Palladium-catalysed asymmetric allylic alkylation in the presence of a chiral 'light fluorous' phosphine ligand

Article abstract of DOI:10.1039/b103074b

The easily accessible, enantiopure (R)-(+)-2-diarylphosphino-2′-alkoxy-1,1′-binaphthyl 1 bearing three fluorous ponytails is an efficient ligand in the palladium-catalysed asymmetric allylic substitution of 1,3-diphenylprop-2-enyl acetate affording chiral

Full text of DOI:10.1039/b103074b

Palladium-catalysed asymmetric allylic alkylation in the presence of a
chiral ‘light fluorous’ phosphine ligand
Marco Cavazzini,a Gianluca Pozzi,*a Silvio Quici,a David Maillardb and Denis Sinou*b
a Centro CNR Sintesi e Stereochimica di Speciali Sistemi Organici, via Golgi 19, 20133 Milano, Italy.
E-mail: gianluca.pozzi@unimi.it; Fax: +39 02 2663354; Tel: +39 02 2663354
b Laboratoire de Synthèse Asymétrique, UMR UCBL/CNRS 5622, Université Claude Bernard Lyon 1, 43,
boulevard du 11 novembre 1918, 69622 Villeurbanne, France.
E-mail: sinou@univ-lyon1.fr; Fax: +33 04 72448160; Tel: +33 04 72446263
Received (in Cambridge, UK) 4th April 2001, Accepted 23rd May 2001
First published as an Advance Article on the web 14th June 2001
The easily accessible, enantiopure (R)-(+)-2-diarylphos-
phino-2A-alkoxy-1,1A-binaphthyl 1 bearing three fluorous
ponytails is an efficient ligand in the palladium-catalysed
asymmetric allylic substitution of 1,3-diphenylprop-2-enyl
acetate affording chiral products of up to 87% ee.
Bis(4-methoxyphenyl)phosphonic acid 3, obtained from the
corresponding para-substituted aryl bromide 2 according to a
literature procedure,12 allowed the easy monophosphinylation
of the commercially available (R)-(2)-1,1A-bi(2-naphthol) bis-
(trifluoromethanesulfonate) (R)-(2)-4. This reaction was car-
ried out in the presence of equimolar amounts of Pd(OAc)2 and
1,4-bis(diphenylphosphino)butane (dppb) in DMSO at 100 °C.
Cleavage of the methoxy group of the phosphinyl derivative
(R)-(+)-5 with BBr3 in CH2Cl2 afforded the dihydroxy deriva-
tive (R)-(+)-6 in 99% yield, after recrystallisation from diethyl
ether. Subsequent hydrolysis of the remaining triflate group
with aqueous sodium hydroxide in a methanol–dioxane mixture
led to (R)-(+)-2-[bis(4-hydroxyphenyl)phosphinyl]-2A-hydr-
oxy-1,1A-binaphthyl (R)-(+)-7 in 91% yield. Three fluorous
ponytails were then introduced by reaction of the free hydroxy
groups of (R)-(+)-7 with 1H,1H-perfluorooctan-1-ol perfluor-
obutanesulfonate 8 in DMF, in the presence of caesium
carbonate.13 Phosphine oxide (R)-(+)-9 was obtained in 70%
yield after simple flash chromatography (eluent Et2O). Finally,
reduction with Cl3SiH in boiling toluene afforded pure (R)-
(+)-1 in 90% yield.
The advantages brought about by the use of CO2 (supercritical
or compressed) or fluorinated solvents in catalytic reactions are
well-documented.1,2 These novel reaction media offer the
possibility of cleaner technology for the chemical industry, and
might also promote reactions that are not attainable in common
organic solvents, along with selectivity improvements related to
the unique solvation environment.3 In both cases, good
solubility of the catalyst in the peculiar reaction medium is a
major requirement. To reach this goal, several ligands featuring
long-chain perfluoroalkyl substituents (‘fluorous ligands’) have
been synthesized,4 including a few examples of chiral com-
pounds.5 Indeed, the presence of long-chain perfluoroalkyl
substituents increases the affinity of an organometallic com-
pound both for CO2 and perfluorocarbons. In the latter case, an
increasing body of literature data indicates that only a fluorine
content of at least 60% can ensure the very high partition
coefficients required for the application of the original fluorous
biphase strategy.6 In order to circumvent this limitation, new
fluorous techniques have been recently proposed, based on the
recovery of fluorinated molecules by liquid–liquid or solid–
phase extraction.7 This makes ‘minimally’ or ‘light’ fluorous
reagents and catalysts (i.e. compounds with a fluorine content
below 60%) potentially useful for small-scale and discovery-
oriented research.8
The partition coefficients for (R)-(+)-1 between n-per-
fluorooctane and three organic solvents (CH2Cl2, toluene and
As phosphorous-based ligands are extensively used in
catalytic reactions, many efforts have been devoted to the
synthesis of their fluorous analogues.1,9 However, such enantio-
pure compounds are not easily available yet.10 Here we describe
the simple synthesis of a fluorous chiral phosphine, namely (R)-
(+)-2-{bis[4-(1H,1H-perfluorooctyloxy)phenyl]phosphino}-
2A-(1H,1H-perfluorooctyloxy)-1,1A-binaphthyl (R)-(+)-1, a new
member of this restricted family of compounds.†
Palladium-catalysed coupling of bis(aryl) phosphonic acids
with commercially available (R)- or (S)-1,1A-bi-2-naphthol
bis(trifluoromethanesulfonate) provides an easy access to
optically pure 2-(diphenylphosphino)-2A-alkoxy-1,1A-bina-
phthyls.11 Leitner and Franciò took advantage of this versatile
reaction in the synthesis of a chiral phosphine/phosphite ligand
bearing two –(CH2)2C6F13 ponytails, structurally similar to
(R,S)-BINAPHOS.10 The introduction of the perfluoroalkyl
substituents required the use of a properly functionalised
bis(aryl) phosphonic acid at an early stage of the synthesis. In
order to increase the flexibility of this approach, we decided to
postpone the introduction of perfluorinated residues. This
allows the insertion of the required perfluoroalkyl chains onto a
preformed ligand structure, thus increasing the number of
possible locations. The synthesis of enantiopure (R)-(+)-1 is
outlined in Scheme 1.
Scheme 1 Reagents and conditions: i, Mg, THF, reflux; ii, ClP(NEt2)2,
220 °C; iii, aqueous 36% HCl, 210 °C; iv, (R)-(2)-4, Pd(OAc)2, dppb,
diisopropylethylamine, DMSO, 100 °C; v, BBr3, CH2Cl2, 0 °C; vi, NaOH,
MeOH, dioxane, rt; vii, C7F15CH2OSO2C4F9 8, Cs2CO3, 100 °C; viii,
Cl3SiH, toluene, 110 °C.
1220
Chem. Commun., 2001, 1220–1221
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b103074b

When toluene was used as a solvent, the simple extraction of
the reaction mixture with n-perfluorooctane (2 3 5 ml) allowed
the complete removal of the fluorous ligand and of the
corresponding palladium complexes, as shown by the absence
of phosphine resonances in the 1H-NMR of the crude product.
As pointed out by Curran, this ease of separation together with
the possible use of standard reaction conditions could be helpful
in discovery-oriented synthesis and parallel synthesis.8 How-
ever, a drawback of this ‘light fluorous’ approach is the absence
of catalytic activity of the recovered fluorous palladium
complex. We are currently investigating this problem, which
seems to be due to the separation procedure followed. Indeed,
recyclability of a ‘light fluorous’ phosphine used in the same
reaction under classical fluorous biphase conditions was
feasible.14
Scheme 2 Reagents and conditions: Nucleophile (see Table 1), 2 eq.; BSA,
2 eq.; KOAc, 0.1 eq.; [Pd(h -C3H5)Cl]2, 2 mol%; (R)-(+)-1, 8 mol%.
3
CH3OH) were found to be 0.20, 0.23 and 7.42, respectively. As
expected, the new ligand shows a certain affinity for organic
solvents, due to the relatively low fluorine content of (R)-(+)-1
(52.4%) and to its aromatic backbone. This mixed behaviour
makes (R)-(+)-1 an ideal candidate for the application of ‘light
fluorous’ techniques. Palladium complexes of enantiopure
2-(diphenylphosphino)-2A-alkoxy-1,1A-binaphthyls (MOPs) cat-
alyse several asymmetric transformations.11 A number of
applications of related fluorous compounds could be thus
envisaged. It was previously shown that palladium(0)-catalysed
allylic substitution reactions can be conveniently performed
under fluorous biphase conditions, in the presence of a ‘light
fluorous’ triarylphosphine with a fluorine content of 57%.14 On
the other hand, chiral MOPs have been recently used for the
asymmetric allylic alkylation of 1,3-diphenylprop-2-enyl ace-
tate 10 in standard solvents (Scheme 2).15 We decided therefore
to investigate the potentiality of this new fluorous MOP (R)-
(+)-1 as a ligand in the same reaction. The results obtained are
summarized in Table 1.‡
We thank the Programme Galilée 1999 no. 99023 for
financial support.
Notes and references
† 1H-NMR (300 MHz, CDCl3): 4.16 (dt, J = 24.6 Hz, 12.6 Hz, 2H), 4.48
(dt, J = 13.1 Hz, 13.1 Hz, 4H), 6.72 (d, J = 8.4 Hz, 2H), 6.86–6.92 (m, 3H),
7.03 (dd, J = 7.1 Hz, 8.5 Hz, 2H), 7.06–7.12 (m, 1H), 7.17–7.35 (m, 6H),
7.41 (dd, J = 3.0 Hz, 8.5 Hz, 1H), 7.44–7.50 (m, 1H), 7.86–7.91 (m, 3H),
8.01 (d, J = 9.1 Hz, 1H); 13C-NMR (75.4 MHz, CDCl3): 65.5 (t, J = 27
Hz), 66.7 (t, J = 27 Hz), 105–120 (m, C7F15), 124.9–131.4, 133.4–136.4,
140.7, 141.1, 153.0, 158.0, 158.2; 31P-NMR (122 MHz, CDCl3): 215.5; mp
= 49 °C, [a]20 = +23.1 (c 0.3, CHCl3). Anal. Calcd. for C56H26F45O3P:
Table 1 Asymmetric allylic alkylation of 1,3-diphenylprop-2-enyl acetate
D
in benzotrifluoride
C, 41.17; H, 1.61; P, 1.90. Found: C, 40.56; H, 1.53; P, 2.19%.
‡ Reactions were run under nitrogen in Schlenk glassware. [Pd(C3H5)Cl]2
and the ligand (R)-(+)-1 was dissolved in 2 ml of solvent. After stirring for
40 min at rt, a solution of 10 in 2 ml of solvent was added. After 20 min, the
resulting solution was transferred into a reactor previously charged with
BSA, KOAc and the nucleophile dissolved in 4 ml of solvent. The reaction
mixture was stirred at the desired temperature for the time indicated in Table
1.
Yielda
(%)
Eea
(%)
Entry
Nucleophile
T/°C t/h
Conf.b
1
CH2(CO2Me)2
CH2(CO2Me)2
CH2(CO2Me)2
CH2(COCH3)2
MeCH(CO2Me)2
MeCH(CO2Me)2
AcNHCH(CO2Et)2
25
25
0
25
25
50
50
36
25
48
1
99
88
95
100
7
81
87
99
85
76
44
85
R
R
R
R
S
2c
3cd
4
5
6
7
48
48
25
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69
67
S
S
a Determined by HPLC analysis (column Chiralpak AD 0.46 3 25 cm).
b Determined by comparison with an authentic sample. c Reaction run in
toluene. d See ref. 15.
The reaction of 10 with dimethyl malonate using MOP (R)-
(+)-1 (8 mol%) and [Pd(C3H5)Cl]2 (2 mol%) in the presence of
bis(trimethylsilyl)acetamide (BSA, 2 eq.) and potassium acetate
(10.1 eq.) in benzotrifluoride (a standard solvent for ‘light
fluorous’ compounds) proceeded quantitatively at rt to give,
after 36 h, the corresponding alkylated product in 99% yield
with 81% ee (Table 1, entry 1). This value is quite close to the
value obtained using toluene as the solvent (Table 1, entry 2). It
is to be noticed that non-perfluorinated MOP gave the alkylated
product in 95% yield and 99% ee using toluene as the solvent
(Table 1, entry 3).
Next we investigated the asymmetric reaction with other
carbon nucleophiles. Reaction of 10 with acetylacetone gave the
product nearly quantitatively after 1 h with 85% ee (Table 1,
entry 4). Substituted dimethyl malonate gave lower chemical
yields. Dimethyl methylmalonate gave the alkylated product
with 69% yield and 44% ee at 50 °C (Table 1, entry 6), although
76% ee was obtained at rt, but in 7% yield (Table 1, entry 5).
Diethyl acetamidomalonate gave also the expected alkylated
compound in 67% yield with 85% ee (Table 1, entry 7).
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Chem. Commun., 2001, 1220–1221
1221