Rhodium-catalyzed asymmetric hydrogenation of olefins with PhthalaPhos, a new class of chiral supramolecular ligands

Article abstract of DOI:10.1002/chem.201102018

A library of 19 binol-derived chiral monophosphites that contain a phthalic acid diamide group (Phthala- Phos) has been designed and synthesized in four steps. These new ligands were screened in the rhodium-catalyzed enantioselective hydrogenation of prochiral dehydroamino esters and enamides. Several members of the library showed excellent enantioselectivity with methyl 2-acetamido acrylate (6 ligands gave >97% ee), methyl (Z)-2- acetamido cinnamate (6 ligands gave >94% ee), and N-(1-phenylvinyl)acetamide (9 ligands gave >95% ee), whilst only a few representatives afforded high enantioselectivities for challenging and industrially relevant substrates N-(3,4-dihydronaphthalen-1- yl)-acetamide (96% ee in one case) and methyl (E)-2-(acetamidomethyl)-3- phenylacrylate (99% ee in one case). In most cases, the new ligands were more active and more stereoselective than their structurally related monodentate phosphites (which are devoid of functional groups that are capable of hydrogen-bonding interactions). Control experiments and kinetic studies were carried out that allowed us to demonstrate that hydrogen-bonding interactions involving the diamide group of the PhthalaPhos ligands strongly contribute to their outstanding catalytic properties. Computational studies carried out on a rhodium precatalyst and on a conceivable intermediate in the hydrogenation catalytic cycle shed some light on the role played by hydrogen bonding, which is likely to act in a substrate-orientation effect.

Full text of DOI:10.1002/chem.201102018

FULL PAPER
DOI: 10.1002/chem.201102018
Rhodium-Catalyzed Asymmetric Hydrogenation of Olefins with
PhthalaPhos, a New Class of Chiral Supramolecular Ligands
Luca Pignataro,*[a] Michele Boghi,[a] Monica Civera,[a] Stefano Carboni,[b]
Umberto Piarulli,*[b] and Cesare Gennari*[a]
Abstract: A library of 19 binol-derived
forded high enantioselectivities for
challenging and industrially relevant
substrates N-(3,4-dihydronaphthalen-1-
yl)-acetamide (96% ee in one case)
and methyl (E)-2-(acetamidomethyl)-3-
phenylacrylate (99% ee in one case).
In most cases, the new ligands were
more active and more stereoselective
than their structurally related mono-
dentate phosphites (which are devoid
of functional groups that are capable of
hydrogen-bonding interactions). Con-
chiral monophosphites that contain a
phthalic acid diamide group (Phthala-
Phos) has been designed and synthe-
sized in four steps. These new ligands
were screened in the rhodium-cata-
lyzed enantioselective hydrogenation
of prochiral dehydroamino esters and
enamides. Several members of the li-
brary showed excellent enantioselectiv-
ity with methyl 2-acetamido acrylate (6
ligands gave >97% ee), methyl (Z)-2-
acetamido cinnamate (6 ligands gave
>94% ee), and N-(1-phenylvinyl)ace-
tamide (9 ligands gave >95% ee),
whilst only a few representatives af-
trol experiments and kinetic studies
were carried out that allowed us to
demonstrate that hydrogen-bonding in-
teractions involving the diamide group
of the PhthalaPhos ligands strongly
contribute to their outstanding catalytic
properties. Computational studies car-
ried out on a rhodium precatalyst and
on a conceivable intermediate in the
hydrogenation catalytic cycle shed
some light on the role played by hydro-
gen bonding, which is likely to act in a
substrate-orientation effect.
Keywords: asymmetric catalysis
·
hydrogenation · olefins · rhodium ·
supramolecular chemistry
Introduction
of asymmetric hydrogenation,[4] for some thirty years since
the pioneering work of Knowles and Kagan chiral bis-phos-
phorus ligands have played a major role in this reaction.[5]
However, around the year 2000, the dominance of bidentate
ligands started being questioned following the work report-
ed by Guillen and Fiaud,[6] and by the groups of Pringle,[7]
Reetz,[8] de Vries, and Feringa.[9] They found that rhodium
complexes of simple, easy-to-make chiral monodentate li-
gands (the most important being phosphonites, phosphites,
and phosphoramidites)[10] catalyzed the hydrogenation of
prochiral olefins with comparable or higher enantioselectivi-
ties than those obtained with the related bidentate systems.
These findings boosted the interest of many research groups
in chiral monodentate ligands, whose easy preparation
makes them particularly attractive for industrial applica-
tions. In 2003, Reetz and co-workers[11] and Feringa and co-
workers[12] independently reported that binary mixtures of
monodentate P ligands can lead to higher conversions and
enantioselectivities in rhodium-catalyzed olefin hydrogena-
tions than those obtained with the individual ligands alone.
This improvement occurs when the heterocomplex [RhLaLb]
is more active and stereoselective than the two homocom-
plexes [RhLaLa] and [RhLbLb]. This methodology, later ex-
tended to other reactions,[13] is of great industrial interest be-
cause it allows for the rapid combinatorial screening of a
number of catalytic systems with a much-larger scope than
just the number of ligands employed. However, in principle,
the simultaneous presence of three complexes ([RhLaLb],
The rhodium-catalyzed asymmetric hydrogenation of prochi-
ral olefins is one of the most-intensely studied stereoselec-
tive reactions, and has been the object of uninterrupted in-
terest from chemists over the last forty years.[1] Unlike many
other enantioselective catalytic processes,[2] this reaction has
become a well-established methodology for the industrial
preparation of chiral building blocks,[3] thanks to its high ef-
ficiency and simple experimental setup. Although chiral
monophosphines were used as ligands in the first examples
[a] Dr. L. Pignataro, M. Boghi, Dr. M. Civera, Prof. Dr. C. Gennari
Universitꢀ degli Studi di Milano
Dipartimento di Chimica Organica e Industriale
Centro Interdipartimentale CISI
Istituto di Scienze e Tecnologie Molecolari
ACHTUNGTRENNUNG(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] Dr. S. Carboni, Prof. Dr. U. Piarulli
Universitꢀ degli Studi dell’Insubria
Dipartimento di Scienze Chimiche e Ambientali
Via Valleggio, 11, 22100, Como (Italy)
Fax : (+39)031-2386449
E-mail: umberto.piarulli@uninsubria.it
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102018.
Chem. Eur. J. 2012, 18, 1383 – 1400
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1383

[RhLaLa], and [RhLbLb]) in the reaction environment lowers
the overall enantioselectivity of the process, unless the activ-
ity of the most stereoselective complex is considerably
higher than that of the other two. This limitation stimulated
several research groups to develop methods for achieving
the exclusive formation of the heterocomplexes, [RhLaLb].
Non-covalent interactions between ligands soon appeared as
the best strategy[14] for achieving this result, and supramolec-
ular phosphorus ligands became the object of increasing in-
terest[15] that soon went beyond the selective formation of
heterocomplexes. Thus, several research groups began devel-
oping monodentate P ligands that possessed a secondary
functional group (besides the metal-coordinating phospho-
rus atom) that was capable of non-covalent interactions (hy-
drogen bonding,[16,17] coordinative bonding,[18] and others[19]).
Such non-covalent interactions can play two major roles:
1) Holding two ligands together that are coordinated to the
same metal center to afford a “supramolecular bidentate
ligand”.[16,18,19] Whether these supramolecular ligands are
made up of different or identical ligands, ligand–ligand inter-
actions create highly organized environments that have a
different conformational space from that of the monoden-
tate ligand complexes. 2) Binding the reaction substrate,[17,20]
in order to position it correctly relative to the catalytic
metal center; this orientation is analogous to what is ob-
served in natural metalloenzymes. These approaches, which
have also been applied together within the same catalytic
system,[17g] both result in an improvement in the activity
and/or regio- and stereoselectivity of the ligands compared
to their structurally simplified monodentate ligands. In
recent years, our research group has provided several contri-
butions both to the use of combinations of monodentate li-
gands (applied to asymmetric hydrogenation[14,21a] and other
reactions[21b–d]) and to the development of supramolecular li-
gands for asymmetric hydrogenation.[19c,d] As part of our
continued interest in the field of supramolecular catalysis,
herein, we report a full account on the development of a
new class of chiral supramolecular phosphite ligands (Phtha-
laPhos),[22] and their application to the rhodium-catalyzed
enantioselective hydrogenation of prochiral dehydroamino
esters and enamides. We also consider the effects of hydro-
gen-bonding interactions on the
pable of this kind of interaction (e.g. amides, ureas, guani-
dines) are usually easy to make, stable, and—most impor-
tantly—form hydrogen bonds spontaneously and reversibly
in solution. As a consequence, preliminary steps in the prep-
aration of supramolecular bidentate ligands are not re-
quired, and such bidentate ligands are formed by simply
combining the metal source with properly functionalized
monodentate ligands in the reaction environment. There-
fore, we set out to design a new class of chiral-binol-derived
monophosphites that are capable of forming corresponding
supramolecular ligands from hydrogen-bonding interactions
between amide groups. We reasoned that primary bis-
amides of phthalic acid were particularly well-suited to this
purpose, thanks to the following properties: 1) they can be
easily prepared by a modular approach starting from cheap
phthalic anhydride, where different amines can be employed
to form the two amide groups; and 2) they can act as both a
donor and as an acceptor for the formation of multiple hy-
drogen bonds. In particular, we expected that two hydrogen
bonds could form between two phthalamide-functionalized
phosphites coordinated to a metal to create a rigid and ster-
eodefined environment around it (see Scheme 1B). Based
on these interesting features, we decided to prepare a library
of binol monophosphites, called “PhthalaPhos”, which
would feature the following sites of diversity (Scheme 1A):
1) the linker between the phosphite and the phthalamide
moiety, 2) the substitution on the binaphtholic portion of
the phosphite group, and 3) the ancillary amide group,
namely the amide group that is not connected to the phos-
phite group.
Preparation of the PhthalaPhos ligand library: The ligands
(shown in Scheme 2) were prepared following an easy and
reliable four-step synthesis (Scheme 3) involving only one or
two chromatographic purification steps: phthalic anhydride
was allowed to react with a primary amine to give the
phthalic acid mono amides 1a and 1b in 94–98% yield.[23]
Dehydration of amides 1a and 1b in the presence of tri-
fluoroacetic anhydride gave phthalisoimides 2a and 2b
(97% and 99% yield, respectively), whose reaction with var-
ious amino alcohols led to phthalic acid diamides 3a–3l and
catalytic properties of the ligands
using spectroscopic and computa-
tional studies and reaction kinet-
ics.
Results and Discussion
Ligand design: Supramolecular bi-
dentate ligands that rely on hy-
drogen-bonding interactions are
arguably the most practical and
amenable ligands for combinatori-
al screening in catalysis.[16] Indeed,
Scheme 1. A) PhthalaPhos ligands: general structure and possible diversification points; B) formation of supra-
the functional groups that are ca- molecular bidentate ligands in the presence of a rhodium source.
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Chem. Eur. J. 2012, 18, 1383 – 1400

Rhodium-Catalyzed Asymmetric Hydrogenation of Olefins
FULL PAPER
Scheme 2. The PhthalaPhos ligand library.
ligands 4a–s (47–78% yield). Diamide-phenol 3m (a precur-
sor of phosphite 4m) could not be prepared via the corre-
sponding n-butyl-substituted phthalisoimide (unstable).
However, it was readily obtained from compound 1c and 3-
aminophenol in the presence of N-(3-dimethylaminoprop-
yl)-N’-ethylcarbodiimide hydrochloride (EDC) and 1-hy-
droxybenzotriazole (HOBT; Scheme 4).
Scheme 4. Synthesis of the diamide-phenol 3m: a) Phthalic anhydride,
CHCl3, reflux, 85%; b) EDC, HOBT, 3-aminophenol, CH2Cl2, 08C to
RT, 71 %.
Scheme 3. General synthesis of PhthalaPhos ligands: a) Phthalic anhy-
dride, CHCl3, reflux, 94–98% yield; b) (CF3CO)2O, Et3N, 1,4-dioxane, or
THF, 08C to RT, 97–99% yield; c) amino alcohol, THF, RT, 58–94%
À
À
yield; d) (S)-binol PCl or (R)-3,3’-dimethyl-binol PCl, Et3N, THF, RT,
47–78%.
Catalytic screening of the library: We set out to investigate
the catalytic properties of our new ligands in the rhodium-
catalyzed enantioselective hydrogenation of several dehy-
droamino esters and enamides. In order to evaluate the
effect of the diamide group on catalytic behavior, two
simple monodentate binol-phosphites (structurally related to
our ligands, but devoid of functional groups capable of
supramolecular interactions) were used as standards in the
3n–3s (58–94% yield), respectively.[24] Some of the amino
alcohols employed are commercially available, whilst the
others were easily prepared as described in the Supporting
Information. The diamide monoalcohols 3a–3s were reacted
with binol-derived chlorophosphites[25] to give PhthalaPhos
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L. Pignataro, U. Piarulli, C. Gennari et al.
catalyst screen: phenyl phosphite 5a[26] and benzyl phosphite
5b[27] (Scheme 5). First, we assessed the catalytic properties
of the new ligands in the hydrogenation of three classical
Table 1. Selected results of the screening of the PhthalaPhos library in
the enantioselective hydrogenation of methyl 2-acetamidoacrylate (S1).[a]
Entry
Ligand
Conv. [%][b]
ee [%][b,c]
1
2
3
4
5
6
7
8
9
4a
4b
4e
4 f
4i
4p
4q
5a
5b
100
100
100
100
100
100
100
100
100
94 (R)
98 (R)
>99 (R)
98 (R)
98 (R)
98 (R)
>99 (R)
84 (R)
90 (R)
Scheme 5. Monodentate phosphites employed as standards in the catalyt-
ic screening.
benchmark substrates: methyl 2-acetamidoacrylate (S1),
methyl (Z)-2-acetamidocinnamate (S2), and N-(1-phenylvi-
nyl)acetamide (S3). Subsequently, the library was also
screened in the hydrogenation of two more-challenging sub-
strates: cyclic enamide S4 [N-(3,4-dihydronaphthalen-1-yl)a-
cetamide] and b2-dehydro aminoester S5 [(E)-methyl 2-
(acetamidomethyl)-3-phenylacrylate], which are both indus-
trially relevant compounds.[17 g] The best results obtained
with each substrate are shown in Tables 1–5, respectively.
The full set of results is represented graphically in Figure 1,
and tabulated in the Supporting Information. In the hydro-
genation of methyl 2-acetamidoacrylate (S1; Table 1,
Figure 1) excellent results were obtained, with 11 ligands
giving >93% ee and six ligands giving >97% ee. Remarka-
bly, monodentate phosphites 5a and 5b gave only 84% and
90% ee, respectively, for this substrate, thus demonstrating
the important role played by the diamide group in determin-
[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 analysis
with a chiral capillary column (MEGADEX DACTBSb, diacetyl-tert-bu-
tylsilyl-b-cyclodextrin). [c] Assignment based on comparison of GC re-
tention times with 5a, whose stereochemical preference is known.[26]
ing the catalytic behavior of the PhthalaPhos ligands. The
same conclusion can be drawn from the results of the screen
of ligands with substrate S2 (Table 2, Figure 1), in which six
ligands gave >94% ee and three ligands gave >97% ee,[28]
whilst the reference ligands afforded only moderate enantio-
selectivities (5a gave 70% ee and 5b 83% ee). Very good
results were also obtained in the screen of ligands with N-
(1-phenylvinyl)acetamide (S3; best results shown in
Table 3): nine ligands gave >95% ee, four ligands gave
Figure 1. Diagram representing the full set of results from the PhthalaPhos ligand screening with substrates S1–S5.
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Rhodium-Catalyzed Asymmetric Hydrogenation of Olefins
FULL PAPER
Table 2. Selected results of the screening of the PhthalaPhos library in
the enantioselective hydrogenation of methyl (Z)-2-acetamidocinnamate
(S2).[a]
Table 4. Selected results of the screening of the PhthalaPhos library in
the enantioselective hydrogenation of N-(3,4-dihydronaphthalen-1-yl)ace-
tamide (S4).[a]
Entry
Ligand
P [bar]
Conv. [%][b]
ee [%][b,c]
Entry
Ligand
Conv. [%][b]
ee [%][b,c]
1
2
3
4
5
6
7
8
9
4b
4e
4e
4 f
4i
4p
4p
5a
5a
5b
1
1
12
1
1
1
12
1
12
1
100
86
100
100
100
91
100
25
100
100
98 (R)
98 (R)
97 (R)
99 (R)
97 (R)
97 (R)
96 (R)
73 (R)
70 (R)
83 (R)
1
2
3
4
5
6
4a
4b
4d
4 f
5a
5b
100
90
98
46
30
96 (R)
93 (R)
92 (R)
86 (R)
53 (R)
96 (R)
100
[a] Reaction conditions: substrate/ligand/[RhACHTUNTGRNEUNG(cod)2BF4]=100:2.2:1, sol-
vent=CH2Cl2, c0 (S4)=0.024m, T=258C. P=12 bar. [b] Determined by
GC analysis with a chiral capillary column (MEGADEX DACTBSb, di-
acetyl-tert-butylsilyl-b-cyclodextrin). [c] Assigned by comparison of the
sign of optical rotation with literature data.[29]
10
[a] Reaction conditions: substrate/ligand/[Rh
vent=CH2Cl2, c0 (S2)=0.048m (when P=1 bar) or 0.024m (when P=
ACHTUGNRTEN(NUGN cod)2BF4]=100:2.2:1, sol-
12 bar), T=258C. [b] Determined by HPLC equipped with
a chiral
À
column (Daicel Chiralpak AD H). [c] Assigned by comparison of the
sign of optical rotation with literature data.[28]
ee at RT, 98% ee at À208C)[30] and a diphosphine ligand
(98% ee at RT).[31] As expected, reference phosphite 5a was
less active and less stereoselective than ligand 4a. On the
contrary, despite being unable to form any supramolecular
interactions, benzyl phosphite 5b showed exactly the same
level of stereocontrol as ligand 4a (Table 4, entry 6 vs.
entry 1). However, kinetic studies showed that the catalytic
rhodium complex of 4a afforded a faster rate of reaction
than that of 5b (Figure 2). The experiments were set up in
parallel using a Parr multireactor, and the conversion values
were calculated from the hydrogen uptake. The reactions
showed a typical pseudo-first-order kinetic profile, which al-
lowed us to calculate first order kapp values (including cata-
lyst concentration), half-life times t1/2, and second-order k
values (Figure 2; Table 5). As anticipated, the kinetic con-
stant (k) of the rhodium complex of ligand 4a was almost
double that of the rhodium complex of 5b, and the TOF
values followed a similar trend. Thus, although ligands 4a
and 5b showed the same levels of stereoselectivity, it is
likely that hydrogen-bonding interactions stabilize the tran-
Table 3. Selected results from a screen of the PhthalaPhos library in the
enantioselective hydrogenation of N-(1-phenylvinyl)acetamide (S3).[a]
Entry
Ligand
Conv. [%][b]
ee [%][b,c]
1
2
3
4
5
6
7
8
4a
4b
4e
4 f
4g
4h
5a
5b
100
100
100
100
100
100
100
100
98 (R)
98 (R)
97 (R)
98 (R)
99 (R)
97 (R)
90 (R)
94 (R)
[a] Reaction conditions: substrate/ligand/[RhACHTUNTGRNEUNG(cod)2BF4]=100:2.2:1, sol-
vent=CH2Cl2, c0 (S3)=0.024m, T=258C, P=5 bar. [b] Determined by
GC analysis with a chiral capillary column (MEGADEX DACTBSb, di-
acetyl-tert-butylsilyl-b-cyclodextrin). [c] Assignment based on GC reten-
tion times, by comparison with the results obtained for 5a and 5b, whose
stereochemical preference is known.[26, 27]
>97% ee. Also in this case, the PhthalaPhos ligands showed
higher enantioselectivity than the reference phosphites, al-
though the improvement was less remarkable than in the
cases discussed above (ligand 5a gave 90% ee, 5b gave
94% ee). In the reactions of the challenging substrates S4
and S5, only a few members of the library showed high
levels of enantioselectivity, unlike the above-described hy-
drogenation reactions of classic benchmark olefins
(Figure 1). The best results from the screen of various li-
gands with substrate S4 under 12 bar hydrogen pressure are
reported in Table 4.[29] Ligand 4a promoted the formation of
product P4 with a stereocontrol that rivaled the best litera-
ture precedents (96% ee; Table 4, entry 1); those precedents
were obtained using a monodentate phosphoramidite (84%
Figure 2. Kinetics of hydrogenation of substrate S4 catalyzed by the rho-
dium complexes of ligand 4a (&) and ligand 5b (^), respectively. Sol-
vent=CH2Cl2; c0 (S4)=0.331m
loading=1 mol%, ccat =3.31 mm.
; Phydrogen =60 bar; T=258C; catalyst
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L. Pignataro, U. Piarulli, C. Gennari et al.
Table 5. Kinetic parameters from the hydrogenation of N-(3,4-dihydro-
naphthalen-1-yl)acetamide (S4) catalyzed by rhodium complexes of li-
gands 4a and 5b.[a]
*
For all substrates, the use of PhthalaPhos ligands led to a
remarkable improvement in activity and stereocontrol
compared to simple monodentate phosphite 5a. This
trend was also observed when reference phosphite 5b
was used as a standard, although in one case this ligand
gave the same ee value as the best PhthalaPhos ligand.
There are a relatively large number of highly effective li-
gands for the hydrogenation of benchmark substrates
(S1–S3), whilst only one or two hits were found for chal-
lenging olefins (S4 and S5).
The best-performing ligands were not the same for all
substrates, which underlines the value of the library ap-
proach in ligand synthesis. Each structural component of
these new modular ligands appears to affect their catalyt-
ic behavior. In particular, a strong influence is exerted by
1) the size and geometry of the linker group and 2) the
nature of the ancillary amide group.
[b]
[b]
[c]
Ligand
kapp [minÀ1
]
t1/2 [min]
k [LmolÀ1 minÀ1
]
TOF [hÀ1
]
4a
5b
0.0508
0.0284
13.6
24.4
15.36
8.59
234
180
[a] Solvent=CH2Cl2; c0 (S4)=0.331m;
Phydrogen =60 bar; catalyst load-
*
*
ing=1 mol%, ccat. =3.31 mm. [b] kapp =k·ccat. [c] Determined at t=15 min.
sition state of the rate-limiting step of the hydrogenation
process in the case of 4a (see below). The hydrogenation of
substrate S5 (best results shown in Table 6) proceeded more
slowly than that of the other substrates; incomplete conver-
Table 6. Selected results of the screening of the PhthalaPhos library in
the enantioselective hydrogenation of methyl (E)-2-(acetamidomethyl)-3-
phenylacrylate (S5).[a]
*
Some ligands behaved poorly in all cases. In particular,
1) the ligands derived from 3,3’-dimethyl-binol (4r and
4s) showed minimal catalytic activity and almost no ste-
reoselectivity; 2) the ligands containing rigid linker
groups (4j–4n) showed lower levels of activity and ste-
reoselectivity than the others.
Entry
Ligand
Conv. [%][b]
ee [%][b] ([a]D sign)[c]
1
2
3
4
5
6
7
4a
4b
4c
4g
4i
96
98
75
73
100
6
64 (+)
62 (+)
91 (+)
74 (+)
99 (+)
32 (+)
90 (+)
The PhthalaPhos ligand library was also screened in the
rhodium-catalyzed hydrogenation of other challenging ole-
fins (Table 7; also see the Supporting Information). Howev-
er, these results were not as good as those presented above.
Low conversions and ee values (up to 36%) were obtained
with N-(3,4-dihydronaphthalen-2-yl)acetamide (S6), whilst
(Z)-methyl 3-acetamido-2-phenylacrylate (S7) gave no con-
version even under forcing conditions (100 bar hydrogen
pressure). b-Amino acid precursor S8, [(Z)-methyl 3-acet-
amidobut-2-enoate], gave promising ee values (up to 83%),
5a
5b
37
[a] Reaction conditions: substrate/ligand/[RhACHTUNTGRNEUNG(cod)2BF4]=100:2.2:1, sol-
vent=CH2Cl2, c0 (S5)=0.024m, T=258C, P=50 bar. [b] Determined by
GC analysis with a chiral capillary column (MEGADEX DACTBSb, di-
acetyl-tert-butylsilyl-b-cyclodextrin). [c] Correlation of the [a]D sign with
absolute configuration has still not been established.
sion was observed in most cases, even under very high hy-
drogen pressures (50 bar). However, ligand 4i gave full con-
version and almost complete stereocontrol (Table 6,
entry 5), which is the highest ee value reported so far for
this substrate (for which only one other highly stereoselec-
tive ligand has been reported[16q]). Interestingly, phosphite
4b, which only differed from ligand 4i in the ancillary
amide group (4-(n-butyl)anilide instead of a 3,5-bis(trifluor-
omethyl)anilide; Scheme 2), was remarkably less stereose-
lective (Table 6, entry 2), which further demonstrates how
strongly the diamide group can influence the reaction. The
rhodium complexes of both of the reference phosphites
were poorly active with substrate S5. As observed with sub-
strate S4, reference ligand 5b gave much-higher stereocon-
trol than 5a (Table 6, entry 7 vs. entry 6). However, the ee
value and conversion remained lower than those obtained
with the best PhthtalaPhos ligand 4i (Table 6, entry 5), once
again confirming the importance of the diamide group. The
full set of results from the catalytic screening of substrates
S1–S5 is represented graphically in Figure 1. From this sum-
mary, the following observations can be drawn:
Table 7. Other hydrogenation substrates screened with PhthalaPhos li-
gands.
Substrate
General results
Best result
Conv. ee Ligand
[%]
[%]
low conversion
and ee values
36
(R)
72
4a
S6
S7
no conversion
83
(R)
poor conversion
16
98
4h
4i
S8
S9
moderate ee
values
70
(S)
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Chem. Eur. J. 2012, 18, 1383 – 1400

Rhodium-Catalyzed Asymmetric Hydrogenation of Olefins
FULL PAPER
but conversion could not be brought up to acceptable
values. The Roche-ester precursor S9, [methyl 2-(hydroxy-
methyl)acrylate], was hydrogenated with good conversions,
but only moderate enantioselectivity (up to 70% ee).
and Aꢀ to give the chelate dihydrides B and Bꢀ, respectively
(Scheme 6). Consequently, the stereochemical outcome
should depend on the face of the substrate that is coordinat-
Computational studies: We carried out a series of spectro-
scopic studies on the precatalyst complex [RhACHTNUTRGENN(UG 4a)2ACHTUNGTNER(NUGN cod)BF4]
(described in detail in our preliminary communication[22]).
From these studies, the NHA protons were found to form in-
tramolecular hydrogen bonds, which is not the case for the
free-ligand 4a. A computational study, carried out on the
basis of these spectroscopic studies, allowed us to draw a
picture of complex [Rh
confirmed the formation of a supramolecular bidentate
ligand through two interli
gand hydrogen bonds.[22] The ri-
ACHTUNGTERNNUG(4a)2ACHTUNGTERN(NUGN cod)BF4] (Figure 3). This study
A
A
gidity and pre-organization of the supramolecular ligand
was considered to be a possible cause of the superior perfor-
mance observed for the PhthalaPhos ligands compared to
simple monodentate phosphites 5a and 5b. However, it
must be recognized that the square-planar complex [Rh-
Scheme 6. The stereodiscriminating step of the rhodium-catalyzed hydro-
genation according to recent literature contributions.[32h,i]
ACHTUNGTRENNUNG(4a)2ACHTUNGTRENNUNG(cod)BF4] is only a precatalyst, from which the actual
catalyst is generated by hydrogenation (and dissociation) of
the cyclooctadiene ligand. Moreover, it is widely accepted[32]
that the hydrogenation catalytic cycle involves octahedral
rhodium complexes, in which the ligand arrangement could
significantly differ from that observed in the square-planar
precatalyst. In particular, according to the most-recent liter-
ature contributions,[32h,i] the stereoselectivity of the process is
likely to be determined during the reversible association of
the double bond in the rapidly interconverting dihydrides A
ed to the rhodium center in the chelate dihydride that has
the lowest activation energy (B, Scheme 6). The subsequent
fast and irreversible migratory-insertion step fixes the result
of the enantioselection forming the monohydride (C) that is
then converted into the product. In order to investigate the
role of hydrogen-bonding interactions in the part of the re-
action coordinate where stereodiscrimination occurs, we de-
cided to build computational models of B-type dihydrides.
Of the possible octahedral dihydrides, we considered those
that satisfied the following requirements: 1) cis disposition
of the phosphite ligands around the rhodium atom, as sug-
gested previously for the catalytic rhodium complexes of
monodentate P ligands,[33] and for the above-discussed struc-
ture of the precatalyst complex [RhACTHNUGTRNNEUG(4a)2ACHTUNGTERN(NGUN cod)BF4]; 2) cis
disposition of the hydrogen atoms, as a consequence of oxi-
dative addition to the rhodium atom;[32] 3) coordination of
the carbonyl oxygen atom trans to a hydride hydrogen atom,
as suggested by experimental evidence reported in the liter-
ature.[32f,i] Therefore, we focused our attention on dihydrides
si-6b and si-7b (Scheme 7), which led to the major enantio-
mer observed experimentally (R, corresponding to coordina-
tion on the si face) from the hydrogenation of substrate S4
promoted by the rhodium complex of ligand 4a (96% ee).[34]
Figure 3. DFT-optimized structure of the precatalyst complex [Rh
ACHTUNGERTN(NUNG 4a)2-
ACHTUNGTRENNUNG
gray, heteroatoms (N, O, P)=black; CPK sphere: Rh=black. For the
sake of clarity, all H atoms bound to carbon are omitted. cod=1,5-cyclo-
octadiene.
Scheme 7. Pro-(R), B-type chelate dihydride complexes (si face of the
substrate coordinated to rhodium) studied by MC/MM and DFT calcula-
tions.
Chem. Eur. J. 2012, 18, 1383 – 1400
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1389

L. Pignataro, U. Piarulli, C. Gennari et al.
The computational workflow used was identical to that
adopted for calculating the structure of complex [Rh(4a)2-
(cod)BF4] (Figure 3):[22] 1) a preliminary DFT optimization
the catalytic cycle, which are closer to the stereodefining
step of the reaction. Because all of the substrates tested pos-
sess a NH hydrogen-bond-donor group, this scenario is fully
consistent with the superior enantioselectivity and activity
of the PhthalaPhos ligands compared to reference phos-
phites 5a and 5b. Unfortunately, this hypothesis cannot be
confirmed directly by spectroscopic methods, because it in-
volves very short-lived intermediates of the catalytic cycle.
Therefore, we decided to seek indirect evidence of ligand–
substrate interactions by carrying out a series of control ex-
periments as described below.
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
(B3LYP/LACVP level of theory)[35] was carried out on dihy-
drides si-6a and si-7a (bearing monodentate phosphite 5b
as ligand P*, see Scheme 7); 2) the diamide groups were in-
troduced onto the ligands (P*=4a without n-butyl group),
and Monte Carlo/energy-minimization conformational
searches[36,37] were performed (AMBER*, CHCl3 GB/
SA),[38] keeping the geometries of the pre-optimized octahe-
dral core (si-6a and si-7a) frozen, and leaving the diamide
groups free to move; 3) the si-6b and si-7b global minimum
geometries of MC/MM searches were optimized at the DFT
B3LYP/LACVP level of theory.[35] Quite unexpectedly, no
structures featuring ligand–ligand hydrogen bonds were
found in the MC/MM conformational search; the octahedral
geometry and the presence of the coordinated substrate
were incompatible with the ligand arrangement found in the
precatalyst complex. Rather, ligand–substrate hydrogen-
bonding interactions were identified; the global minimum
(MC/MM) of si-7b featured a hydrogen bond between the
carbonyl oxygen of the 4a ancillary amide group and the
NH proton of the substrate, whilst the global minimum of
si-6b had a distorted hydrogen bond between the same
groups. In each of the DFT-optimized structures (shown in
Figure 4) a hydrogen bond between the carbonyl oxygen of
the ancillary amide group of 4a
Control experiments: In order to confirm the role of ligand–
substrate hydrogen-bonding interactions suggested by the
computational studies, we decided to carry out a series of
control experiments in the hydrogenation of challenging
substrates S4 and S5, in which single experimental parame-
ters were modified in turn. First, we investigated the catalyt-
ic behavior of ligand 4a-Me, a bis-N-methylated version of
ligand 4a that was readily prepared from the alcohol 3a as
shown in Scheme 8. This ligand, which lacks hydrogen-bond-
donor NH groups, is unable to form a corresponding supra-
molecular bidentate ligand, but still possesses the Lewis-
basic amide oxygen atoms required for substrate coordina-
tion according to the computational models, si-6b and si-7b,
as discussed above. For this reason, a similar level of catalyt-
and the NH of the substrate
was present, and si-7b was
14.8 kcalmolÀ1 more stable than
si-6b.[34] Therefore, these com-
putational studies suggest that
the role of the diamide group
of the PhthalaPhos ligands is in
binding and orientating the sub-
strate relative to the catalytic
metal center, in a “metalloen-
zyme-like” fashion. The behav-
ior of the supramolecular bi-
dentate ligand, observed in the
precatalyst [Rh
did not appear to be retained in
the octahedral intermediates of para-toluenesulfonic acid.
ACHTUNGTRENNUNG(4a)2HCATUNGTRENN(UGN cod)BF4],
Scheme 8. Reaction conditions: a) 3,4-dihydro-2H-pyran, PTSA (cat.), THF, RT, 96%; b) 1) NaH, DMF, 08C;
À
2) MeI, 08C to RT, 99%; c) PTSA (cat.), MeOH, RT, 84%; d) (S)-binol PCl, Et3N, THF, RT, 66%. PTSA=
Figure 4. DFT-optimized structures of dihydrides si-6b and si-7b. Wires (P ligands) and tubes (substrate S4): C=gray, amide H=light gray, heteroatoms
(N, O, P)=black; CPK spheres: Rh=black, gray=H. For the sake of clarity, all H atoms bound to carbon are omitted.
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Chem. Eur. J. 2012, 18, 1383 – 1400

Rhodium-Catalyzed Asymmetric Hydrogenation of Olefins
FULL PAPER
ic performance by ligands 4a and 4a-Me could be taken as
indirect proof of substrate-orientation effects. Conversely,
poorer catalytic behavior (compared to ligand 4a), should
be expected from ligand 4a-Me if ligand–ligand interactions
were the main cause of the outstanding performance of the
PhthalaPhos ligands. Our results (Table 8) seem to substanti-
in hydrogen-bonding interactions with the ligand (such inter-
actions are not possible for ligand 4a-Me). Rather, the NH
group of substrate S5 is likely to interact with a carbonyl
oxygen atom on the ligand; this interaction is consistent
with the scenario depicted for substrate S4 by the computa-
tional studies (see above). We developed computational
models of dihydride intermediates si-6c and si-7c (Figure 5)
that would lead to the experimentally determined major
enantiomer in the hydrogenation of substrate S4 promoted
by the rhodium complex of ligand 4a-Me (R, corresponding
to coordination on the si face); these models were created
following the same computational methods described for si-
6b and si-7b (see above). The DFT-optimized geometries of
dihydride intermediates si-6c and si-7c featured a single hy-
drogen bond between the carbonyl oxygen atom of the an-
cillary amide and the NH group of the substrate, consistent
with the experimental results. Dihydride si-7c was more
stable than si-6c by 6.09 kcalmolÀ1. Hydrogen-bonding inter-
actions between dissolved molecules are expected to
become weaker with increasing solvent polarity, with protic
solvents displaying the strongest disrupting effect. Although
ligand–ligand hydrogen bonds have been detected in even
protic solvents in a few cases,[16i,39] in general a negative
effect of solvent polarity on catalytic performance is inter-
preted as a sign of the important role played by hydrogen-
bonding interactions in supramolecular ligands.[15a,16a,h,l] Un-
fortunately, high enantioselectivities have only been report-
ed for the hydrogenation of prochiral olefins with chiral
monophosphite–rhodium complexes in dichloromethane and
1,2-dichloroethane, whilst more-polar or protic solvents
cause a dramatic drop in enantiomeric excess.[40] According-
ly, we have experimentally confirmed that the PhthalaPhos
ligands as well as the reference phosphites 5a and 5b
(devoid of the binding motif) behave poorly (i.e. with very
low enantioselectivity) in polar or protic solvents (e.g.
EtOAc, THF, iPrOH). However, we found an interesting ex-
ception: in 2,2,2-trifluoroethanol, benzyl phosphite 5b main-
tained its high performance practically unaltered with both
substrates S4 and S5 (Table 9, cf. entries 1, 2, 7, 8). Fluori-
nated alcohols, which are highly polar solvents but poor hy-
drogen-bond acceptors, have been reported to not disturb
the hydrogen bonds of self-assembling rhodium–phosphine
Table 8. Use of bis-N-methylated ligand 4a-Me in the enantioselective
hydrogenation of N-(3,4-dihydronaphthalen-1-yl)acetamide (S4) and
methyl (E)-2-(acetamidomethyl)-3-phenylacrylate (S5).[a]
Entry
Substrate
Ligand
Conv. [%]
ee [%]
(abs. config or [a]D sign)
1
2
3
4
S4
S4
S5
S5
4a
4a-Me
4a
100
100
96
96 (R)
96 (R)
64 (+)
81 (+)
4a-Me
100
[a] For substrate S4, see the footnotes of Table 4; for substrate S5, see
the footnotes of Table 6.
ate the hypothesis that a key role is played by ligand–sub-
strate interactions. Indeed, in the hydrogenation of enamide
S4, ligand 4a-Me gave exactly the same result as ligand 4a
in terms of conversion and stereocontrol (Table 8, entry 2 vs.
entry 1). Kinetic studies were carried out under the same
conditions as for the hydrogenation of S4 promoted by the
rhodium complexes of ligands 4a and 5b (see above). The
rhodium complex of ligand 4a-Me (kapp =0.0259 minÀ1, k=
7.81 LmolÀ1 minÀ1) was slower than the comparable reaction
with the rhodium complex of 4a, and of similar activity
compared to the complex of 5b (see Table 5). Thus, the ter-
tiary amide groups of ligand 4a-Me did not display the same
accelerating effect as the secondary amide groups of 4a,
which is likely to be due to different stereoelectronic fea-
tures. Remarkably, in the hydrogenation of substrate S5,
ligand 4a-Me afforded superior enantioselectivity to ligand
4a (Table 8, entry 4 vs. entry 3). This result suggests that the
two carbonyl oxygen atoms of substrate S5 are not involved
Figure 5. DFT-optimized structures of dihydrides si-6c and si-7c. Wires (P ligands) and tubes (substrate S4): C=gray, amide H=light gray, heteroatoms
(N, O, P)=black; CPK spheres: Rh=black, H=gray. For the sake of clarity, all H atoms bound to carbon are omitted.
Chem. Eur. J. 2012, 18, 1383 – 1400
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1391

L. Pignataro, U. Piarulli, C. Gennari et al.
Table 9. Solvent screen in the hydrogenation of substrates S4 and S5 with ligands 4a,
4i, 4a-Me, and 5b.[a]
and of the best-performing PhthalaPhos ligand with
the parent olefin were investigated. Although the
modifications introduced on the substrates may
have affected their stereoelectronic properties far
beyond the simple loss of hydrogen-bond-donor
ability, we believe that these experiments could be
useful in evaluating our hypotheses on ligand–sub-
strate interactions. The results of the screen of non-
hydrogen-bond-donor analogues of substrate S4 are
shown in Table 10. Remarkably, both ligand 4a and
4a-Me gave significantly lower conversion and ee
values with the N-methylated substrate (S4-Me)
than with substrate S4 (Table 10, entries 3 and 4 vs.
entries 1 and 2). This result is due the lack of an
NH proton in substrate S4-Me, which is then
unable to interact with the ligandꢂs amide oxygen.
Consistently very low conversion (if any) was ob-
served in the hydrogenation of enol ester S4-O,
even under 100 bar hydrogen pressure (Table 10,
entries 5-8). However, this result can also be ex-
plained by the different stereoelectronic properties
of enol esters and enamides. The hypothesized role
Entry Substrate Ligand Solvent
Conv. [%] ee [%] (abs. config
or [a]D sign)
1
2
3
4
5
6
7
8
S4
S4
S4
S4
S4
S4
S5
S5
S5
S5
S5
S5
5b
5b
4a
4a
CH2Cl2
CF3CH2OH/CH2Cl2 (7:1) 100
CH2Cl2 100
CF3CH2OH/CH2Cl2 (7:1) 100
100
4a-Me CF3CH2OH/CH2Cl2 (7:1) 100
100
96 (R)
93 (R)
96 (R)
38 (R)
96 (R)
8 (R)
90 (+)
93 (+)
99 (+)
47 (+)
81 (+)
4 (+)
4a-Me CH2Cl2
5b
5b
4i
CH2Cl2
CF3CH2OH/CH2Cl2 (7:1) 45
CH2Cl2 100
CF3CH2OH/CH2Cl2 (7:1) 95
100
4a-Me CF3CH2OH/CH2Cl2 (7:1) 100
37
9
10
11
12
4i
4a-Me CH2Cl2
[a] For substrate S4, see the footnotes of Table 4; for substrate S5, see the footnotes of
Table 6.
complexes.[39] In the case of the phthalamide-functionalized
phosphites 4a, 4i, and 4a-Me, 2,2,2-trifluoroethanol caused
a substantial drop in enantiomeric excess (Table 9, cf. en-
tries 3–6, 9–12), presumably by disrupting either the ligand–
ligand or ligand–substrate hydrogen bonds. In particular, the
observation of a strong solvent effect in the case of ligand
4a-Me (Table 9, cf. entries 5, 6, and 11, 12) lends support to
the computational studies regarding the crucial role of
ligand–substrate hydrogen-bonding interactions. In order to
substantiate our interpretation of the observed catalytic be-
havior, we decided to carry out experiments on analogues of
substrates S4 and S5 that contained no hydrogen-bond-
donor atoms. The N-methylated analogues S4-Me and S5-
Me were synthesized by methylation of compounds S4 and
S5 (Scheme 9A), whilst their corresponding esters, S4-O[41]
and S5-O[42] (Scheme 9 B), were prepared according to liter-
ature procedures. For each series of analogues (Table 10 and
Table 11, respectively), the rhodium complexes of 4a-Me
of ligand–substrate hydrogen-bonding interactions is also
consistent with the results obtained with substrate S5 and its
non-hydrogen-bond-donor analogues S5-Me and S5-O
(Table 11). With both ligands 4i and 4a-Me, substrate S5-
Me was converted into the product in low yields (Table 11,
entries 4 and 5). The dramatic drop in conversion observed
(compared to substrate S5, entries 1 and 2) supports the
postulated key role of hydrogen-bonding interactions be-
tween the NH atom of substrate S5 and the amide oxygen
atom of the catalyst. It appears that the stereoselectivity of
the hydrogenation with N-methylated substrate S5-Me is rel-
atively high, irrespective of the ligand used (Table 11, en-
tries 4–6). Even the poorly performing ligand 5a, which is
devoid of hydrogen-bonding functionalities, gave a much-
higher ee value with substrate S5-Me compared to S5
(Table 11, entry 6 vs. entry 3). None of the ligands tested af-
forded the conversion of enol ester S5-O, even under
100 bar hydrogen pressure (Table 11, entries 7–10). This
latter result is of particular in-
terest if one considers that,
unlike S4-O, substrate S5-O is
not an enol ester and thus—
apart from the lack of hydro-
gen-bond-donor
ability—the
stereoelectronic properties of
its double bond should quite-
closely resemble those of sub-
strate S5. Taken together, these
control experiments confirm
that hydrogen bonding has a
strong influence on the catalytic
properties of the PhthalaPhos
ligands, and are consistent with
the results of the computational
studies on an intermediate that
Scheme 9. A) Synthesis of the N-methylated substrates S4-Me and S5-Me. B) Enol ester substrates S4-O[41]
and S5-O.[42]
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Rhodium-Catalyzed Asymmetric Hydrogenation of Olefins
FULL PAPER
Table 10. Hydrogenation of substrate S4 and its analogues (S4-Me and
S4-O) using ligands 4a and 4a-Me.[a]
vant for the outstanding catalytic performances of the
PhthalaPhos ligands.
Conclusions
A library of 19 chiral binol–monophosphite ligand that con-
tain a phthalic acid secondary bis-amide group has been syn-
thesized and screened in the rhodium-catalyzed hydrogena-
tion of several prochiral dehydroamino esters and enamides.
An outstanding level of stereocontrol has been achieved
with three benchmark alkenes and two industrially relevant
olefins that are commonly considered as challenging hydro-
genation substrates. The role of the diamide group has been
investigated by means of spectroscopic and computational
studies on both a precatalyst complex and an intermediate
in the hydrogenation catalytic cycle that is formed close to
the stereodiscriminating step. As demonstrated for ligand
Entry Substrate Ligand P [bar] Conv. [%] ee [%] (abs. config
or [a]D sign)
1
2
3
4
5
S4[b]
4a
4a-Me
4a
4a-Me
4a
12
12
12
12
12
100
100
72
62
0
96 (R)
96 (R)
87 (+)
87 (+)
S4[b]
S4-Me[c]
S4-Me[c]
S4-O[d]
–
6
7
S4-O[d]
S4-O[d]
4a
4a-Me
100
12
3
0
n.d.
–
8
S4-O[d]
4a-Me
100
2
n.d.
4a, interACTHUNRTGENNUGliACHUTGTNRENNUGgand hydrogen-bonding interactions are likely to
[a] Reaction conditions: substrate/ligand/[RhACHTUNTGRNEUNG(cod)2BF4]=100:2.2:1, sol-
be present in all of the PhthalaPhos square-planar precata-
lyst rhodium complexes, and thus the ligands behave as
“supramolecular bidentate ligands”. However, as suggested
by both computational and experimental evidence, the for-
mation of a hydrogen bond between the amide oxygen atom
of the ligand and the amide NH of the substrate may take
place in the octahedral intermediates of the catalytic cycle
and thus be responsible for substrate orientation during the
hydrogenation process. The reversible and dynamic nature
of hydrogen bonding is thus consistent with a scenario
where the ligand–ligand interactions present in the precata-
lyst may break during the catalytic cycle (after dissociation
of the cod ligand), and ligand–substrate interactions may
take place instead, thereby possibly accounting for the faster
rate of reaction and higher enantioselectivities observed.
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
determined by GC analysis with a chiral capillary column (MEGADEX
DACTBSb, diacetyl-tert-butylsilyl-b-cyclodextrin); correlation of [a]D
sign with absolute configuration has still not been established. [d] Con-
version determined by H NMR spectroscopic analysis of the crude reac-
tion mixture; ee determined by HPLC equipped with a chiral column
(Phenomenex Lux Cellulose 3).
1
Table 11. Hydrogenation of substrate S5 and its analogues (S5-Me and
S5-O) using ligands 4i and 4a-Me.[a]
Entry Substrate Ligand P [bar] Conv. [%] ee [%] ([a]D sign)[b]
1
2
3
4
5
6
7
8
S5[c]
4i
4a-Me
5a
4i
4a-Me
5a
50
50
50
50
50
50
50
100
50
100
100
6
31
14
4
0
0
0
0
99 (+)
81 (+)
32 (+)
97 (+)
88 (+)
91 (+)
–
–
–
–
S5[c]
Experimental Section
S5[c]
S5-Me[d]
S5-Me[d]
S5-Me[d]
S5-O[e]
S5-O[e]
S5-O[e]
S5-O[e]
General remarks: All reactions were carried out in flame-dried glassware
with magnetic stirring under a nitrogen atmosphere unless otherwise
stated. The solvents were distilled over the following drying agents (given
in parentheses) and transferred under nitrogen: CH2Cl2 (CaH2), MeOH
(CaH2), THF (Na), 1,4-dioxane (Na), Et3N (CaH2). Dry Et2O and CHCl3
(molecular sieves in bottles with crown cap) were purchased from Fluka
and stored under nitrogen. The reactions were monitored by analytical
thin-layer chromatography (TLC) using silica gel 60 F254 pre-coated glass
plates (0.25 mm thickness). Visualization was accomplished by irradiation
with a UV lamp and/or staining with alkaline potassium permanganate
solution. Flash chromatography was performed on silica gel (60 ꢃ, parti-
cle size 40–64 mm) as the stationary phase, following the procedure by
Still et al.[43] Proton NMR spectra were recorded on a spectrometer oper-
ating at 400.13 MHz. Proton chemical shifts are reported in ppm (d) with
residual solvent referenced relative to tetramethylsilane (TMS) as the in-
ternal standard (CDCl3, d=7.26 ppm; CD2Cl2, d=5.32 ppm; [D6]DMSO,
d=2.50 ppm; CD3OD, d=3.33 ppm). The following abbreviations are
used to describe spin multiplicity: s=singlet, d=doublet, t=triplet, q=
quartet, m=multiplet, br=broad signal, dd=doublet of doublet, td=
triplet of doublets. 13C NMR spectra were recorded on a 400 MHz spec-
trometer operating at 100.56 MHz, with complete proton decoupling.
Carbon chemical shifts are reported in ppm (d) relative to TMS with the
respective solvent resonance as the internal standard (CDCl3, d=
4i
4i
9
10
4a-Me
4a-Me 100
[a] Reaction conditions: substrate/ligand/[RhACHTUNTGRNEUNG(cod)2BF4]=100:2.2:1, sol-
vent=CH2Cl2, c0 (substrate)=0.024m, T=258C. [b] Correlation of [a]D
sign with absolute configuration has still not been established. [c] Conver-
sion and ee determined as specified in the footnotes of Table 6. [d] Con-
1
version determined by H NMR spectroscopic analysis on the crude reac-
tion mixture; ee determined by HPLC equipped with a chiral column
(Phenomenex Lux Cellulose 2). [e] Conversion determined by 1H NMR
spectroscopic analysis on the crude reaction mixture; ee determined by
À
HPLC equipped with a chiral column (Daicel Chiralcel OD H).
forms very close to the stereodiscriminating step of the hy-
drogenation process. Accordingly, the substrate orientation
achieved by the formation of a hydrogen bond between its
NH group and the ancillary amide oxygen of a ligand is rele-
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1393

L. Pignataro, U. Piarulli, C. Gennari et al.
77.23 ppm; CD2Cl2, d=54.00 ppm; [D]6DMSO, d=39.51 ppm; CD3OD,
d=49.05 ppm). 31P NMR spectra were recorded on a 400 MHz spectrom-
eter operating at 162 MHz, with complete proton decoupling. 31P NMR
spectroscopic chemical shifts are reported in ppm (d) relative to external
85% H3PO4 at 0 ppm (positive values indicate downfield shifts).
19F NMR spectra were recorded on a 300 MHz spectrometer operating at
282 MHz. 19F NMR spectroscopic chemical shifts are reported in ppm (d)
relative to external CFCl3 at 0 ppm (positive values indicate downfield
shifts). The coupling constant values are given in Hz. Infrared spectra
were recorded on a standard FT/IR spectrometer. Optical rotation values
were measured on an automatic polarimeter with a 1 dm3 cell at the
sodium D line (l=589 nm). Gas chromatography was performed on a
GC instrument equipped with a flame-ionization detector, using a chiral
capillary column. High-resolution mass spectra (HRMS) were performed
on a Fourier Transform Ion Cyclotron Resonance (FT-ICR) Mass Spec-
trometer APEX II & Xmass software (Bruker Daltonics), 4.7 T Magnet
(Magnex) equipped with an ESI source, available at CIGA (Centro Inter-
dipartimentale Grandi Apparecchiature) c/o Universitꢀ degli Studi di
Milano. Low-resolution mass spectra (MS) were acquired either on a
Thermo-Finnigan LCQ Advantage mass spectrometer (ESI ion source)
or on a VG Autospec M246 spectrometer (FAB ion source). Elemental
analyses were performed on a Perkin–Elmer Series II CHNS/O Analyzer
2000.
under reduced pressure and the product was purified by flash chromatog-
raphy on silica gel through a short pad of silica (1:1 n-hexane/CH2Cl2).
Compound 2b was obtained as a white solid. Yield: 471 mg (99%); m.p.
127–1298C; 1H NMR (400 MHz, CDCl3): d=8.15 (d, 3J
ACTHNUGRTENUNG(H,H)=7.6 Hz,
3
3
4
1H), 8.06 (d, J
0.9 Hz, 1H), 7.90 (td, 3J
2H), 7.80 ppm (s, 1H); 13C NMR (100 MHz, CDCl3): d=164.4, 150.7,
146.5, 136.7, 136.5, 134.7, 132.7 (q, 2J
(C,F)=33.5 Hz), 128.3, 126.2, 124.5,
124.5, 123.9 (q, 1J(C,F)=272.2 Hz), 119.9 ppm (m); 19F NMR (282 MHz,
N
ACHUTGTNRENN(GU H,H)=7.6 Hz, JACHTUNGTRENNUNG(H,H)=
G
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
CDCl3): d=À62.2 ppm; IR (film): n˜ =3083.6, 3042.2, 1827.2, 1796.4,
1700.9, 1279.5, 1118.5 cmÀ1; MS (FAB+): m/z 360.0 [M+H]+ (calcd for
C16H8F6NO2: 360.0); elemental analysis calcd (%) for C16H7F6NO2:
C 53.50, H 1.96, N 3.90; found: C 53.35, H 1.88, N 3.90.
General procedure for the preparation of alcohols 3a–l and 3n–3s:
Phthalisoimide 2a or 2b (1 equiv, typical scale 0.3 g) was added to stir-
ring solution of the chosen amino alcohol (1.2 equiv, 0.11m) in THF. The
mixture was stirred overnight at room temperature. Two alternative
workup procedures were followed depending on whether the product
precipitated out of solution or not.
Workup 1 (soluble product): the mixture was diluted with EtOAc (triple
the volume of THF) and washed three times with 1m HCl. The organic
phase was dried with Na2SO4 and evaporated. The product was purified
by flash chromatography on silica gel.
Materials: Phthalic anhydride sometimes contains large amounts of
phthalic acid. In such cases, the mixture can be easily re-converted into
the pure anhydride by melting it in an open flask and strongly heating it
for 10 min. On cooling to room temperature, pure phthalic anhydride
crystallizes as a white solid. Phthalic anhydride was stored in a desiccator.
The other commercially available starting materials were used as re-
ceived. For the synthesis of non-commercially available amino alcohols,
see the Supporting Information.
Workup 2 (insoluble product): the precipitate was collected by filtration
using a Buchner funnel and washed on the frit with small volumes of 1:1
Et2O/n-hexane until the yellow impurities had disappeared. The product
obtained from this workup procedure did not need chromatographic pu-
rification.
General procedure for the preparation of phosphites 4a–4s and 4a-Me:
Two alternative, slightly different procedures were followed depending
on whether the starting alcohol was soluble in THF or not.
General procedure for the preparation of phthalic acid mono-amides 1a–
1c: The amine (1 equiv) was added to a stirring solution of phthalic anhy-
dride (1 equiv, 1.44m; typical scale=15 g) in CHCl3; a white precipitate
soon began to form. The mixture was heated to reflux and stirred for 3 h,
then it was cooled with an ice bath. The precipitate was collected using a
Buchner funnel and washed on the frit with 6:1 CHCl3/n-hexane until the
red impurities had disappeared. The product was dried under high
vacuum.
À
À
General procedure 1: (S)-binol PCl or (R)-3,3’-dimethyl-binol PCl
(1 equiv, typical scale=0.3 g) was added to a stirring solution of the se-
lected alcohol (1 equiv, 0.1m) and Et3N (3 equiv) in THF. The obtained
mixture was stirred overnight and then collected by filtration through a
pad of Celite (washing with THF). The solvent was evaporated under re-
duced pressure and the crude product was purified by flash chromatogra-
phy on silica gel.
General procedure 2: (S)-Binol-PCl (1 equiv, typical scale=0.3 g) was
added to a stirring suspension of the selected alcohol (1 equiv) and Et3N
(3 equiv) in 6:4 THF/CH2Cl2 (ca. 0.1m). The obtained mixture was stirred
overnight and then Et2O (half of the volume of the THF/CH2Cl2 mix-
ture) was added. The mixture was collected by filtration through a pad of
Celite (washing with THF), then the solvent was evaporated under re-
duced pressure and the crude product was purified by flash chromatogra-
phy on silica gel.
Preparation of phthalisoimides 2a,b:
(3-(4-butylphenylimino)isobenzofuran-1ACTHNUTRGNEUNG
(3H)-one) 2a:[24] Trifluoroacetic
anhydride (2.1 mL, 15.13 mmol, 1.5 equiv) was added dropwise to a stir-
ring solution of acid 1a (3 g, 10.09 mmol, 1 equiv) and Et3N (4.2 mL,
30.27 mmol, 3 equiv) in 1,4-dioxane (45 mL) that was kept at 08C with an
ice bath. After 5 min the yellow solution was allowed to warm to room
temperature and was stirred for 15 min, then it was poured in cold H2O
(120 mL). A pale-yellow precipitate formed, which was collected by fil-
tration using a Buchner funnel and washed with H2O. The product was
dried for 20 min on the filter and then overnight under high vacuum. A
pale yellow solid was obtained. Yield: 2.72 g (97%); m.p. 58–618C;
N1-(4-Butylphenyl)-N2-(3-(((11bS)-dinaphtho[2,1-d:1’,2’-f]
AHCTUNGERTGpNNUN hosphepin-4-yloxy)methyl)phenyl)phthalamide 4a: The product was
ACHTUNGTREN[NUNG 1,3,2]dioxa-
À
prepared according to general procedure 1 starting from (S)-binol PCl
(0.314 g) and alcohol 3a (0.36 g) in the presence of Et3N (0.375 mL). Pu-
rification by flash chromatography on silica gel (CH2Cl2 and then 95:5
CH2Cl2/Et2O) gave the product as a white solid. Yield: 0.473 g (74%);
m.p. 114–1218C; [a]1D9 =+277.6 (c=1.0 in CH2Cl2); 1H NMR (400 MHz,
1H NMR (400 MHz, CD2Cl2): d=8.11 (d, 3J
(d, 3J(H,H)=7.6 Hz, 1H), d 7.90 (t, 3J(H,H)=7.6 Hz, 1H), 7.80 (t, 3J-
(H,H)=7.6 Hz, 1H), 7.41 (d, 3J(H,H)=8.2 Hz, 2H), 7.28 (d, 3J
(H,H)=
8.2 Hz, 2H), 2.69 (t, 3J
(H,H)=7.8 Hz, 2H), 1.68 (m, 2H), 1.43 (m, 2H),
1.00 ppm (t, J
(H,H)=7.4 Hz, 3H); 13C NMR (100 MHz, CD2Cl2): d=
ACHTUNGERTN(NUNG H,H)=7.6 Hz, 1H), d 8.00
A
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
CD2Cl2): d=9.40 (s, 1H), 9.02 (s, 1H), 8.04 (d, 3J
ACTHNUTRGNE(NUG H,H)=8.8 Hz, 1H),
ACHTUNGTRENNUNG
3
3
3
8.00 (d, J
(H,H)=8.2 Hz, 1H), 7.59–7.56 (m, 3H), 7.53–7.42 (m, 6H), 7.39–7.27 (m,
7H), 7.23 (t, 3J(H,H)=8.0 Hz, 1H), 7.04 (d, 3J
(H,H)=8.4 Hz, 2H), 7.00
(d, 3J(H,H)=8.0 Hz, 1H), 4.92 (dd, 2J(H,H)=12.3 Hz, 3J
(H,P)=8.0 Hz,
1H), 4.70 (dd, 2J(H,H)=12.3 Hz, 3J(H,P)=8.0 Hz, 1H), 2.53 (t, 3J-
(H,H)=
ACHUTGTNREN(NUG H,H)=8.4 Hz, 1H), 7.93 (d, JCAHTUNGTRNE(NUGN H,H)=8.8 Hz, 1H), 7.92 (d, J-
165.5, 147.2, 142.2, 142.1, 137.8, 136.0, 133.6, 129.5, 128.2, 125.7, 125.1,
124.0, 35.8, 34.2, 22.9, 14.3 ppm; IR (KBr): n˜ =2956.3, 2855.1, 1791.6,
1689.3, 915.1 cmÀ1; MS (ESI+): m/z 280.3 [M+H]+ (calcd for C18H18NO2:
280.1); elemental analysis calcd (%) for C18H17NO2: C 77.40, H 6.13,
N 5.01; found: C 77.33, H 6.32, N 4.97.
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
ACHUTNGRENNUG ACHTUNGTRENNUNG
(H,H)=7.8 Hz, 2H), 1.54 (m, 2H), 1.33 (m, 2H), 0.92 ppm (t, 3J
7.3 Hz, 3H); 13C NMR (100 MHz, CD2Cl2): d=167.9, 149.2, 148.1, 139.8,
139.0, 138.5, 136.3, 135.7, 135.6, 133.3, 133.1, 132.2, 131.7, 131.1, 131.0,
130.9, 129.5, 129.3, 129.1, 129.1, 128.8, 127.4, 127.0, 126.9, 125.8, 125.6,
3-(3,5-Bis(trifluoromethyl)phenylimino)isobenzofuran-1
G
2b:
Trifluoroacetic anhydride (0.276 mL, 1.988 mmol, 1.5 equiv) was added
dropwise to a stirring solution of acid 1b (0.5 g, 1.325 mmol, 1 equiv) and
Et3N (0.185 mL, 1.325 mmol, 1 equiv) in THF (6 mL) kept at 08C with
an ice bath. After 5 min the solution was allowed to warm to room tem-
perature and was stirred for 10 min. A second portion of Et3N (0.37 mL,
3.976 mmol, 2 equiv) was added dropwise, and the solution was stirred
for 20 min at room temperature. The volatile compounds were removed
124.1, 123.2, 122.5, 122.3, 121.6, 120.8, 120.4, 119.8, 67.2 (d, 2J
ACHTUNGTRENNUNG(C,P)=
5.6 Hz), 35.6, 34.3, 23.0, 14.3 ppm; 31P NMR (162 MHz, CD2Cl2): d=
141.3 ppm (s); IR (film): n˜ =3238.9, 3060.5, 2954.4, 1639.2, 1541.8, 1230.3,
823.5 cmÀ1; HRMS (ESI+): m/z calcd for C45H37N2O5PNa: 739.23469
[M+Na]+; found: 739.23323.
1394
www.chemeurj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 1383 – 1400

Rhodium-Catalyzed Asymmetric Hydrogenation of Olefins
FULL PAPER
N1-(4-Butylphenyl)-N2-(3-(((11bS)-dinaphtho[2,1-d:1’,2’-f]
phosphepin-4-yloxy)methyl)benzyl)phthalamide 4b: The product was
C
prepared according to the general procedure 2 starting from (S)-binol
À
ACHTUNGTRENNUNG
PCl (0.287 g) and alcohol 3e (0.340 g) in the presence of Et3N
(0.342 mL). Purification by flash chromatography on silica gel (CH2Cl2
and then 95:5 CH2Cl2/Et2O) gave the product as a white solid. Yield:
0.412 g (69%); m.p. 115–1228C; [a]2D0 =+313.5 (c=0.87 in CH2Cl2);
À
prepared according to the general procedure 2 starting from (S)-binol
PCl (0.337 g) and alcohol 3b (0.40 g) in the presence of Et3N (0.40 mL).
Purification by flash chromatography on silica gel (CH2Cl2 and then 95:5
CH2Cl2/Et2O) gave the product as a white solid. Yield: 0.475 g (67%);
m.p. 139–1458C; [a]2D3 =+120.1 (c=1.0 in CH2Cl2); 1H NMR (400 MHz,
1H NMR (400 MHz, CD2Cl2): d=8.91 (s, 1H), 8.04 (d, 3J
1H), 8.00 (d, 3J(H,H)=8.2 Hz, 1H), 7.89 (d, 3J
(H,H)=8.8 Hz, 1H), 7.88
(d, 3J(H,H)=8.0 Hz, 1H), 7.70 (d, 3J
(H,H)=7.7 Hz, 1H), 7.52–7.38 (m,
7H), 7.34–7.20 (m, 10H), 7.16 (d, 3J(H,H)=8.3 Hz, 2H), 6.76 (t, 3J-
(H,H)=5.4 Hz, 1H), 5.13 (dd, 2J(H,H)=12.1 Hz, 3J
(H,P)=7.8 Hz, 1H),
4.98 (dd, 2J(H,H)=12.1 Hz, 3J(H,P)=8.4 Hz, 1H), 4.61 (dd, 2J
(H,H)=
14.7 Hz, 3J(H,P)=5.9 Hz, 1H), 4.53 (dd, 2J(H,H)=14.7 Hz, 3J
(H,P)=
5.7 Hz, 1H), 2.63 (t, 3J
(H,H)=7.8 Hz, 2H), 1.64 (m, 2H), 1.40 (m, 2H),
0.98 ppm (t, 3J(H,H)=7.8 Hz, 3H); 13C NMR (100 MHz, CD2Cl2): d=
ACHTUNGTREN(NUNG H,H)=8.8 Hz,
A
ACHTUNGTRENNUNG
CD2Cl2): d=8.80 (s, 1H), 8.06 (d, 3J
(H,H)=8.2 Hz, 1H), 7.95 (d, 3J(H,H)=9.0 Hz, 1H), 7.92 (d, 3J
7.8 Hz, 1H), 7.79 (d, 3J(H,H)=7.1 Hz, 1H), 7.62 (dd, 3J
(H,H)=7.4 Hz,
4J(H,H)=1.5 Hz, 1H), 7.58–7.43 (m, 7H), 7.39–7.20 (m, 9H), 7.15 (d, 3J-
(H,H)=8.3 Hz, 2H), 6.89 (t, 3J(H,H)=6.0 Hz, 1H), 4.91 (dd, 2J
(H,H)=
12.3 Hz, 3J(H,P)=8.0 Hz, 1H), 4.71 (dd, 2J(H,H)=12.3 Hz, 3J
(H,P)=
8.2 Hz, 1H), 4.60 (d, 3J(H,H)=6.0 Hz, 2H), 2.62 (t, 3J
(H,H)=7.8 Hz,
2H), 1.62 (m, 2H), 1.39 (m, 2H), 0.97 ppm (t, 3J
(H,H)=7.3 Hz, 3H);
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
169.6, 166.8, 148.9, 147.8, 139.7, 137.3, 136.5, 135.7, 135.6, 134.7, 133.3,
133.0, 132.2, 131.6, 131.1, 130.8, 130.7, 130.4, 130.2, 129.7, 129.6, 129.3,
129.0, 128.9, 128.5, 128.3, 127.3, 127.3, 126.9, 126.9, 125.8, 125.6, 124.5,
13C NMR (100 MHz, CD2Cl2): d=170.0, 167.3, 149.2, 148.1, 139.7, 139.1,
138.2, 136.6, 135.7, 135.0, 133.4, 133.1, 132.2, 131.7, 131.0, 130.8, 130.8,
129.4, 129.1, 129.0, 128.9, 128.7, 127.3, 126.8, 126.8, 125.7, 125.5, 124.6,
2
123.2, 122.2, 122.0, 121.9, 120.6, 65.6 (d, J
A
124.0, 123.1, 122.4, 122.2, 120.7, 120.3, 119.7, 67.1 (d, 2J
ACHTNUTRGNE(NUG C,P)=5.7 Hz),
22.9, 14.3 ppm; 31P NMR (162 MHz, CD2Cl2): d=144.0 ppm (s); IR
44.3, 35.5, 34.2, 22.9, 14.3 ppm; 31P NMR (162 MHz, CD2Cl2): d=
141.8 ppm (s); IR (film): n˜ =3243.7, 3058.6, 2954.4, 1635.3, 1538.9, 1230.0,
825.4 cmÀ1; HRMS (ESI+): m/z calcd for C46H39N2O5PNa: 753.24888
[M+Na]+; found: 753.24782.
(film): n˜ =3245.6, 3058.8, 2954.4, 1636.3, 1541.8, 1230.0, 824.4 cmÀ1
;
HRMS (ESI+): m/z calcd for C46H39N2O5PNa: 753.24888 [M+Na]+;
found: 753.24983.
N1-(4-Butylphenyl)-N2-(3-(((11bS)-dinaphtho[2,1-d:1’,2’-f]
ACHTUNGTREN[NUNG 1,3,2]dioxa-
N1-(4-Butylphenyl)-N2-(4-(((11bS)-dinaphtho[2,1-d:1’,2’-f]
ACHTUNGTREN[NUNG 1,3,2]dioxa-
AHCTUNGERTGpNNUN hosphepin-4-yloxy)methyl)phenethyl)phthalamide 4 f: The product was
ACHTUNGTRENNUNG
À
prepared according to the general procedure 1 starting from (S)-binol
PCl (0.137 g) and alcohol 3 f (0.390 g) in the presence of Et3N
(0.163 mL). Purification by flash chromatography on silica gel (CH2Cl2
and then 95:5 CH2Cl2/Et2O) gave the product as a white solid. Yield:
0.183 g (63%); m.p. 105–1168C; [a]2D0 =+201.7 (c=0.8 in CH2Cl2);
À
prepared according to the general procedure 1 starting from (S)-binol
PCl (0.174 g) and alcohol 3c (0.200 g) in the presence of Et3N
(0.208 mL). Purification by flash chromatography on silica gel (CH2Cl2
and then 95:5 CH2Cl2/Et2O) gave the product as a white solid. Yield:
0.219 g (62%); m.p. 150–1598C; [a]1D8 =+209.1 (c=0.8 in CH2Cl2);
1H NMR (400 MHz, CD2Cl2): d=8.96 (s, 1H), 8.53 (s, 1H), 8.06 (d, 3J-
1H NMR (400 MHz, CD2Cl2): d=9.21 (s, 1H), 8.06 (d, 3J
1H), 8.01 (d, 3J(H,H)=8.3 Hz, 1H), 7.96 (d, 3J
(H,H)=8.7 Hz, 2H), 7.73
(d, 3J(H,H)=7.4 Hz, 1H), 7.58 (d, 3J(H,H)=8.8 Hz, 1H), 7.57 (d, 3J-
(H,H)=8.1 Hz, 2H), 7.52–7.28 (m, 11H), 7.19–7.17 (m, 5H), 6.55 (bs,
1H), 5.00 (dd, 2J(H,H)=12.2 Hz, 3J(H,P)=7.9 Hz, 1H), 4.80 (dd, 2J-
(H,H)=12.2 Hz, 3J(H,P)=8.4 Hz, 1H), 3.64 (m, 2H), 2.88 (t, 3J
(H,P)=
7.1 Hz, 2H), 2.62 (t, 3J
(H,P)=7.6 Hz, 2H), 1.63 (m, 2H), 1.38 (m, 2H),
0.96 ppm (t, 3J(H,P)=7.3 Hz, 3H); 13C NMR (100 MHz, CD2Cl2): d=
ACHTUNGTREN(NUNG H,H)=8.8 Hz,
A
ACHTUNGTRENNUNG
A
R
ACHTUNGTRNE(NUNG H,H)=
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
(100 MHz, CD2Cl2): d=168.2, 168.0, 149.3, 148.2, 139.2, 136.8, 135.6,
135.5, 133.4, 133.1, 132.2, 131.7, 131.0, 130.7, 130.3, 130.2, 129.0, 128.8,
128.5, 127.3, 126.8, 125.7, 125.5, 124.7, 124.6, 123.2, 122.4, 122.2, 120.6,
170.3, 167.1, 149.2, 148.1, 139.9, 139.6, 138.1, 136.8, 135.6, 135.4, 133.4,
133.1, 132.2, 131.7, 131.1, 130.8, 130.4, 129.3, 129.2, 129.1, 129.0, 128.6,
128.2, 127.3, 126.9, 126.3, 125.7, 125.6, 124.6, 123.2, 122.4, 122.1, 120.7,
67.2 (d, 2J(C,P)=4.6 Hz), 41.8, 35.8, 35.6, 34.3, 22.9, 14.3 ppm; 31P NMR
ACTHNUTRGNEUNG
(162 MHz, CD2Cl2): d=142.2 ppm (s); IR (film): n˜ =3240.6, 3058.5,
2954.4, 1636.3, 1541.8, 1230.0, 825.4 cmÀ1; HRMS (ESI+): m/z calcd for
C47H42N2O5P: 745.28259 [M+H]+; found: 745.28262, and m/z calcd for
C47H41N2O5PNa: 767.26453 [M+Na]+; found: 767.26300.
ACHTUNGTRENNUNG
120.5, 67.1 (d, 2J(C,P)=4.6 Hz), 35.6, 34.2, 22.9, 14.3 ppm; 31P NMR
(162 MHz, CD2Cl2): d=141.8 ppm (s); IR (film): n˜ =3240.1, 3059.1,
2954.4, 1639.2, 1541.8, 1230.0, 823.5 cmÀ1; HRMS (ESI+): m/z calcd for
C45H37N2O5PNa: 739.23323 [M+Na]+; found: 739.23437.
N1-(4-Butylphenyl)-N2-(4-(((11bS)-dinaphtho[2,1-d:1’,2’-f]
ACHTUNGTREN[NUNG 1,3,2]dioxa-
ACHTUNGTRENNUNGphosphepin-4-yloxy)methyl)benzyl)phthalamide 4d: The product was
N1-(4-Butylphenyl)-N2-(4-(((11bS)-dinaphtho[2,1-d:1’,2’-f]
ACHTUNGTREN[NUNG 1,3,2]dioxa-
À
prepared according to the general procedure 1 starting from (S)-binol
PCl (0.278 g) and alcohol 3d (0.30 g) in the presence of Et3N (0.30 mL).
Purification by flash chromatography on silica gel (CH2Cl2 and then 95:5
CH2Cl2/Et2O) gave the product as a white solid. Yield: 0.342 g (65%);
m.p. 110–1308C; [a]1D8 =+239.6 (c=0.93 in CH2Cl2); 1H NMR (400 MHz,
AHCTUNGERTGpNNUN hosphepin-4-yloxy)methyl)phenethyl)phthalamide 4g: The product was
À
prepared according to the general procedure 2 starting from (S)-binol
PCl (0.275 g) and alcohol 3g (0.338 g) in the presence of Et3N
(0.328 mL). Purification by flash chromatography on silica gel (CH2Cl2
and then 95:5 CH2Cl2/Et2O) gave the product as a white solid. Yield:
0.415 g (71%); m.p. 109–1178C; [a]2D0 =+248.8 (c=0.8 in CH2Cl2);
CD2Cl2): d=8.88 (s, 1H), 8.06 (d, 3J
(H,H)=8.3 Hz, 1H), 7.97 (d, 3J(H,H)=8.7 Hz, 2H), 7.80 (d, 3J
7.0 Hz, 1H), 7.62–7.46 (m, 8H), 7.39–7.30 (m, 7H), 7.20 (d, 3J
7.4 Hz, 2H), 7.18 (d, 3J(H,H)=7.4 Hz, 2H), 6.88 (t, 3J
(H,H)=5.9 Hz,
1H), 4.97 (dd, 2J(H,H)=12.2 Hz, 3J(H,P)=8.0 Hz, 1H), 4.76 (dd, 2J-
(H,H)=12.2 Hz, 3J(H,P)=8.2 Hz, 1H), 4.60 (d, 3J
(H,H)=5.9 Hz, 2H),
2.61 (t, 3J
(H,H)=7.6 Hz, 2H), 1.61 (m, 2H), 1.37 (m, 2H), 0.95 ppm (t,
3J(H,H)=7.3 Hz, 3H); 13C NMR (100 MHz, CD2Cl2): d=170.0, 167.4,
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
1H NMR (400 MHz, CD2Cl2): d=9.22 (s, 1H), 8.06 (d, 3J
1H), 8.01 (d, 3J(H,P)=8.3 Hz, 1H), 7.96 (d, 3J
(H,P)=9.0 Hz, 2H), 7.74
(d, 3J
(H,P)=7.4 Hz, 1H), 7.58 (m, 3H), 7.52–7.29 (m, 10H), 7.23 (m,
4H), 7.19 (d, 3J(H,P)=8.5 Hz, 2H), 6.62 (t, 3J
(H,P)=5.6 Hz, 1H), 4.98
(dd, 2J(H,H)=12.1 Hz, 3J(H,P)=8.0 Hz, 1H), 4.77 (dd, 2J
(H,H)=
12.1 Hz, 3J(H,P)=8.2 Hz, 1H), 3.65 (q, 3J (H,H)=6 Hz, 2H), 2.89 (t, 3J-
(H,P)=7.1 Hz, 2H), 2.63 (t, 3J
(H,P)=7.6 Hz, 2H), 1.63 (m, 2H), 1.39
(m, 2H), 0.97 ppm (t, 3J(H,P)=7.3 Hz, 3H); 13C NMR (100 MHz,
ACHTUNGTREN(NUNG H,P)=8.8 Hz,
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
U
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
149.3, 148.1, 139.7, 138.7, 137.0, 136.6, 135.7, 135.0, 133.4, 133.1, 132.2,
131.7, 131.1, 130.8, 130.7, 130.6, 129.2, 129.1, 129.0, 129.0, 128.5, 128.4,
128.3, 127.3, 126.9, 126.9, 125.7, 125.6, 124.6, 123.2, 122.3, 122.1, 120.8,
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
CD2Cl2): d=170.2, 167.5, 149.3, 148.1, 139.8, 139.4, 137.0, 135.9, 135.7,
135.4, 133.4, 133.1, 132.2, 131.7, 131.1, 130.8, 130.5, 130.2, 129.4, 129.1,
129.0, 129.0, 128.4, 128.1, 127.3, 126.9, 126.9, 125.7, 125.6, 124.6, 123.2,
ACHTUNGTRENNUNG
67.0 (d, 2J(C,P)=5.7 Hz), 44.2, 35.6, 34.3, 22.9, 14.3 ppm; 31P NMR
(162 MHz, CD2Cl2): d=141.6 ppm (s); IR (film): n˜ =3259.1, 3058.6,
2954.4, 1637.3, 1540.8, 1230.0, 824.4 cmÀ1; HRMS (ESI+): m/z calcd for
C46H39N2O5PNa: 753.24888 [M+Na]+; found: 753.24963.
122.4, 122.1, 120.7, 67.2 (d, 2J
ACTHNUGRTENUNG(C,P)=4.8 Hz), 41.8, 35.6, 35.5, 34.3, 22.9,
14.4 ppm; 31P NMR (162 MHz, CD2Cl2): d=141.9 ppm (s); IR (film): n˜ =
3252.4, 3073.0, 2954.3, 1635.3, 1540.8, 1230.0, 823.5 cmÀ1; HRMS (ESI+):
m/z calcd for C47H41N2O5PNa: 767.26453 [M+Na]+; found: 767.26494.
N1-(4-Butylphenyl)-N2-(2-(((11bS)-dinaphtho[2,1-d:1’,2’-f]
ACHTUNGTREN[NUNG 1,3,2]dioxa-
ACHTUNGTRENNUNGphosphepin-4-yloxy)methyl)benzyl)phthalamide 4e: The product was
Chem. Eur. J. 2012, 18, 1383 – 1400
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1395

L. Pignataro, U. Piarulli, C. Gennari et al.
N1-(3,5-Bis(trifluoromethyl)phenyl)-N2-(3-(((11bS)-dinaphtho[2,1-d:1’,2’-
f][1,3,2]dioxaphosphepin-4-yloxy)methyl)phenyl)phthalamide 4h: The
according to the general procedure
1
starting from (S)-binol PCl
À
G
(0.861 g) and alcohol 3k (0.778 g) in the presence of Et3N (0.93 mL). Pu-
rification by flash chromatography on silica gel (CH2Cl2 and then 95:5
CH2Cl2/Et2O) gave the product as a yellow solid. Yield: 0.927 g (60%);
m.p. 140–1458C; [a]2D0 =+51.4 (c=1.0 in CH2Cl2); 1H NMR (400 MHz,
product was prepared according to the general procedure 1 starting from
À
(S)-binol PCl (0.168 g) and alcohol 3h (0.230 g) in the presence of Et3N
(0.2 mL). Purification by flash chromatography on silica gel (CH2Cl2 and
then 95:5 CH2Cl2/Et2O) gave the product as a white solid. Yield: 0.296 g
(78%); m.p. 165–1768C; [a]2D1 =+216.7 (c=0.75 in CH2Cl2); 1H NMR
(400 MHz, CD2Cl2): d=10.53 (s, 1H), 9.16 (s, 1H), 8.07 (s, 2H), 7.96 (d,
CD2Cl2): d=9.21 (s, 1H), 8.75 (s, 1H), 8.00 (d, 3J
ACTHNUTRGNE(NUG H,H)=8.8 Hz, 1H),
3
3
3
7.97 (d, J
(H,H)=8.2 Hz, 1H), 7.62 (d, 3J
7.13 (m, 4H), 2.6 (t, 3J
(H,H)=7.7 Hz, 2H), 1.57 (m, 2H), 1.32 (m, 2H),
0.91 ppm (t, 3J(H,H)=7.3 Hz, 3H); 13C NMR (100 MHz, CD2Cl2): d=
A
ACHTUNGTNER(NUNG H,H)=8.9 Hz, 1H), 7.92 (d, J-
A
ACHTUNGTRENNUNG
3J
8.7 Hz, 1H), 7.83 (d, 3J
(H,H)=8.8 Hz, 1H), 7.42–7.34 (m, 4H), 7.31–7.15 (m, 6H), 7.04 (m,
1H), 6.96 (d, 3J(H,H)=7.7 Hz, 2H), 6.89 (m, 2H), 4.87 (dd, 2J
(H,H)=
12.4 Hz, 3J(H,P)=8.1 Hz, 1H), 4.69 ppm (dd, 2J(H,H)=12.4 Hz, 3J-
(H,P)=8.2 Hz, 1H); 13C NMR (100 MHz, CD2Cl2): d=168.7, 168.4,
149.1, 148.0, 140.6, 138.7, 138.5, 135.7, 134.8, 133.3, 133.1, 132.2, 132.1 (q,
2J
(C,F)=33.3 Hz), 131.6, 131.2, 131.0, 130.8, 130.7, 129.6, 129.0, 128.9,
128.5, 128.0, 127.3, 127.3, 126.9, 126.8, 125.7, 125.5, 124.6, 124.5, 123.7 (q,
1J
(C,F)=272.6 Hz), 123.1, 122.3, 122.0, 120.4, 119.9, 119.4, 117.8,
66.9 ppm (d, 2J
A
E
N
ACHTUNGTRENNUNG
U
ACHTUNGTRENNUNG
N
168.2, 168.1, 148.1, 148.0, 147.6, 139.3, 136.9, 136.2, 135.6, 135.4, 133.3,
133.0, 132.3, 131.8, 131.0, 130.5, 130.2, 130.1, 129.0, 128.8, 128.5, 128.4,
127.4, 127.2, 126.9, 126.8, 125.8, 125.6, 124.8, 123.4, 122.3, 122.0, 120.6,
35.7, 34.3, 23.0, 14.3 ppm; 31P NMR (162 MHz, CD2Cl2): d=146.2 ppm;
IR (film): n˜ =3067.2, 2954.4, 1640.2, 1540.9, 1410.7, 1328.7, 1202.4,
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
A
826.3 cmÀ1
; HRMS (ESI+): m/z calcd for C44H35N2O5P: 725.21813
[M+Na]+; found: 725.21599.
N1-(4-Butylphenyl)-N2-(7-((11bS)-dinaphtho[2,1-d:1’,2’-f]
ACHTNUTRGNE[NUG 1,3,2]dioxa-
AHCTUNGERTGpNNUN hosphepin-4-yloxy)naphthalen-1-yl)phthalamide 4l: The product was
prepared according to the general procedure 1 starting from (S)-binol
PCl (0.190 g) and alcohol 3l (0.238 g) in the presence of Et3N (0.23 mL).
Purification by flash chromatography on silica gel (CH2Cl2 and then 95:5
CH2Cl2/EtOAc) gave the product as a white solid. Yield: 0.271 g (67%);
m.p. 150–1608C; [a]2D0 =+76.5 (c=1.0 in CH2Cl2); 1H NMR (400 MHz,
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
(C,P)=6.7 Hz); 31P NMR (162 MHz, CD2Cl2): d=
141.0 ppm (s); 19F NMR (282 MHz, CD2Cl2): d=À62.2 ppm (s); IR
À
(film): n˜ =3220.4, 1638.2, 1380.8, 1276.0, 1230.0, 823.5 cmÀ1
; HRMS
(ESI+): m/z calcd for C43H27F6N2O5PNa: 819.14540 [M+Na]+; found:
819.14729.
N1-(3,5-Bis(trifluoromethyl)phenyl)-N2-(3-(((11bS)-dinaphtho[2,1-d:1’,2’-
f]
N
CD2Cl2): d=8.62 (s, 1H), 8.46 (s, 1H), 8.05 (d, 3J
7.99 (d, 3J(H,H)=8.3 Hz, 1H), 7.89–7.72 (m, 7H), 7.60 (d, 3J
8.8 Hz, 1H), 7.57–7.22 (m, 12H), 7.49 (d, 3J
(H,H)=8.2 Hz, 2H), 7.07 (d,
3J(H,H)=8.2 Hz, 2H), 2.51 (t, 3J
(H,H)=7.7 Hz, 2H), 1.51 (m, 2H), 1.3
ACHTUNGTRENNUNG
product was prepared according to the general procedure 1 starting from
N
ACHTUNGTRENNUNG
À
(S)-binol PCl (0.234 g) and alcohol 3i (0.330 g) in the presence of Et3N
ACHTUNGTRENNUNG
(0.279 mL). Purification by flash chromatography on silica gel (CH2Cl2
and then 95:5 CH2Cl2/Et2O) gave the product as a white solid. Yield:
0.413 g (76%); m.p. 138–1458C; [a]2D1 =+229.8 (c=0.95 in CH2Cl2);
1H NMR (400 MHz, CD2Cl2): d=10.81 (s, 1H), 8.16 (s, 2H), 8.02 (d, 3J-
A
ACHTUNGTRENNUNG
(m, 2H), 0.88 ppm (m, 3H); 13C NMR (100 MHz, CD2Cl2): d=168.6,
167.6, 150.8, 148.5, 147.6, 140.2, 136.1, 135.8, 135.6, 133.4, 133.0, 132.7,
132.4, 131.9, 131.9, 131.8, 131.2, 130.5, 129.6, 129.4, 129.1, 129.0, 127.4,
127.2, 127.1, 126.9, 127.0, 125.9, 125.7, 125.4, 124.9, 123.2, 122.3, 122.3,
121.7, 120.8, 111.8, 111.7, 35.6, 34.2, 22.9, 14.3 ppm; 31P NMR (162 MHz,
CD2Cl2): d=144.3 ppm; IR (film): n˜ =3247.5, 3057.6, 2954.4, 1644.0,
1538.0, 1411.6, 1328.7, 1229.4, 825.4 cmÀ1; HRMS (ESI+): m/z calcd for
C48H37N2NaO5P: 775.23378 [M+Na]+; found: 775.23122.
A
R
ACHTUNGTRNE(NUNG H,H)=
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
2
3
3J
ACHTUNGTRENNUNG(H,P)=8.2 Hz, 1H), 4.85 (dd, JAHCTUGNTENRNUG(H,H)=12.3 Hz, JACTHUGNTRENNUGN
4.65 ppm (AB system, 2H); 13C NMR (100 MHz, CD2Cl2): d=170.0,
N1-Butyl-N2-(3-((11bS)-dinaphtho[2,1-d:1’,2’-f]
ACTHNUTRGNE[NUG 1,3,2]dioxaphosphepin-4-
loxy)phenyl)phthalamide 4m: The product was prepared according to
168.8, 149.2, 148.0, 141.2, 139.5, 138.3, 135.1, 134.4, 133.3, 133.1, 132.2,
132.1 (q, 2J
ACHTUNGTRENNUNG
À
the general procedure 1 starting from (S)-binol PCl (0.225 g) and alcohol
ACHTUNGTRENNUNG
3m (0.200 g) in the presence of Et3N (0.27 mL). Purification by flash
chromatography on silica gel (CH2Cl2 and then 98:2 to 9:1 CH2Cl2/
EtOAc) gave the product as a white solid. Yield: 0.202 g (50%); m.p.
163–1708C; [a]2D0 =+83.8 (c=1.0 in CH2Cl2); 1H NMR (400 MHz,
ACHTUNGTRENNUNG
(C,P)=6.5 Hz), 44.3 ppm; 31P NMR (162 MHz, CD2Cl2): d=
140.6 ppm (s); 19F NMR (282 MHz, CD2Cl2): d=À62.2 ppm (s); IR
(film): n˜ =3219.2, 1635.3, 1382.7, 1281.0, 1230.0, 823.5 cmÀ1
; HRMS
(ESI+): m/z calcd for C44H29F6N2O5PNa: 833.16105 [M+Na]+; found:
CD2Cl2): d=9.61 (s, 1H), 8.05 (d, 3J
(H,H)=8.8 Hz, 1H), 7.99–7.95 (m, 2H), 7.87 (d, 3J
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
833.16280.
A
3
N1-(4-Butylphenyl)-N2-(3-((11bS)-dinaphtho[2,1-d:1’,2’-f]
[1,3,2]dioxa-
7.74 (s, 1H), 7.61 (d, J
(m, 6H), 6.96 (d, 3J
ACHTUNGTRENNUNG
E
A
ACHTUNGTRENNUNG
À
according to the general procedure
1
starting from (S)-binol PCl
ACHTUNGTRENNUNG
(0.351 g) and alcohol 3j (0.223 g) in the presence of Et3N (0.24 mL). Pu-
rification by flash chromatography on silica gel (CH2Cl2 and then 95:5
CH2Cl2/Et2O) gave the product as a white solid. Yield: 0.245 g (61%);
m.p. 158–1648C; [a]2D0 =+101.8 (c=1.0 in CH2Cl2); 1H NMR (400 MHz,
3H); 13C NMR (100 MHz, CD2Cl2): d=170.6, 166.9, 152.4, 148.1, 147.6,
140.6, 135.5, 135.2, 133.4, 133.1, 132.3, 131.9, 131.2, 131.1, 130.7, 130.6,
130.5, 130.1, 129.0, 128.2, 127.4, 127.3, 127.0, 126.9, 125.9, 125.7, 124.9,
123.4, 122.3, 122.2, 116.6, 116.5, 112.7, 112.6, 40.6, 32.0, 20.6, 14.0 ppm;
31P NMR (162 MHz, CD2Cl2): d=146.1 ppm; IR (film): n˜ =2958.3,
1633.9, 1547.6, 1436.7, 1324.9, 1229.4, 824.4 cmÀ1; HRMS (ESI+): m/z
calcd for C38H31N2NaO5P: 649,18683 [M+Na]+; found: 649.18507.
CD2Cl2): d=9.17 (s, 1H), 8.58 (s, 1H), 8.03 (d, 3J
7.98 (d, 3J(H,H)=8.2 Hz, 1H), 7.91 (d, 3J
(m, 2H), 7.62 (m, 1H), 7.58 (d, J
8.4 Hz, 2H), 7.49–7.42 (m, 5H), 7.38–7.24 (m, 6H), 7.12 (d, 3J
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
3
3
ACHUTNGRENNU(G H,H)=8.8 Hz, 1H), 7.52 (d, JCAHTUNGTRENNNUG
N1-(4-Butylphenyl)-N2-(7-((11bS)-dinaphtho[2,1-d:1’,2’-f]
AHCTUNGTREGUN[NN 1,3,2]dioxa-
3
4
3
8.3 Hz, 2H), 6.92 (dd, J
ACHTUNGTRENNUNG(H,H)=8.0 Hz, JACHTNUGTRENNUNG
AHCTUNGERTGpNNUN hosphepin-4-yloxy)naphthalen-2-yl)phthalamide 4n: The product was
G
ACHTUNGTRENNUNG
À
prepared according to the general procedure 1 starting from (S)-binol
PCl (0.352 g) and alcohol 3n (0.438 g) in the presence of Et3N (0.42 mL).
Purification by flash chromatography on silica gel (98:2 and then 95:5
CH2Cl2/Et2O) gave the product as a white solid. Yield: 0.300 g (40%);
m.p. 170–1788C; [a]2D0 =À23.1 (c=1.0 in CH2Cl2); 1H NMR (400 MHz,
7.3 Hz, 3H); 13C NMR (100 MHz, CD2Cl2): d=168.4, 168.1, 151.8, 148.0,
147.5, 140.7, 139.1, 136.9, 135.5, 134.8, 133.2, 132.9, 132.2, 131.8, 131.0,
130.5, 130.2, 129.8, 129.0, 129.0, 128.7, 128.5, 127.3, 127.2, 126.8, 125.8,
125.5, 124.8, 123.3, 122.3, 122.2, 120.5, 116.9, 116.2, 112.4, 35.6, 34.3, 23.0,
14.3 ppm; 31P NMR (162 MHz, CD2Cl2): d=145.8 ppm (s); IR (film): n˜ =
CD2Cl2): d=10.48 (s, 1H), 9.65 (s, 1H), 8.32 (s, 1H), 7.97 (d, 3J
ACHTUNGTRENNUNG
3238.9, 3064.3, 2954.4, 1642.1, 1541.8, 1412.6, 1326.8, 1228.4, 824.4 cmÀ1
;
8.8 Hz, 1H), 7.97 (d, 3J
2H), 7.64 (d, 3J
4H), 7.38 (t, 3J
4H), 6.94 (d, 3J
(H,H)=8.0 Hz, 1H), 7.87 (t, 3J
ACHUTGTNRENNUG CAHTUNGTRENNUNG
HRMS (ESI+: m/z calcd for C44H35N2NaO5P: 725.21813 [M+Na]+;
AHCTUNGTRENNUNG
found: 725.21637.
N1-(4-Butylphenyl)-N2-(4-((11bS)-dinaphtho[2,1-d:1’,2’-f]
AHCTUNGTRENNUNG
[1,3,2]dioxa-
G
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
1396
www.chemeurj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 1383 – 1400

Rhodium-Catalyzed Asymmetric Hydrogenation of Olefins
FULL PAPER
(100 MHz, CD2Cl2): d=168.5, 168.2, 150.1, 148.2, 147.7, 139.6, 137.9,
136.6, 135.8, 135.0, 133.4, 133.1, 132.4, 131.9, 131.1, 130.5, 130.4, 130.1,
129.0, 128.9, 128.7, 128.5, 128.4, 128.2, 127.4, 127.3, 127.0, 126.9, 125.9,
125.7, 124.9, 123.5, 122.3, 120.6, 120.1, 120.0, 116.5, 116.4, 35.5, 34.1, 22.9,
14.3 ppm; 31P NMR (162 MHz, CD2Cl2): d=146.2 ppm; IR (film): n˜ =
3066.3, 2954.4, 1638.2, 1541.8, 1429.0, 1332.6, 1230.4, 827.3 cmÀ1; HRMS
(ESI+: m/z calcd for C48H37N2NaO5P: 775.23378 [M+Na]+; found:
775.23177.
13C NMR (100 MHz, CD2Cl2): d=170.4, 166.6, 149.2, 148.0, 139.7, 138.1,
136.6, 135.8, 135.5, 135.3, 133.3, 133.1, 132.2, 131.1, 131.0, 130.8, 130.7,
130.5, 130.1, 129.9, 129.3, 129.0, 128.9, 128.3, 127.7, 127.4, 127.3, 126.9,
125.7, 125.6, 124.7, 124.5, 124.4, 123.2, 122.3, 122.1, 120.6, 118.4, 65.4,
41.4, 35.6, 34.3, 32.4, 22.9, 14.3 ppm; 31P NMR (162 MHz, CD2Cl2): d=
142.4 ppm; IR (film): n˜ =3066.3, 2954.4, 1633.4, 1539.9, 1432.9, 1326.8,
1230.4, 824.4 cmÀ1
; HRMS (ESI+): m/z calcd for C47H41N2NaO5P:
767.26508 [M+Na]+; found: 767.26290.
N1-(4-Butylphenyl)-N2-(3-((11bS)-dinaphtho[2,1-d:1’,2’-f]
G
N1-(4-Butylphenyl)-N2-(3-((((11bR)-2,6-dimethyldinaphtho[2,1-d:1’,2’-f]-
A
ACHTUNGERTN[NUNG 1,3,2]dioxaphosphepin-4-yl)oxy)methyl)phenyl)phthalamide 4r: The
À
pared according to the general procedure 2 starting from (S)-binol PCl
(0.253 g) and alcohol 3o (0.300 g) in the presence of Et3N (0.30 mL). Pu-
rification by flash chromatography on silica gel (CH2Cl2 and then 98:2 to
95:5 CH2Cl2/Et2O) gave the product as a white solid. Yield: 0.277 g
(52%); m.p. 130–1438C; [a]2D0 =+150.7 (c=1.0 in CH2Cl2); 1H NMR
product was prepared according to the general procedure 1 starting from
À
(R)-3,3’-dimethyl-binol PCl (0.283 g) and alcohol 3r (0.300 g) in the
presence of Et3N (0.32 mL). Purification by flash chromatography on
silica gel (8:2 CH2Cl2/n-hexane, then CH2Cl2, then 98:2 to 9:1 CH2Cl2/
Et2O) gave the product as a white solid. Yield: 0.260 g (47%); m.p. 129–
(400 MHz, CD2Cl2): d=9.01 (s, 1H), 8.04 (d, 3J
(d, 3J(H,H)=8.2 Hz, 1H), 7.93 (d, 3J(H,H)=8.6 Hz, 2H), 7.78 (d, 3J-
(H,H)=7.6 Hz, 1H), 7.57 (d, 3J(H,H)=8.8 Hz, 1H), 7.54 (d, 3J
(H,H)=
8.4 Hz, 2H), 7.50–7.40 (m, 6H), 7.37–7.23 (m, 5H), 7.16 (d, 3J
(H,H)=
8.4 Hz, 2H), 7.01 (m, 3H), 6.37 (t, 3J(H,H)=5.5 Hz, 1H), 3.60 (q, 3J-
(H,H)=6.9 Hz, 2H), 2.83 (t, 3J(H,H)=7.0 Hz, 2H), 2.58 (t, 3J
(H,H)=
7.6 Hz, 2H), 1.58 (m, 2H), 1.33 (m, 2H), 0.91 ppm (t, 3J
(H,H)=7.3 Hz,
(H,H)=8.8 Hz, 1H), 7.98
1338C; [a]2D0 =À322.5 (c=1.0 in CH2Cl2); 1H NMR (400 MHz, CD2Cl2):
3
A
U
d=8.94 (s, 1H), 8.59 (s, 1H), 7.87 (d, J
G
A
E
U
7.83 (d, 3J
1H), 7.52–7.47 (m, 5H), 7.42–7.35 (m, 2H), 7.26–7.15 (m, 5H), 7.10 (d,
3J(H,H)=8.2 Hz, 2H), 6.99 (d, 3J(H,H)=7.6 Hz, 1H), 4.95 (dd, 2J-
(H,H)=12.2 Hz, 3J(H,P)=8.2 Hz, 1H), 4.55 (dd, 2J(H,H)=12.2 Hz, 3J-
(H,P)=6.7 Hz, 1H), 2.60 (s, 3H), 2.54 (t, 3J
(H,H)=7.6 Hz, 2H), 2.51 (s,
3H), 1.50 (m, 2H), 1.30 (m, 2H), 0.90 ppm (t, 3J
(H,H)=7.3 Hz, 3H);
ACHTUNGTREN(NUGN H,H)=9.0 Hz, 1H), 7.81 (s, 1H), 7.65–7.61 (m, 2H), 7.54 (s,
AHCTUNGTRENNUNG
R
A
ACHTUNGTRENNUNG
A
E
U
A
R
ACHTUNGTRENNUNG
R
A
ACHTUNGTRENNUNG
3H); 13C NMR (100 MHz, CD2Cl2): d=170.3, 166.7, 152.4, 148.2, 147.5,
141.7, 139.8, 136.6, 135.5, 135.4, 133.4, 133.0, 132.3, 131.9, 131.2, 131.0,
130.8, 130.5, 129.7, 129.3, 128.0, 128.9, 128.3, 127.4, 127.3, 127.0, 126.9,
125.9, 125.7, 125.5, 124.8, 123.4, 122.3, 122.2, 121.4, 121.3, 120.6, 119.1,
119.0, 41.7, 35.7, 35.6, 34.3, 22.9, 14.3 ppm; 31P NMR (162 MHz, CD2Cl2):
d=145.4 ppm; IR (film): n˜ =3067.2, 2954.4, 1632.5, 1540.9, 1411.6, 1327.8,
ACHTUNGTRENNUNG
13C NMR (100 MHz, CD2Cl2): d=167.8, 167.6, 148.9, 147.5, 140.0, 138.9,
138.6, 136.1, 135.6, 135.5, 132.2, 132.0, 132.0, 131.6, 131.1, 130.9, 130.4,
129.5, 129.3, 129.2, 128.8, 128.2, 127.2, 127.1, 125.8, 125.6, 125.4, 124.6,
124.0, 123.2, 120.7, 120.2, 119.6, 66.9, 35.5, 34.2, 22.8, 18.1, 17.8, 14.3 ppm;
31P NMR (162 MHz, CD2Cl2): d=138.1 ppm; IR (film): n˜ =3283.2,
1224.6, 824.4 cmÀ1
;
HRMS (ESI+): m/z calcd for C46H39N2NaO5P:
3068.2, 2953.5, 1641.1, 1541.8, 1443.5, 1331.6, 1241.0, 905.4, 787.2 cmÀ1
;
753.24943 [M+Na]+; found: 753.24709.
HRMS (ESI+): m/z calcd for C47H41N2NaO5P: 767.26508 [M+Na]+;
N1-(4-Butylphenyl)-N2-(3-((11bS)-dinaphtho[2,1-d:1’,2’-f]
ACHTNUTRGNE[NUG 1,3,2]dioxa-
found: 767.26263.
A
N1-(4-Butylphenyl)-N2-(3-((((11bR)-2,6-dimethyldinaphtho[2,1-d:1’,2’-f]-
was prepared according to the general procedure 1 starting from (S)-
ACHTUNGERTN[NUNG 1,3,2]dioxaphosphepin-4-yl)oxy)methyl)benzyl)phthalamide 4s: The
À
binol PCl (0.183 g) and alcohol 3p (0.200 g) in the presence of Et3N
product was prepared according to the general procedure 2 starting from
À
(0.22 mL). Purification by flash chromatography on silica gel (CH2Cl2
and then 96:4 to 9:1 CH2Cl2/Et2O) gave the product as a white solid.
Yield: 0.235 g (65%); m.p. 113–1258C; [a]2D0 =+381.1 (c=1.0 in CH2Cl2);
(R)-3,3’-dimethyl-binol PCl (0.300 g) and alcohol 3s (0.300 g) in the
presence of Et3N (0.30 mL). Purification by flash chromatography on
silica gel (CH2Cl2 and then 98:2 CH2Cl2/Et2O) gave the product as a
white solid. Yield: 0.336 g (62%); m.p. 112–1208C; [a]2D0 =À326.4 (c=1.0
1H NMR (400 MHz, CD2Cl2): d=9.16 (s, 1H), 7.99 (d, 3J
ACHTUNGTRENNUNG
1H), 7.96 (d, 3J
7.5 Hz, 1H), 7.50 (d, J
(m, 5H), 7.18 (t, 3J
6.56 (t, 3J
3J
A
E
in CH2Cl2); 1H NMR (400 MHz, CD2Cl2): d=8.75 (s, 1H), 7.87 (d, 3J-
3
3
U
G
N
A
U
2H), 7.72 (d, 3J
4H), 7.25 (d, 3J
(H,H)=8.4 Hz, 1H), 6.90 (t, 3J
12.3 Hz, 3J
(H,P)=8.1 Hz, 1H), 4.59–4.46 (m, 3H), 2.59 (s, 3H), 2.57 (t,
3J
(H,H)=7.8 Hz, 3H), 2.48 (s, 3H), 1.57 (m, 2H), 1.34 (m, 2H),
0.92 ppm (t, 3J(H,H)=7.3 Hz, 3H); 13C NMR (100 MHz, CD2Cl2): d=
ACHTUNGTRENNUNG
A
U
ACHTUNGTRENNUNG
A
E
U
A
R
ACHTUNGTRENNUNG
7.6 Hz, 2H), 1.58 (m, 2H), 1.34 (m, 2H), 0.94–0.90 (m, 6H), 0.86 ppm (s,
3H); 13C NMR (100 MHz, CD2Cl2): d=170.4, 168.8, 147.8, 139.4, 136.7,
135.7, 135.3, 133.3, 133.0, 132.2, 131.6, 131.0, 130.7, 130.6, 130.5, 129.6,
129.1, 129.0, 128.0, 127.3, 127.2, 126.9, 125.7, 125.5, 124.6, 123.1, 122.2,
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
169.9, 167.0, 148.9, 147.5, 139.9, 138.8, 138.4, 136.3, 135.6, 135.0, 132.2,
132.0, 131.6, 131.0, 130.9, 130.5, 130.4, 129.5, 129.3, 128.7, 128.2, 127.8,
122.1, 121.4, 120.6, 72.4 (d, 2J
ACTHNUGRTENUNG(C,P)=5.4 Hz), 47.5, 36.9, 35.6, 34.3, 22.9,
22.7, 22.6, 14.3 ppm; 31P NMR (162 MHz, CD2Cl2): d=143.0 ppm; IR
(film): n˜ =3112.6, 3056.6, 2955.4, 1631.5, 1540.9, 1438.6, 1329.7, 1231.3,
825.4 cmÀ1; HRMS (ESI+): m/z calcd for C43H41N2NaO5P: 719.26508
[M+Na]+; found: 719.26346.
127.3, 127.2, 125.9, 125.6, 125.5, 124.6, 123.2, 120.6, 66.9 (d, 2J
ACHTUNGTRENNUNG(C,P)=
3.2 Hz), 44.4, 35.6, 34.3, 22.9, 18.0, 17.8, 14.3 ppm; 31P NMR (162 MHz,
CD2Cl2): d=138.2 ppm; IR (film): n˜ =3066.3, 2954.4, 1637.3, 1540.9,
1412.6, 1331.6, 1240.0, 905.4, 788.7 cmÀ1; HRMS (ESI+): m/z calcd for
C48H43N2NaO5P: 781.28073 [M+Na]+; found: 781.27897.
N1-(4-Butylphenyl)-N2-(2-(((11bS)-dinaphtho[2,1-d:1’,2’-f]
ACHTUNGTREN[NUNG 1,3,2]dioxa-
E
N1-(4-Butylphenyl)-N2-(3-(((11bS)-dinaphtho[2,1-d:1’,2’-f]
ACHTUNGTRENNUNG
ACHTUNGTREN[NUNG 1,3,2]dioxa-
prepared according to the general procedure 2 starting from (S)-binol
PCl (0.326 g) and alcohol 3q (0.400 g) in the presence of Et3N (0.39 mL).
Purification by flash chromatography on silica gel (CH2Cl2, then 95:5 to
9:1 CH2Cl2/EtOAc) gave the product as a white solid. Yield: 0.503 g
(71%); m.p. 125–1308C; [a]2D0 =+298.4 (c=1.0 in CH2Cl2); 1H NMR
phosphepin-4-yloxy)methyl)phenyl)-N1,N2-dimethylphthalamide 4a-Me:
À
The product was prepared according to the general procedure 1 starting
À
from (S)-binol PCl (0.242 g) and alcohol 3a-Me (0.297 g) in the presence
of Et3N (0.29 mL). Purification by flash chromatography on silica gel
(98:2 and then 9:1 CH2Cl2/EtOAc) gave the product as a white solid.
Yield: 0.343 g (66%); m.p. 117–1238C; [[a]2D0 =+268.0 (c=1.0 in
(400 MHz, CD2Cl2): d=9.23 (s, 1H), 8.00 (d, 3J
(d, 3J(H,H)=8.2 Hz, 1H), 7.89 (d, 3J(H,H)=8.8 Hz, 1H), 7.84 (d, 3J-
(H,H)=8.2 Hz, 1H), 7.69 (d, 3J(H,H)=7.7 Hz, 1H), 7.52 (d, 3J
(H,H)=
8.4 Hz, 2H), 7.48–7.43 (m, 2H), 7.40–7.34 (m, 2H), 7.31–7.26 (m, 6H),
7.25–7.17 (m, 5H), 7.11 (d, 3J(H,H)=8.4 Hz, 2H), 6.45 (t, 3J
(H,H)=
5.7 Hz, 1H), 5.01 (dd, 2J(H,H)=12.1 Hz, 3J
(H,P)=7.4 Hz, 1H), 4.84 (dd,
2J(H,H)=12.1 Hz, 3J(H,P)=7.8 Hz, 1H), 3.50–3.32 (m, 2H), 2.78 (td, 3J-
(H,H)=7.5 Hz, 3J(H,H)=1.7 Hz, 2H), 2.56 (t, 3J
(H,H)=7.6 Hz, 2H),
1.56 (m, 2H), 1.33 (m, 2H), 0.91 ppm (t, 3J
(H,H)=7.3 Hz, 3H);
ACHTUNGERTN(NUNG H,H)=8.8 Hz, 1H), 7.96
N
R
CH2Cl2); 1H NMR (400 MHz, CD2Cl2): d=8.04 (d, 3J
ACHTUNGTRENNUNG
A
E
U
1H), 7.97 (d, 3J
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
U
6H), 2.50 (t, 3J
ACHTNUGETRNNU(G H,H)=6.7 Hz, 2H), 1.51 (m, 2H), 1.31 (m, 2H),
A
U
0.90 ppm (m, 3H); 13C NMR (100 MHz, CD2Cl2): d=170.7, 170.5, 149.2,
148.1, 145.5, 142.9, 141.8, 139.0, 137.3, 133.4, 133.1, 132.2, 131.7, 131.1,
130.8, 129.5, 129.4, 129.0, 129.0, 128.8, 128.1, 127.3, 127.0, 126.9, 125.9,
A
R
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
Chem. Eur. J. 2012, 18, 1383 – 1400
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1397

L. Pignataro, U. Piarulli, C. Gennari et al.
125.7, 125.6, 124.6, 123.2, 122.3, 122.1, 66.7 (d, 2J
(C,P)=4.4 Hz), 37.9,
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General procedure for asymmetric hydrogenations under atmospheric
pressure:: Each ligand (0.0042 mmol, 0.022 equiv) was weighed and
placed in one of seven oven-dried glass test tubes equipped with stirrer
bars and Schlenk apparatus and subjected to three vacuum/nitrogen
cycles. A solution of [Rh
(cod)2BF4] (0.9 mL, 0.001909 mmol, 2.12 mm,
[13] For a review on this approach, see: M. T. Reetz, Angew. Chem.
2008, 120, 2592–2626; Angew. Chem. Int. Ed. 2008, 47, 2556–2588.
[14] For an alternative, non-supramolecular approach, see: L. Pignataro,
0.01 equiv) in CH2Cl2 was added to each tube and the mixtures were
stirred for 10 min under nitrogen. A solution of the substrate in CH2Cl2
(1 mL, 0.1909 mmol, 0.1909m, 1 equiv) was finally added to each tube,
followed by 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 conversion and ee determination (see the Supporting Information).
ˇ
B. Lynikaite, R. Colombo, S. Carboni, M. Krupicka, U. Piarulli, C.
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General procedure for the asymmetric hydrogenation reaction at higher
than atmospheric pressure: A Parr multireactor was employed that al-
lowed six reactions to be performed in parallel under hydrogen pressure.
The selected ligands (0.0042 mmol, 0.022 equiv) were weighed in special
glass vials. The vials were purged with nitrogen and a solution of [Rh-
ACHTUNGTRENNUNG(cod)2BF4] in CH2Cl2 (0.9 mL, 0.001909 mmol, 2.12 mm, 0.01 equiv) was
added to each vial. After 10 min, a solution of the substrate in CH2Cl2
(1 mL, 0.1909 mmol, 0.1909m, 1 equiv) was added followed by CH2Cl2
(6.1 mL), and the vials were placed in their respective autoclaves and
purged three times with hydrogen at the selected pressure. The reactions
were stirred overnight at room temperature under 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.P. thanks
Milan University for a postdoctoral fellowship (ꢄAssegno di ricerca’).
M.C. thanks the MIUR (FIRB ꢄFuturo in Ricercaꢂ RBFR088ITV) for a
postdoctoral fellowship and financial support.
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ˇ
1398
www.chemeurj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 1383 – 1400

Rhodium-Catalyzed Asymmetric Hydrogenation of Olefins
FULL PAPER
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Chem. Eur. J. 2012, 18, 1383 – 1400
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1399

L. Pignataro, U. Piarulli, C. Gennari et al.
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Received: June 30, 2011
Published online: December 28, 2011
1400
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Chem. Eur. J. 2012, 18, 1383 – 1400