Cavitand supported tetraphosphine: Cyclodextrin offers a useful platform for Suzuki-Miyaura cross-coupling

Article abstract of DOI:10.1039/c1cc12241j

The cyclodextrin-tetraphosphine hybrid coined α-Cytep allows turnover numbers up to 340000000000 and turnover frequencies up to 1000000000 h ^-1 to be reached in Suzuki-Miyaura reactions. These exceptional figures are clearly linked to the outst

Full text of DOI:10.1039/c1cc12241j

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COMMUNICATION
Cavitand supported tetraphosphine: cyclodextrin offers a useful platform
for Suzuki-Miyaura cross-couplingwzy
Elena Zaborova, Julia Deschamp, Samuel Guieu, Yves Bleriot, Giovanni Poli,
´
Mickael Menand, David Madec,* Guillaume Prestat* and Matthieu Sollogoub*
¨
´
Received 18th April 2011, Accepted 20th May 2011
DOI: 10.1039/c1cc12241j
The cyclodextrin-tetraphosphine hybrid coined a-Cytep allows
turnover numbers up to 340 000 000 000 and turnover frequencies
up to 1 000 000 000 hꢀ1 to be reached in Suzuki–Miyaura
reactions. These exceptional figures are clearly linked to the
outstanding longevity of the reactive species induced by the
ligand a-Cytep and illustrates the rising potential of cyclodextrins
in catalytic applications.
bring an added value in the efficiency of the Suzuki-Miyaura
coupling.12 Furthermore, although cavity-shaped tetraphosphines
derived from calixarenes,13 resorcinarenes14 or cyclodextrins15
(CDs) have been synthesized, none of them has been probed in
a low-loading catalytic system to the best of our knowledge. In
addition, we have shown that perbenzylated CDs regio-
selectively functionalized with two phosphines could serve as
pseudo-enantiomeric platforms in enantioselective catalysis.16
Furthermore, a benzylated CD platform would provide high
steric hindrance that might prevent the agglomeration of Pd0
into inactive species.17 It was hence tempting and logical to
study the potential of a CD-tetraphosphine hybrid in ultra-low
loading catalysis. CD-appended multiphosphines are easy to
synthesize, as first demonstrated by Matt and Armspach, who
developed a tetraphosphine-CD called a-TEPHOS that was
used to obtain tetra-metalated CDs.15 However, we reasoned
that hemilabile alkoxy groups remaining on the CD primary
rim could be detrimental to efficiency due to parasital
oxygen coordination. Accordingly, we designed the dideoxy-
tetraphosphine a-cyclodextrine a-Cytep (Fig. 1).
Since the original discovery and development of Pd-catalyzed
coupling reactions that led to the recent chemistry Nobel Prize
awarded to Heck, Suzuki and Negishi, a great deal of attention
has been focused on the development of catalytic systems that
would improve efficiency of the cross-coupling reactions.
The practicality of the Suzuki-Miyaura reaction made it
particularly popular in the pharmaceutical and chemical
industries for which cost is a fundamental parameter.1 The
use of Herrmann-Beller palladacycles2 or NHC-based ligands
allows very high turn-over numbers (TONs) to be reached in
Suzuki-Miyaura couplings,3,4 and the search for catalytic
systems allowing ultra-low loadings is still an ongoing field.5
However, Buchwald’s bulky monodentate dialkyl-biaryl
phosphines are indubitably the current reference in terms of
reactivity and efficiency,6 the main reason for this increased
reactivity of the monodentate bulky phosphine being the
access to underligated reactive Pd species.7 Disclosure of the
tetradentate ligand Tedicyp by Doucet and Santelli8 displaying
exceptionally high TONs, was therefore a somewhat paradoxical
breakthrough in this area. This discovery prompted the
examination of various carbocyclic (cyclohexane,9 cyclo-
pentane,8 cyclopropane10) or ferrocenyl-based11 multiphosphines
in low catalyst loading Suzuki-Miyaura couplings. Recently,
a-Cytep was easily synthesized in 28% overall yield from
native a-CD. An in-house perbenzylation/bis-debenzylation
sequence afforded diol 1,18 which was dehydroxylated through
LAH reduction of the corresponding dimesylate to afford
compound 2.19 Regioselective acetolysis of the primary benzyloxy
groups20 to yield tetracetate 3 followed by deacetylation gave
tetrol 4 in 76% yield. Subsequent mesylation afforded tetra-
mesylate 5 which upon treatment with an excess of in situ
formed lithium diphenylphosphide furnished a-Cytep in 61%
yield. The tetraphosphine a-Cytep was protected and stored as
its tetra borane complex 6 by simple treatment with BH3ꢁTHF.
The free ligand was regenerated using diethylamine right
before its use in catalytic reactions. (Scheme 1)
Matt and Semeril showed that cavity-shaped ligands could
´
´
UPMC Univ Paris 06, Sorbonne Universites, Institut Universitaire de
France, Institut Parisien de Chimie Moleculaire (UMR CNRS 7201),
´
FR 2769, C. 181, 4 place Jussieu, 75005 Paris, France.
E-mail: matthieu.sollogoub@upmc.fr; Tel: 33 1 44 27 61 63
w In memory of David Gin, a great Glycoscientist.
z This article is part of the ChemComm ‘Glycochemistry and glyco-
biology’ web themed issue.
y Electronic supplementary information (ESI) available: Experimental
details of the synthesis of a-Cytep, spectroscopic analysis of the
products, experimental details of the catalytic reaction. See DOI:
10.1039/c1cc12241j
Fig. 1 Structure of a-Cytep.
c
9206 Chem. Commun., 2011, 47, 9206–9208
This journal is The Royal Society of Chemistry 2011

Table 2 Pd-catalysed cross-coupling variation of the aryl halides
Entrya
Y
R
Yield, %b TOF, hꢀ1 TON
1
2
3
4
MeCO
MeO
Me
H
H
H
H
73 (70)c
19
38
1 400 000
380 000
670 000
790 000
240 000 000
60 000 000
110 000 000
130 000 000
F3C
40c
5d
H
10
950
160 000
a
The reactions were carried out in xylenes (0.25 M) at 120 1C under
argon in presence of the appropriate aryl-halide (1 mmol), phenyl-
boronic acid (2 mmol), K2CO3 (2 mmol) and [PdCl(Z3-C3H5)]2/
Scheme 1 Synthesis of a-Cytep from a-cyclodextrin (a-CD).
a-Cytep: 1/2 (catalyst/substrate: 3 ꢂ 10ꢀ9) for 7 days. Determined
b
We then studied the a-Cytep catalyst’s scope and limitations
in Suzuki-Miyaura coupling at low loadings. We applied the
same conditions as those reported for the Tedicyp tetraphosphine,
using [PdCl(Z3-C3H5)]2 as a palladium(0) precursor together
with a-Cytep, in a 1 : 2 ratio but at a slightly lower (3 ꢂ 10ꢀ7%)
loading than the lowest used with Tedicyp (10ꢀ6%),8 and
K2CO3 in refluxing xylenes for 7 days. Variation of the
substitution pattern of the arylboronic acids did not induce
any significant changes of reactivity, TONs remaining above
108, with TOF around 106 hꢀ1 (Table 1). A survey of aryl
halides showed more drastic reactivity changes (Table 2). As
expected, electron-deficient aryl bromides gave better TONs
(4108) than the electron-rich ones including the 4-MeO and
4-Me substituted aryl bromides, which were nevertheless still
coupled with 6 ꢂ 107 and 108 TONs respectively.
by 1H NMR analysis by using butadiene sulfone as external standard.
c
d
Isolated yield. Catalyst/Substrate = 10ꢀ6
.
catalyst/substrate ratio (entries 3–5, Table 3) and observed a
steady increase of the yield with a constant 106 hꢀ1 TOF
indicative of a remarkable lasting of the catalyst. Those very
encouraging results prompted us to further investigate this
ability of our catalyst by lowering its loading to a 10ꢀ12 catalyst/
substrate ratio, which led to vertiginous 340 000 000 000 TON
and 1 000 000 000 hꢀ1 TOF (entries 1–8, Table 3). As ligand-free
Suzuki-Miyaura couplings have been also reported,22 blank
experiments were carried out. Predictably, no coupling
product was observed in the absence of both palladium and
a-Cytep (entry 9). When only a-Cytep was omitted, reaction
occurred even at extremely low loadings (entries 10–12,
Table 3). However, the presence of a-Cytep in the coupling
process dramatically increases the observed TON when
decreasing the loading (entry 12 vs. 5). Replacement of
K2CO3 and [PdCl(Z3-C3H5)]2 by AcOK and Pd(OAc)2
respectively did not improve the transformation (entries 14
and 15). As for Tedicyp, the 31P NMR spectrum of the
Those results compare well with the best reported TONs
(9.7 ꢂ 107) for Suzuki-Miyaura cross-coupling reactions
obtained with Tedicyp8 and Buchwald’s phosphines.6 However,
this catalytic system is not as efficient as Buchwald’s ligand for
aryl chlorides. These observations suggest that these high
TONs and TOFs are not due to a facilitated oxidative addition
step, but as mentioned before, longevity of the catalyst
can be the key to reaching high TONs.21 We therefore
monitored the progress of the reaction between phenylboronic
acid and 4-bromoacetophenone over a 7-day period at 3 ꢂ 10ꢀ9
ꢀ
[Pd(Z3-C3H5)(a-Cytep)]+ BF4 complex synthesized using a
known protocol23 was recorded. It led to a similar observation:
the presence of broad peaks exclusively around 25 ppm,
indicative of phosphorous bound to the metal, in the
220–350 K temperature range, which also suggests a fast
coordination–dissociation process of the four phosphines of
the ligand.
Table 1 Pd-catalysed cross-coupling variation of the boronic acids
In conclusion, we have synthesized and assessed a new
CD-tetraphosphine hybrid coined a-Cytep which displayed
exceptionally high TONs and TOFs in the Suzuki-Miyaura
coupling. This property is clearly associated with its ability to
super-stabilize the catalytic species over an exceptionally long
period of time via multiple dynamic binding of the metal. We
have hence shown that CDs can serve as interesting platforms
for catalysis.24 Indeed, a distinct feature of those platforms is
their steric bulk and their relative flexibility allowing access to
a wide variety of conformations, both of which contrast with
the smaller rings studied so far in this area. It seems that our
sugar-based platform is hence well suited to stabilize the
catalytic species over time. In view of our results, other
cavitand-based tetraphosphines should now be tested in low-
loading catalysis.
Entrya
X
Yield, %b
TOF, hꢀ1
TON
1
2
3
4
5
6
7
8
H
4-F
4-Cl
4-BuO
4-tBu
4-Me
3-Me
2-Me
73%
58%
98%
47%
41%
46%
79%
38%
1 400 000
1 100 000
2 000 000
930 000
810 000
890 000
240 000 000
190 000 000
330 000 000
160 000 000
140 000 000
150 000 000
260 000 000
130 000 000
1 500 000
750 000
a
The reactions were carried out in xylenes (0.25 M) at 120 1C under
argon in presence of 4-AcC6H4Br (1 mmol), the appropriate
ArylB(OH)2 (2 mmol), K2CO3 (2 mmol) and [PdCl(Z3-C3H5)]2/
a-Cytep: 1/2 (catalyst/substrate: 3 ꢂ 10ꢀ9) for 7 days. Determined
b
by 1H NMR analysis by using butadiene sulfone as external standard.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 9206–9208 9207

Table 3 Pd-catalysed cross-coupling variation of catalyst loading
Entry
Ligand
c/s
Conversiond (yield),e %
t, d
TOF, hꢀ1
TON
1a
2a
3a
4a
5a
6a
7a
8a
9
10
11
12
13
14b
15c
a-Cytep
a-Cytep
a-Cytep
a-Cytep
a-Cytep
a-Cytep
a-Cytep
a-Cytep
No Pd
—
—
—
—
a-Cytep
a-Cytep
10ꢀ3
100
64
1
2
2.5
4
7
7
10
14
14
1
2
7
6
1000
640 000
73 000 000
10ꢀ6
3800
1 200 000
1 200 000
1 400 000
12 000 000
25 000 000
1 000 000 000
—
3 ꢂ 10ꢀ9
3 ꢂ 10ꢀ9
3 ꢂ 10ꢀ9
3 ꢂ 10ꢀ10
10ꢀ10
22 (22)
35 (34)
84 (73)f
61 (59)
78 (59)
34 (34)
0
100
53
27 (21)
Traces
19 (17)
65 (63)
110 000 000
240 000 000
2 000 000 000
5 900 000 000
340 000 000 000
—
10ꢀ12
—
10ꢀ3
6
3000
420 000
—
370 000
1 250 000
1000
530 000
70 000 000
—
60 000 000
210 000 000
10ꢀ6
3 ꢂ 10ꢀ9
3 ꢂ 10ꢀ10
3 ꢂ 10ꢀ9
3 ꢂ 10ꢀ9
7
7
7
a
The reactions were carried out, at least twice, in xylenes (0.25 M) at 120 1C under argon in the presence of 4-AcC6H4Br (1 mmol), PhB(OH)2
(2 mmol), K2CO3 (2 mmol) and the appropriate amount of [PdCl(Z3-C3H5)]2/ a-Cytep: 1/2. See supporting information for details.y The reaction
b
was performed with AcOK as base. The reaction was performed with [Pd(OAc)2] as pre-catalyst. Determined by 1H NMR analysis of reaction
c
d
e
1
f
mixture samples, based on bromoacetophenone. Determined by H NMR analysis by using butadiene sulfone as external standard. Isolated
yield: 70%.
11 J.-C. Hierso, A. Fihri, R. Amardeil, P. Meunier, H. Doucet,
M. Santelli and B. Donnadieu, Organometallics, 2003, 22, 4490;
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c
9208 Chem. Commun., 2011, 47, 9206–9208
This journal is The Royal Society of Chemistry 2011