to Rh).
dium in the chelate dihydride with the lowest activation
energy of formation (B in Scheme 4). The subsequent mi-
gratory-insertion step, a fast and irreversible step, fixes the
result of the enantioselection, forming the monohydride C,
which is then converted into the product. Although this
mechanistic interpretation was initially developed for hydro-
genations promoted by rhodium complexes of chiral diphos-
phines, a recent study has demonstrated its validity in the
presence of chiral monophosphine–rhodium catalysts.[27] Re-
markably, in the latter, migratory insertion should be includ-
ed among the reversible steps, and only the final reductive
elimination (C!catalyst+reaction product) would be irre-
versible.
On the basis of this mechanistic interpretation, we decid-
ed to build computational models of B-type dihydride inter-
mediates for the hydrogenation of substrate S4 promoted by
the rhodium complex of ligand 1p, with the expectation of
finding structures featuring the ligand–substrate hydrogen
bond suggested by the experimental data. Among the eight
possible dihydride complexes,[26d,h] we considered only those
satisfying the following criteria: 1) a cis disposition of the
phosphite ligands around rhodium, as suggested by the liter-
ature for the catalytic rhodium complexes of monodentate P
ligands,[27,28] and by the aforementioned structure of the pre-
trans to a hydride H atom, as suggested by experimental evi-
dence reported in the literature.[26f,i]
We thus focused our attention on the four dihydrides
shown in Figure 9, two of which (Si-6b and Si-7b) are pre-
cursors of the experimentally determined major enantiomer
of the product (R, >99% ee), whereas the others (Re-6b
and Re-7b) lead to the minor enantiomer. Computational
models of dihydrides Si-6b, Si-7b, Re-6b, and Re-7b were
built by implementing the following workflow:[29] 1) a pre-
liminary DFT optimization (B3LYP/LACVP level of
theory)[30] was carried out on dihydrides Si-6a, Si-7a, Re-6a,
and Re-7a (containing monodentate phosphite 3b as ligand
P*, see Figure 9); 2) the amide group was introduced on the
ligands (P*=1p), and Monte Carlo/energy minimization
conformational searches[31,32] were performed (AMBER*,
CHCl3 GB/SA)[33] keeping the geometries of the preopti-
mized octahedral core (Si-6a, Si-7a, Re-6a, and Re-7a)
frozen and leaving the amide groups free to move; and fi-
nally, 3) the Si-6b, Si-7b, Re-6b, and Re-7b global-minimum
geometries of MC/EM searches were optimized at the DFT
B3LYP/LACVP level of theory.[30]
catalytic complex [RhACTHNURGTENN(UG 1p)2HCATUNGTNER(NUGN cod)BF4]; 2) a cis disposition of
hydride H atoms, as a consequence of oxidative addition to
The structures of the dihydride complexes and their rela-
tive energies, resulting from these computational studies, are
rhodium;[26] and 3) the coordination of the carbonyl oxygen
Figure 10. DFT-optimized structures of dihydrides Si-6b, Si-7b, Re-6b, and Re-7b with relative energies in kcalmolꢀ1 [wires (P ligands) and tubes (sub-
strate S4): grey=C, light grey=amide H atoms, black=heteroatoms (N, O, P); CPK spheres: black=Rh, grey=H. For the sake of clarity, all H atoms
bound to carbon are omitted].
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L. Pignataro, U. Piarulli, C. Gennari et al.
displayed in Figure 10; in two of the structures (Si-7b and
Re-7b), the expected hydrogen bond between the ligandꢁs
amide oxygen and the substrateꢁs NH is present, whereas
the others (Si-6b and Re-6b) do not contain any hydrogen
bonds. The hydrogen-bonded structures Si-7b and Re-7b are
far more stable than the others; dihydrides Si-6b and Re-6b
lie 7.56 and 11.28 kcalmolꢀ1, respectively, above the mini-
mum energy structure Si-7b. Remarkably, the observed
order of stability is in qualitative agreement with the experi-
mental stereochemical preference of the rhodium complex
of ligand 1p, with the most stable dihydride (Si-7b) being
the precursor for the major enantiomer of the product (R,
as shown in Figure 9). Moreover, it must be noted that the
narrow energy gap between the hydrogen-bonded dihy-
drides Si-7b and Re-7b—inconsistent with the very high ex-
perimental ee value (>99%)—cannot be used for a quantita-
tive energy comparison because these intermediates were
not identified as the transition states of the stereodiscrimi-
nating step. However, the results of the computational stud-
ies are in perfect agreement with the experimental informa-
tion we could gather in the preceding section; the hydrogen-
bonding interaction responsible for the outstanding catalytic
properties of this new class of chiral ligands seems to take
place between the BenzaPhos amide oxygen and the sub-
strate hydrogen-bond donor group.
Experimental Section
General procedure for the synthesis of BenzaPhos ligands 1a–s and 1p-
Me: (S)-BINOL-PCl (1.05 equiv) was added to a stirred solution (0.1m)
of the selected alcohol (1 equiv, typical scale 0.2 g) and Et3N (2.5 equiv)
in THF. The mixture was stirred overnight and then filtered through
a pad of Celite (washing with Et2O). The solvent was evaporated under
reduced pressure and the crude product was purified by flash column
chromatography over silica gel. In some cases, 1H NMR analysis of the
collected fraction revealed the presence of some BINOL (derived from
partial degradation of the ligand during the column), which could be re-
moved with an alkaline workup: the collected fraction was dissolved in
AcOEt or Et2O (40 mL) and rapidly washed three times with aqueous
NaOH (1m) and twice with water. The organic phase was dried over an-
hydrous Na2SO4, and the solvent was removed in vacuo to give the de-
sired product (for full details and characterization, see the Supporting In-
formation).
General procedure for asymmetric hydrogenations under atmospheric
pressure: Seven oven-dried glass test tubes with stirring bars were em-
ployed: in each, the ligand (0.0042 mmol, 0.022 equiv) was added, then
the test tubes were placed in a Schlenk flask and subjected to three
vacuum/nitrogen cycles. A solution (2.12 mm) of [RhACTHUNTRGNE(UNG cod)2BF4] (0.9 mL,
0.001909 mmol, 0.01 equiv) in CH2Cl2 was added and the mixtures were
stirred for 10 min under nitrogen. A solution (0.1909m) of the substrate
(1 mL, 0.1909 mmol, 1 equiv) in CH2Cl2 was added, followed by more
CH2Cl2 (2.1 mL). The reaction mixtures were subjected to three vacuum/
hydrogen cycles and then left stirring overnight at room temperature
under 1 bar of hydrogen. Samples were taken and analyzed for conver-
sion and ee determination (see the Supporting Information).
General procedure for asymmetric hydrogenations under pressures
higher than atmospheric: A Parr multireactor was employed, allowing six
reactions in parallel under hydrogen pressure. The selected ligands
(0.0042 mmol, 0.022 equiv) were weighed into special glass vessels. The
vessels were purged with nitrogen and a solution (2.12 mm) of [Rh-
Conclusion
AHCTNUGTERN(GNUN cod)2BF4] (0.9 mL, 0.001909 mmol, 0.01 equiv) in CH2Cl2 was added to
Our results effectively show the method by which the intrin-
sic advantages of supramolecular transition-metal catalysis
(i.e., high selectivity achieved by employing ligands capable
of noncovalent interactions in addition to catalytic metal co-
ordination)[6h] can be accessed with catalysts amenable to
automation for both high-throughput ligand synthesis and
catalytic screening. Indeed, on the one hand the BenzaPhos
ligands are of simple modular nature and very easy to pre-
pare (only two steps from commercially or readily available
staring materials), which allowed rapid optimization of the
ligandsꢁ catalytic properties by simply varying one structural
element (the benzamide group) of the most promising rep-
resentatives of the first-generation library. On the other
hand, the BenzaPhos ligands possess a functional group ca-
pable of a substrate-orientating effect during the catalytic
cycle of rhodium-catalyzed hydrogenation, which allows
access to outstanding levels of stereocontrol [the best ever
reported ee values (>99%) have been obtained for the hy-
drogenation of two industrially relevant substrates, S4 and
S5]. Control experiments and computational studies strongly
suggest that such substrate orientation takes place in the
catalytic cycle by formation of a hydrogen bond between
the ligandsꢁ amide oxygen atom and the substrateꢁs amide
hydrogen atom.
each vessel. After 10 min, a solution (0.1909m) of the substrate (1 mL,
0.1909 mmol, 1 equiv) in CH2Cl2 was added, followed by more CH2Cl2
(6.1 mL), and the vessels were placed in the respective autoclaves and
purged three times with hydrogen at the selected pressure. The reactions
were stirred overnight at RT under the required pressure of hydrogen,
and then analyzed for conversion and ee determination (see the Support-
ing Information).
Acknowledgements
We thank the European Commission [RTN Network (R)Evolutionary
Catalysis MRTN-CT-2006–035866] for financial support. L. Pignataro
thanks Milan University for a postdoctoral fellowship (Assegno di ricer-
ca). M. Civera thanks MIUR (FIRB Futuro in Ricerca RBFR088ITV)
for a postdoctoral fellowship and financial support. C. Bovio thanks
Nerviano Medical Sciences for a postgraduate fellowship.
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Revised: May 22, 2012
Published online: && &&, 0000
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The Development of BenzaPhos Ligands
FULL PAPER
Asymmetric Catalysis
L. Pignataro,* C. Bovio, M. Civera,
U. Piarulli,* C. Gennari* . . . &&&& — &&&&
A Library Approach to the Develop-
ment of BenzaPhos: Highly Efficient
Chiral Supramolecular Ligands for
Asymmetric Hydrogenation
As simple as selective: BenzaPhos
ligands, benzamide-containing chiral
monophosphites of modular structure
and trivial synthesis, have been
screened in the Rh-catalyzed hydroge-
nation of olefins (see scheme), giving
excellent enantioselectivities with
three benchmark and two industrially
relevant substrates. Control experi-
ments and computational studies sug-
gest an important role of ligand–sub-
strate hydrogen bonding in the stereo-
discriminating step of the catalytic
cycle.
Chem. Eur. J. 2012, 00, 0 – 0
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