Combination of a binaphthol-derived phosphite and a C1-symmetric phosphinamine generates heteroleptic catalysts in Rh- and Pd-mediated reactions

Article abstract of DOI:10.1039/b908167d

Heteroleptic complexes, formed selectively by using a 1: 1 combination of a σ-donor and a π-acceptor ligand, are involved in Rh- and Pd-catalysed reactions.

Full text of DOI:10.1039/b908167d

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Combination of a binaphthol-derived phosphite and a C1-symmetric
phosphinamine generates heteroleptic catalysts in Rh- and Pd-mediated
reactionswz
Luca Pignataro,ab Benita Lynikaite,a Raffaele Colombo,a Stefano Carboni,b
Martin Krupicka,c Umberto Piarulli*b and Cesare Gennari*a
Received (in Cambridge, UK) 23rd April 2009, Accepted 11th May 2009
First published as an Advance Article on the web 21st May 2009
DOI: 10.1039/b908167d
Heteroleptic complexes, formed selectively by using a 1 : 1
combination of a r-donor and a p-acceptor ligand, are involved
in Rh- and Pd-catalysed reactions.
statistical value (2 : 1 : 1). For example, Feringa and Minnaard
reported that up to 91% of the heterocomplex is formed by
mixing Rh(acac)(C2H4)2 with two different monodentate
phosphoramidites.8b In these cases, the preferential formation
of heteroleptic catalysts from two monodentate ligands is
probably favoured by weak interactions, such as van der
Waals, p-stacking or dipole–dipole interactions.
In recent years, monodentate phosphorus ligands (e.g. phosphites,1
phosphonites,2 phosphoramidites3 and phosphinamines4)
have held the stage in asymmetric catalysis.5 In addition to
their outstanding activity and selectivity, comparable or even
superior to those of bidentate ligands, the convenient, fast and
practical preparation from commercially available materials
underlines their potential for industrial applications.6 Further-
more, the modular nature of all these ligands allows the
synthesis of a wide variety of representatives, thereby making
a combinatorial approach possible. In 2002–3, an important
breakthrough in this area was made independently by the
groups of Reetz7 and Feringa,8 who used a binary mixture of
chiral monodentate P-ligands in several asymmetric rhodium-
catalysed reactions. By mixing two ligands (La and Lb) in the
presence of Rh, three species can be formed: RhLaLa, RhLbLb
(homocomplexes), and RhLaLb (heterocomplex). Once n
different ligands have been prepared, not only are n different
catalyst systems accessible (homocombinations), but also
[n(n + 1)/2 ꢀ n] additional catalysts in the form of the respective
heterocombinations. The heterocombination is often more
reactive and more (regio-, diastereo- and enantio-) selective
than either of the two homocombinations.9 Moreover, under
thermodynamic control (fast and reversible ligand exchange)
the heterocomplex : homocomplexes ratios usually exceed the
The ideal case would constitute an equilibrium completely
in favour of the heterocomplex [RhLaLb] because then only a
single well-defined catalyst would exist in the reaction, and the
undesired competition of the less selective homocomplexes
would be avoided. We were intrigued by the remarkable
selectivities reported for the mixtures of chiral ligands
(binol-derived phosphites, phosphonites and phosphoramidites)
with achiral phosphines.9,10 In particular, the 1 : 1 mixture of a
chiral phosphite with an achiral phosphine was reported to
induce reversal of the enantioselectivity in the Rh-catalysed
hydrogenation of N-acetamido acrylate (compared to the
chiral phosphite alone).7c,9 The only possible explanation for
this peculiar behaviour is the selective formation of the
phosphite–phosphine Rh-heterocomplex, favoured by electro-
nically matching one s-donor ligand (phosphine) and
one p-acceptor ligand (phosphite). DFT calculations at the
B3LYP/SDD level of theory11 were performed (eqn (1))
and showed that the phosphite–phosphine rhodium hetero-
complex is more stable than the two homocomplexes by
5.11 kcal molꢀ1
.
a Dipartimento di Chimica Organica e Industriale, Centro
Interdipartimentale C.I.S.I., Universita` degli Studi di Milano,
Via G. Venezian 21, 20133 Milano, Italy.
E-mail: cesare.gennari@unimi.it; Fax: +39 02 5031 4072;
Tel: +39 02 5031 4091
ð1Þ
b
`
Dipartimento di Scienze Chimiche e Ambientali, Universita
Moreover, when Rh(acac)(C2H4)2 was added to a 1 : 1
mixture of PPh3 (1) and binaphthyl phenyl phosphite (S)-2a,
a quite clean heterocomplex (3a) was formed with cis dis-
position of the two P-ligands and heterocomplex : homocomplexes
ratio = 94 : 6 (Fig. 1, 2JP,P = 85 Hz; 1JRh,phosphite = 318 Hz;
1JRh,phosphine = 182 Hz).
dell’Insubria, via Valleggio 11, 22100 Como, Italy.
E-mail: umberto.piarulli@uninsubria.it; Fax: +39 031 238 6444;
Tel: +39 031 238 6449
c Laboratory of Computational Chemistry, Institute of Chemistry,
´
Slovak Academy of Sciences, Du´bravska cesta 9, 84538 Bratislava,
Slovakia
w This article is part of a ChemComm ‘Catalysis in Organic Synthesis’
web-theme issue showcasing high quality research in organic chem-
istry. Please see our website to access the other papers in this issue
(http://www.rsc.org/chemcomm/organicwebtheme2009).
z Electronic supplementary information (ESI) available: Experimental
procedures, characterisation data for all new compounds, complexa-
tion experiments (along with copies of 31P- and 1H-NMR spectra), full
screening of the ligands in the Rh- and Pd-catalysed reactions, and
details of the DFT calculations. See DOI: 10.1039/b908167d
As enantiomerically pure chiral phosphines are not easy to
synthesize, we were wondering whether the phosphine ligand
could be substituted by another s-donor phosphorus ligand,
still retaining the thermodynamic preference for the formation
of the Rh-heterocomplex. For this reason, we turned our
attention to chiral phosphinamines,4 which are easy to prepare
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This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 3539–3541 | 3539

Complexation studies were then performed by means of
31P-NMR, using Rh(acac)(C2H4)2 as the rhodium source.
Uneventfully, the homocombinations of phosphites and of
C1-symmetric phosphinamines displayed two doublets, due
to the P–Rh coupling, which correspond to the mono-
[LRh(acac)(C2H4)] and bis-ligated [L2Rh(acac)] complexes,
depending on the L : Rh ratio. In contrast, in the case of the
C2-symmetric phosphinamine (4a) only the doublet of the
mono-ligated species [LRh(acac)(C2H4)] was observed, even
in the presence of excess ligand (a singlet signal of the non-
coordinated ligand appeared). This is probably due to the
steric repulsion between the bulky ligands, which prevents
them from occupying two adjacent coordination sites [only a
cis complex can form with Rh(acac)(C2H4)2].
The formation of the Rh-heterocomplexes was then
investigated by adding Rh(acac)(C2H4)2 (1 equiv.) to a
solution of phosphite 2b and
a phosphinamine ligand
Fig. 1 31P-NMR spectrum of the heterocomplex 3a, formed by the
1 : 1 : 1 mixture of Rh(acac)(C2H4)2, PPh3 (1) and binol-derived
phosphite (S)-2a. A small doublet due to the phosphite homocomplex
[Rh(acac)(2a)2] is evident at 150.5 ppm.
(1 equiv. each) in CD2Cl2. When C1-symmetric phosphin-
amine ligands (4b–e) were employed, the cis-heterocomplexes
were formed with selectivities ranging from moderate
(70%) to excellent ( Z 99%). For example, the 31P-NMR
spectrum of the heterocomplex 3b formed from
phosphite (R)-2b and phosphinamine (R)-4b displayed a
enantiomerically pure, and have 31P-NMR spectral properties
fairly similar to those of phosphines, thus reflecting a similar
electronic situation.
2
heterocomplex : homocomplexes ratio = 99 : 1 (Fig. 3, JP,P
= 84 Hz; 1JRh,phosphite = 310 Hz; 1JRh,phosphinamine = 193 Hz).
A similar selectivity in favour of the heterocomplex (99%) was
observed also using Rh(COD)2BF4 as the rhodium source
(see the ESIz). When the C2-symmetric phosphinamine ligand
(4a) was used, no selective formation of the heterocomplex
was observed.
DFT calculations at the B3LYP/SDD level of theory11
were performed (eqn (2)) and showed that the phosphite–
phosphinamine rhodium heterocomplex is more stable than
the two homocomplexes by 11.29 kcal molꢀ1. We synthesized
a library of enantiomerically pure phosphites1 (2a–d, Fig. 2)
and phosphinamines4 (4a–e), reacting in the latter case Ph2PCl
with a number of C2-symmetric secondary amines and
C1-symmetric secondary and primary amines.
The homo- and heterocombinations of phosphites (2a–d)
and of the C1-symmetric phosphinamines (4b–e) were
then screened in the rhodium-catalysed hydrogenation of
methyl 2-acetamidoacrylate and N-(1-phenylvinyl)acetamide
(Scheme 1, Table 1). The phosphinamines behaved poorly
in this reaction, providing N-acetylalanine methyl ester and
N-(1-phenylethyl)acetamide with moderate conversions and
low enantiomeric excesses (see, for example, entries 2, 3, 5, 6).
Remarkably, the 1 : 1 combination of binol-derived phosphite
(R)-2b and phosphinamine (R)-4b induced reversal of the
ð2Þ
Fig. 3 31P-NMR spectrum of the heterocomplex 3b, formed by the
1 : 1 : 1 mixture of Rh(acac)(C2H4)2, binol-derived phosphite (R)-2b
and phosphinamine (R)-4b.
Fig. 2 Library of phosphites (2a–d) and phosphinamines (4a–e).
3540 | Chem. Commun., 2009, 3539–3541
ꢁc
This journal is The Royal Society of Chemistry 2009

Table 2 Selected results from the screening (homo- and hetero-
combinations) of phosphites (2a–d) and C1-symmetric phosphinamines
(4b–e) in the palladium-catalysed asymmetric allylic substitution of
rac-1,3-diphenyl-3-acetoxyprop-1-ene with dimethyl malonatea
Scheme 1 Rhodium-catalysed asymmetric hydrogenation of methyl
2-acetamidoacrylate and N-(1-phenylvinyl)acetamide.
Entry
Ligands
Conv. (%)
e.e. (%) (R,S)
Homocombinations
1
2
3
(R)-2b
(R)-4b
(S)-4b
100
100
100
58 (S)
68 (R)
68 (S)
Table 1 Selected results from the screening (homo- and hetero-
combinations) of phosphites (2a–d) and C1-symmetric phosphin-
amines (4b–e) in the rhodium-catalysed asymmetric hydrogenation
of methyl 2-acetamidoacrylate and N-(1-phenylvinyl)acetamidea
Heterocombinations
4
5
(R)-2b/(R)-4b
(R)-2b/(S)-4b
100
100
69 (S)
69 (S)
a
Entry
R
Ligands
Conv. (%)
e.e. (%) (R,S)
Reaction conditions: ligand (0.0311 mmol) or mixture of ligands
(0.0155 mmol each), [Pd(allyl)Cl]2 (0.0077 mmol), rac-1,3-diphenyl-3-
acetoxyprop-1-ene (0.51 mmol), dimethyl malonate (1.5 mmol),
N,O-bis(trimethylsilyl)acetamide (BSA) (1.5 mmol), a pinch of AcOK,
Homocombinations
1
2
3
4
5
6
COOMe
COOMe
COOMe
Ph
Ph
Ph
(R)-2b
(R)-4b
(S)-4b
(R)-2b
(R)-4b
(S)-4b
100
52
57
100
83
74
96 (S)
12 (S)
12 (R)
92 (S)
7 (R)
1
CH2Cl2 (2.0 ml), RT, 1 h. Conversions were determined by H-NMR
analysis of the crude reaction mixtures, while e.e.’s were determined
by HPLC equipped with a chiral column (CHIRALCEL OD-H,
hexane–isopropanol 99 : 1, flow rate 0.3 ml minꢀ1, 250 nm, see
the ESIz).
7 (S)
Heterocombinations
7
8
9
10
COOMe
COOMe
Ph
(R)-2b/(R)-4b
(R)-2b/(S)-4b
(R)-2b/(R)-4b
(R)-2b/(S)-4b
87
48
99
96
60 (R)
40 (R)
57 (R)
38 (R)
Ph
generates heteroleptic catalysts in Rh- and Pd-mediated
reactions.
a
Reaction conditions: ligand (0.0154 mmol) or mixture of ligands
(0.0077 mmol each), Rh(COD)2BF4 (0.007 mmol), substrate
(0.7 mmol), CH2Cl2 (8.0 ml), RT, 16 h. Substrate = methyl 2-acetamido-
acrylate: H2 (1 bar); Substrate = N-(1-phenylvinyl)acetamide: H2 (5 bar).
Conversions and e.e.’s were determined by GC equipped with a chiral
capillary column (MEGADEX DACTBSb, diacetyl-t-butylsilyl-b-cyclo-
dextrin, see the ESIz).
We thank the European Commission [RTN Network
(R)Evolutionary Catalysis MRTN-CT-2006-035866] for
financial support and for predoctoral fellowships (to B. Lynikaite
and M. Krupicka). L. Pignataro gratefully acknowledges
the Universita degli Studi dell’Insubria for a postdoctoral
fellowship (assegno di ricerca).
Notes and references
enantioselectivity in the hydrogenation of methyl 2-acetamido-
acrylate (60% e.e., R, entry 7), compared to both the
phosphite (96% e.e., S, entry 1) and the phosphinamine alone
(12% e.e., S, entry 2)! A similar behaviour was also
observed in the hydrogenation of N-(1-phenylvinyl)acetamide
(cf. entries 4–6 and 9–10). This is clearly the sign
that a heteroleptic catalyst is active in the hydrogenation
reaction.
Unfortunately, contrary to the literature precedents9 and
our own expectations, in these reactions the heteroleptic
catalyst induced a lower rate and a diminished enantiomeric
excess compared to the phosphite homocomplex.
1 M. T. Reetz and G. Mehler, Angew. Chem., Int. Ed., 2000, 39,
3889.
2 (a) M. T. Reetz and T. Sell, Tetrahedron Lett., 2000, 41, 6333;
(b) C. Claver, E. Fernandez, A. Gillon, K. Heslop, D. J. Hyett,
A. Martorell, A. G. Orpen and P. G. Pringle, Chem. Commun.,
2000, 961.
3 M. van den Berg, A. J. Minnaard, E. P. Schudde, J. Van Esch, A.
H. M. de Vries, J. G. de Vries and B. L. Feringa, J. Am. Chem.
Soc., 2000, 122, 11539.
4 L. Palais, I. S. Mikhel, C. Bournaud, L. Micouin, C. A. Falciola,
M. Vuagnoux-d’Augustin, S. Rosset, G. Bernardinelli and
A. Alexakis, Angew. Chem., Int. Ed., 2007, 46, 7462.
5 T. Jerphagnon, J.-L. Renaud and C. Bruneau, Tetrahedron:
Asymmetry, 2004, 15, 2101, and references therein.
6 (a) J. G. De Vries and L. Lefort, Chem.–Eur. J., 2006, 12, 4722, and
The 1 : 1 combination of binol-derived phosphite (R)-2b and
phosphinamine (R)-4b induced a peculiar stereochemical
outcome also in the palladium-catalysed asymmetric allylic
substitution of rac-1,3-diphenyl-3-acetoxyprop-1-ene with
dimethyl malonate12 (Scheme 2, Table 2, 69% e.e., S, entry 4),
compared to both the phosphite (58% e.e., S, entry 1) and the
phosphinamine alone (68% e.e., R, entry 2).
references therein; (b) C. Jakel and R. Paciello, Chem. Rev., 2006,
106, 2912.
¨
7 (a) M. T. Reetz, T. Sell, A. Meiswinkel and G. Mehler, patent
application DE20021047633 (application date 11 October 2002);
(b) M. T. Reetz, T. Sell, A. Meiswinkel and G. Mehler, Angew.
Chem., Int. Ed., 2003, 42, 790; (c) M. T. Reetz and G. Mehler,
Tetrahedron Lett., 2003, 44, 4593.
8 (a) D. Pena, A. J. Minnaard, J. A. F. Boogers, A. H. M. de Vries,
J. G. de Vries and B. L. Feringa, Org. Biomol. Chem., 2003, 1,
1087; (b) A. Duursma, R. Hoen, J. Schuppan, R. Hulst,
A. J. Minnaard and B. L. Feringa, Org. Lett., 2003, 5, 3111.
9 M. T. Reetz, Angew. Chem., Int. Ed., 2008, 47, 2556, and references
therein.
In summary, we have shown that the binaphthol-derived
phosphite : C1-symmetric phosphinamine ligand combination
10 P.-A. R. Breuil, F. W. Patureau and J. N. H. Reek, Angew. Chem.,
Int. Ed., 2009, 48, 2162.
11 A. D. Becke, J. Chem. Phys., 1993, 98, 5648.
12 (a) M. Dieguez, O. Pamies and C. Claver, J. Org. Chem., 2005, 70,
´
3363; (b) S. Deerenberg, H. S. Schrekker, G. P. F. van Strijdonck,
P. C. J. Kamer, P. W. N. M. van Leeuwen, J. Fraanje and
K. Goubitz, J. Org. Chem., 2000, 65, 4810.
Scheme 2 Palladium-catalysed asymmetric allylic substitution of
rac-1,3-diphenyl-3-acetoxyprop-1-ene with dimethyl malonate.
ꢁc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 3539–3541 | 3541