Dendritic phosphoramidite ligands for Rh-catalyzed [2+2+2] cycloaddition reactions: Unprecedented enhancement of enantiodiscrimination

Article abstract of DOI:10.1039/c2cc32992a

Phosphorus dendrimers containing terminal phosphoramidite ligands have been found to be highly effective and recoverable catalysts for the rhodium(i) catalyzed [2+2+2] cycloaddition reactions. A strong positive dendritic effect is observed both in the activity and enantiodiscrimination leading to axially chiral biaryl compounds.

Full text of DOI:10.1039/c2cc32992a

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COMMUNICATION
Dendritic phosphoramidite ligands for Rh-catalyzed [2+2+2]
cycloaddition reactions: unprecedented enhancement of
enantiodiscriminationw
a
b
b
a
Lı
´
dia Garcia,ab Anna Roglans, Regis Laurent, Jean-Pierre Majoral, Anna Pla-Quintana*
´
and Anne-Marie Caminade*b
Received 26th April 2012, Accepted 31st July 2012
DOI: 10.1039/c2cc32992a
Phosphorus dendrimers containing terminal phosphoramidite
ligands have been found to be highly effective and recoverable
catalysts for the rhodium(I) catalyzed [2+2+2] cycloaddition
reactions. A strong positive dendritic effect is observed both in
the activity and enantiodiscrimination leading to axially chiral
biaryl compounds.
The metal-catalyzed [2+2+2] cycloaddition reaction of three
alkynes is a powerful method for the construction of poly-
substituted benzenes.1 A plethora of studies have shown the
utility of this method in total synthesis.2 Among the catalytic
systems used, the combination of rhodium with bidentate
phosphines has led to excellent results.3 Rovis et al. have
successfully applied phosphoramidite ligands in rhodium catalyzed
[2+2+2] cycloadditions of alkynes and alkenylisocyanates
achieving moderate regioselectivities but good enantio-
selectivities.4 However, to the best of our knowledge, the use
of the chiral monodentate phosphoramidites, which have
shown excellent properties in combination with rhodium, for
instance in hydrogenation reactions,5 has never been described
in the [2+2+2] cycloaddition of three alkynes.
Scheme 1 Synthesis of phosphorus dendrimers from generation 1 to
3 containing terminal phosphoramidite ligands.
surface of dendrimers nor the use of dendrimers as ligands for
the [2+2+2] cycloaddition reaction of alkynes have apparently
been reported, and this has inspired the present study.
New phosphorus dendrimers G1–G3 (Scheme 1 and Fig. 1)
were prepared from dendrimers bearing 12, 24 or 48-CHO
end groups respectively. Imine formation with n-butylamine,
followed by NaBH4 reduction afforded the secondary amine to
which the chlorophosphite derived from (S)-BINOL was added
furnishing the desired phosphoramidite capped dendrimers
(Scheme 1).
Dendrimers, nano-objects with astonishing applications in
areas ranging from biology to materials science,6 have also
been successfully applied in catalysis.7 The precise incorporation of
ligands in the different domains of the dendrimeric structure has
enabled the complexation of metals leading to good catalysts in
a number of reactions. Phosphoramidite ligands have been
immobilized at the core8 or used as the focal point of a
dendrimer wedge,9 and their rhodium complexes have been
successfully used in asymmetric hydrogenations. However,
neither the immobilization of phosphoramidite ligands at the
In this way, a new family of phosphorus dendrimers
containing terminal phosphoramidite ligands was obtained
(Fig. 1). Both monomeric and a branch ligand (M and B in
Fig. 1), which serve as references for the catalytic results, were
prepared following the synthetic strategy outlined in Scheme 1
but starting from p-anisaldehyde and a branch grown on
p-anisaldehyde, respectively.
a
´
Departament de Quımica, Universitat de Girona, Facultat de
Ciencies, Campus de Montilivi, s/n, E-17071 Girona, Spain.
`
E-mail: anna.plaq@udg.edu; Fax: +34 972 41 81 50;
Tel: +34 972 41 82 75
The catalytic activity conferred by dendritic ligands to
rhodium was first evaluated in the partial intramolecular
cycloaddition between an N-tosyl tethered 1,6 diyne 1 and
phenylacetylene 2, and compared to that of the commercially
available phosphoramidite (S)-MonoPhos and the model
monomeric ligand M (Table 1). The cycloaddition was performed
in refluxing toluene using the dimer [Rh(C2H4)2Cl]2 as the
b Laboratoire de Chimie de Coordination, CNRS,
205 route de Narbonne, 31077 Toulouse Cedex 4, France.
E-mail: caminade@lcc-toulouse.fr; Fax: +33 561 55 30 03;
Tel: +33 561 33 31 25
w Electronic supplementary information (ESI) available: Synthesis
and characterization of dendrimers; procedures for catalysis and
complete catalytic results. See DOI: 10.1039/c2cc32992a
c
9248 Chem. Commun., 2012, 48, 9248–9250
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Fig. 1 Dendrimers G1, G2 and G3, monomer M and branch B models synthesized for the present study.
Table 1 [2+2+2] cycloaddition reaction between N-tosyl 1,6-diyne 1
and phenylacetylene 2a
Table 2 [2+2+2] cycloaddition reaction between N-tosyl 1,6-diyne 1
and 2-methoxynaphthalene alkynyl derivatives 4a
Entry
Run
L* (% mol)/ligand units
Yieldb (%)
1
2
3
4
5
6
7
1
1
1
1
(S)-MonoPhos (5)/1
M (5)/1
33
61
93
89
96
94
95
Entry
R
L* (% mol)/ligand units Yieldb (%) eec (%)
1
2
3
4
5
6
7
8
P(O)(OEt)2 (S)-MonoPhos (5)/1
P(O)(OEt)2 M (5)/1
P(O)(OEt)2 B (2.5)/2
P(O)(OEt)2 G1 (0.4)/12
P(O)(OEt)2 G2 (0.2)/24
P(O)(OEt)2 G3 (0.1)/48
CO2iPr
CO2iPr
CO2iPr
CO2 Pr
46
49
32
99
97
98
11
13
70
74
77
14
o5
3
98
96
97
2
G1 (0.4)/12
G2 (0.2)/24
G3 (0.1)/48
G3 (0.1)/48
G3 (0.1)/48
1
2c
3c
a
i
Conditions:
1
(0.15 mmol), 2 (0.75 mmol), [Rh(C2H4)2Cl]2
b
M (5)/1
B (2.5)/2
G1 (0.4)/12
G2 (0.2)/24
G3 (0.1)/48
(2.5 mol%) and L* (0.1–5 mol%) in PhMe at 110 1C for 2 h. Yield
of the isolated product. The catalytic system was recovered on
8
c
9
10
11
81
88
90
hexane precipitation and filtered and reused without further manipulation.
Ts = p-toluenesulfonyl.
i
CO2 Pr
a
Conditions:
(2.5 mol%) and L* (0.1–5 mol%) in PhMe at room temperature
4
(0.10 mmol), 1 (0.15 mmol), [Rh(C2H4)2Cl]2
b
c
metal source loaded to give a Rh/phosphoramidite ratio equal
to one in all cases.
for 48 h. Yield of the isolated product. Enantiomeric excess
determined by chiral HPLC.
Considerably enhanced catalytic activity was observed when
using dendrimers G1–G3 as ligands as compared to both the model
monomer M and (S)-MonoPhos. Indeed, almost quantitative yields
were achieved by using any of the three dendrimer ligands and,
most remarkably, the catalytic system could be recovered by
precipitation in hexane followed by filtration and reused up to
three times without reduction in the yield.10 Recyclability and reuse
of a catalytic system active in the [2+2+2] cycloaddition reaction
have been only sparingly reported.11
In order to explore the possibility that the enhanced enantioselec-
tivity arose from a cooperative effect of two proximal centres, the
catalytic activity of the branch model B was also evaluated. To our
surprise, decreased yield and enantioselectivity were obtained
(entry 3, Table 2) ruling out this possibility and pointing to an
effect of the packing of the dendrimeric structure or a large
number of chiral ligands in close proximity as being possible
explanations for the dendritic effect observed. To the best of our
knowledge, this is the strongest dendritic effect on the stereo-
selectivity reported in the literature.9b,13
These promising preliminary results encouraged us to check
the capacity for enantiodiscrimination of the catalytic system.
The reaction of choice was the [2+2+2] cycloaddition towards
axially chiral biaryl phosphorus compounds described by Tanaka
et al. using a Rh(I)–BINAP catalytic system.12 Diyne 1 was treated
with the alkynyl phosphonate derived from 2-methoxy-
naphthalene under the conditions described above but at room
temperature (entries 1–6, Table 2). We were pleased to find
that G1, G2 and G3 enabled almost quantitative conversion of
the substrate into the product with excellent enantioselectivity,
showing a strong dendritic effect, since both (S)-MonoPhos
and the monomer model gave only residual enantioselectivity.
Furthermore, [2+2+2] cycloaddition of alkynyl phosphonate
quantitatively occurred with excellent enantioselectivity in
three consecutive runs using the phosphoramidite dendrimeric
ligands (Fig. 2).
We tested the generality of enantioselective biaryl synthesis
using a 2-methoxynaphthalene derived alkynylester as the
cycloaddition partner.14 Good yields and excellent enantio-
selectivities were again achieved in a process with a strong
dendritic effect (entries 7–11, Table 2).
c
This journal is The Royal Society of Chemistry 2012
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Fig. 2 Enantiomeric excesses achieved in the cycloaddition of 1 and 4
(R = P(O)(OEt)2) using (S)-MonoPhos, M and dendrimeric ligands
G1–G3 in three successive runs (yields above 97% in all runs).
In conclusion, we have described a new highly active and
recyclable catalytic system based on the combination of rhodium(I)
and phosphoramidite capped phosphorus dendrimers for the
stereoselective [2+2+2] cycloaddition reaction of alkynes. An
unprecedented dendrimer enhancement of the stereoselectivity
has been observed showing the importance of the dendrimer
scaffold not only in the recovery and recyclability of the catalyst
but also most importantly in the activity and enantioinduction
of the phosphoramidite-based catalysts.
Further investigation with regard to the scope of this new
catalytic system in [2+2+2] cycloaddition reaction is currently
in progress.
We would like to thank the Spanish MICINN (project
CTQ2011-23121), the Generalitat de Catalunya (project
2009SGR637) and the CNRS (France) for their financial
support. L.G. thanks the Universitat de Girona (UdG) for a
predoctoral fellowship.
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10 Recyclability and reuse were checked for the three dendrimers with
similar results.
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c
9250 Chem. Commun., 2012, 48, 9248–9250
This journal is The Royal Society of Chemistry 2012