Asymmetric palladium-catalyzed benzylic nucleophilic substitution: High enantioselectivity with the DUPHOS family ligands

Article abstract of DOI:10.1016/j.tetasy.2005.01.032

The asymmetric palladium-catalyzed benzylic reaction of 1-(2-naphthyl)ethyl acetate and its 6-methoxy substituted analogue with dimethyl malonate anion led to substitution products with up to 90% ee when the iPr-DUPHOS chiral ligand was used.

Full text of DOI:10.1016/j.tetasy.2005.01.032

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1183–1187
Asymmetric palladium-catalyzed benzylic
nucleophilic substitution: high enantioselectivity with the
DUPHOS family ligands
*
Martine Assie, Jean-Yves Legros and Jean-Claude Fiaud
*
´
´ ´ ´ ´
Laboratoire de Catalyse Moleculaire associe au C.N.R.S., UMR 8075, Institut de Chimie Moleculaire et des Materiauxd’Orsay,
Batiment 420, Universite de Paris-Sud, F91405 Orsay Cedex, France
ˆ
´
Received 16 December 2004; accepted 21 January 2005
Abstract—The asymmetric palladium-catalyzed benzylic reaction of 1-(2-naphthyl)ethyl acetate and its 6-methoxy substituted ana-
logue with dimethyl malonate anion led to substitution products with up to 90% ee when the iPr-DUPHOS chiral ligand was used.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
with the dimethylmalonate anion as nucleophile.3,8 Poor
enantioselectivities (<35%) were recorded with bidentate
chiral BINAP, PROPHOS, DIOP, CHIRAPHOS or
BDPP11 ligands.3 Me-DUPHOS11 gave a much better
result (up to 74% ee) but to the detriment of the che-
moselectivity of the reaction and hence the chemical
yield of the substitution product. The major pathway
in this case was a base-promoted elimination leading
to vinylnaphthalene.8
Palladium-catalyzed nucleophilic substitution on benz-
ylic esters has been developed in our laboratory over
the past decade (Eq. 1).1–9 A condensed aromatic system
(Ar = naphthyl, phenanthryl, quinolyl, isoquinolyl, ben-
zofuryl, benzothienyl) is needed to obtain a satisfactory
yield of substitution product with a catalytic system
including Pd(dba)2 [dba = bis(dibenzylidene)acetone]
and a diphosphine ligand. Recently, the reactivity of
benzyl methyl carbonate (Ar = Ph, R1 = H, R2 = OMe)
was disclosed using a quite different catalyst [Pd-
(g3-C3H5)(COD)ÆBF4 in combination with dppf as the
diphosphine ligand].10 However, no reaction on racemic
chiral esters (R1 = Me) has been reported.
Herein we report that the substituents of the DUPHOS
phospholane rings have a notable influence on the
enantioselectivity of the reaction. An enantiomeric ex-
cess of 90% was reached with iPr-DUPHOS using
slightly modified reaction conditions.
R1
Nucleophile
[Pd] cat.
R1
2. Results and discussion
Ar
OCOR2
Ar
Nu
The following chiral diphosphine ligands were tested in
the optimized experimental conditions precedently
determined (Fig. 1).8 The (R,R)-Et ferroTANEꢁ was
chosen because of its similarity in terms of bite angle
with the dppf ligands used by Kuwano et al.10 Since
the Trost ligands have proven to be very efficient in a
great number and variety of asymmetric allylic alkyl-
ation (AAA) reactions,12 we decided to study their effi-
ciency in our asymmetric benzylic alkylation reaction.
The substitution was conducted on two substrates: 1-
(2-naphthyl)ethyl acetate 1a and its 6-methoxy analogue
1b (Eq. 2). The results are shown in Table 1.
R1 = H, Me; R2 = Me,OMe
ð1Þ
Nucleophile = MCH(CO2Me)2, HCO2M (Nu = H),
amine
The asymmetric version of this reaction was realized on
racemic substrates (Ar = 1- or 2-naphthyl, R1 = Me)
*
Corresponding authors. Tel.: +33 1 69 15 47 36; fax: +33 1 69 15 46
80; e-mail addresses: jylegros@icmo.u-psud.fr; fiaud@icmo.u-psud.fr
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.01.032

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M. Assie et al. / Tetrahedron: Asymmetry 16 (2005) 1183–1187
1184
R
Trost (phenyl or naphthyl) ligands lead to palladium
iPr
complexes, which are totally unreactive in the benzylic
substitution. Substrates 1a and 1b were recovered from
the reaction mixture after 48 h stirring at 70 ꢂC. The
inertness of these diphosphines may result from a strong
steric hindrance between the chiral palladium(0) com-
plex and the aromatic substrate, preventing the oxida-
tive addition step, the first step of the catalytic
transformation.
P
P
P
P
R
iPr
iPr
R
R
iPr
R,R
R = Me: ( )-Me-DUPHOS
R,R)
(
-iPr-DUPHOS
R,R
R = Et: ( )-Et-DUPHOS
With all reactive phosphines, with the exception of
(R,R)-Me-DUPHOS, a mixture of three reaction prod-
ucts was obtained: the expected substituted chiral malo-
nate 2, the vinylnaphthalene 4 and a third compound 3
resulting from demethoxycarbonylation of 2 (Krapcho
reaction).13 We checked that 3a was obtained from 2a
in the presence of KOAc (produced during the catalytic
process) in DMSO at 70 ꢂC. This transformation has
precedent under these conditions although at higher
(115–140 ꢂC) temperatures.14 Demethoxycarbonylation
was previously observed by us in palladium-catalyzed
benzylic substitutions on benzofuran- and benzothio-
phene-based substrates9 and also by others during the
course of Pd-catalyzed reactions.15 Unfortunately, we
did not succeed in the analytical resolution of 3 and
hence unable to check that malonate 2 and decarboxyl-
ation product 3 had the same enantiomeric composition
(it should be the case if the former was the precursor of
the latter). Due to the formation of side product 3, the
selectivity of the reaction (substitution vs elimination)
was determined as the (2 + 3)/4 ratio.
Et
P
Fe
Et
Et
Et
®
R,R
(
)-Et-FerroTANE
O
O
R
NH HN
PPh2 Ph2P
R
R
R
R,R
R = H: ( )-Trost phenyl ligand
(R,R)-Et-ferroTANEꢁ gave a good selectivity in favour
of the substitution product (92/8 from 1a and 80/20 from
1b), but with poor to moderate enantioselectivity (35%
and 16%, respectively, entries 1 and 5). In contrast,
R,R
R = (CH)4: ( )-Trost naphthyl ligand
Figure 1. Chiral ligands.
CHE2
CH2E
OAc
(i)
+
+
R
R
R
R
ð2Þ
2
3
4
1
a
b
R = H; R = OMe; E = CO2Me
(i) 2 eq. KCHE2, 2 mol% Pd(dba)2, 3 mol% chiral ligand, DMSO, 70 ˚C, 48h.
Table 1. Effect of the chiral ligand structure (Eq. 2)
Entry
Chiral ligand
Substrate
2
3 (%)
4 (%)
Substitution/elimination ratio
Yield (%)
Ee (%)
1
2
3
4
5
6
7
8
(R,R)-Et-FerroTANEꢁ
(R,R)-Me-DUPHOS
(R,R)-Et-DUPHOS
(R,R)-iPr-DUPHOS
(R,R)-Et-FerroTANEꢁ
(R,R)-Me-DUPHOS
(R,R)-Et-DUPHOS
(R,R)-iPr-DUPHOS
1a
1a
1a
1a
1b
1b
1b
1b
51
37
2
35 (S)
66 (S)
S)
14
0
6
61
92/8
38/62
40/60
48/52
80/20
18/82
27/73
5
774 (
10
19
0
48
44
30
53
16
17
2
80 (R)
16 (S)
78 (S)
80 (S)
R)
18
75
5
877 (
59
4243/57
4

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M. Assie et al. / Tetrahedron: Asymmetry 16 (2005) 1183–1187
1185
CHE2
CH2E
OAc
(i)
+
MeO
+
MeO
ð3Þ
MeO
MeO
2b
3b
4b
1b
R,R
(i) 2 eq. KCHE2, 2 mol% Pd(dba)2, 3 mol% ( )-iPr-DUPHOS, DMSO, 48h.
DUPHOS ligands led to vinylnaphthalene 4 as the ma-
jor product and to a better asymmetric induction from
methoxy-substituted acetate 1b than from the parent
substrate 1a. Enantiomeric excess as well as the substitu-
tion/elimination ratio increased with steric hindrance on
phospholane rings of the chiral ligand. 1-(2-Naphthyl)-
ethyl acetate 1a gave substitution product 2a in 80%
ee using a Pd/(R,R)-iPr-DUPHOS catalyst (entry 4).
Methoxy analogue 1b was more prone to elimination,
but 2b was obtained with 87% ee in 24% isolated yield
with the same catalyst (entry 8). These results show an
interesting electronic effect in this substitution. Obten-
tion of opposite enantiomers of product 2 using DU-
PHOS ligands with the same (R,R) descriptors (entries
2, 3 vs 4 and 6, 7 vs 8) resulted only from the application
of the CIP sequential rules: (R,R)-iPr-DUPHOS has an
inverted stereochemistry compare to Me or Et analogues
(see Fig. 1).
strate 1b/catalyst solution. The modification of the malo-
nate concentration indirectly affected the efficiency of
the interconversion of the two cationic g3-benzylic inter-
mediates, which are involved in the expression of the
asymmetric induction (Fig. 2).8 The major elimination
pathway observed with DUPHOS ligands may also con-
tribute to the high enantioselectivity of the substitution
reaction. The two cationic diastereomeric g3-benzylic
intermediates may eliminate at different rates; one pre-
dominantly giving substitution product 2 and the other
being more prone to elimination. This kinetic resolution
phenomenon enhanced the asymmetric induction of the
substitution at the expense of the yield.8
3. Conclusion
In conclusion, optimization of the DUPHOS ligand
structure and of experimental conditions allowed us to
reach an enantiomeric excess of 90% for dimethyl 2-[1-
(2-6-methoxynaphthyl)ethyl]propanedioate 2b in the
palladium-catalyzed benzylic nucleophilic substitution.
Work is currently in progress in order to understand
the factors governing the substitution/elimination selec-
tivity and the electronic effect of the substrate on the
asymmetric induction.
The effect of temperature on the reaction selectivities
was then briefly examined on substrate 1b (Eq. 3, Table
2). Decreasing or increasing the oil bath temperature
from 20 ꢂC resulted in both cases to a slight decrease
in the enantiomeric excess of the product 2b. As ex-
pected, demethoxycarbonylation was favoured at higher
temperatures, leading to a very poor isolated yield (4%)
of 2b at 90 ꢂC. The substitution/elimination ratio was
also affected by the temperature, the former process
becoming the major pathway at 90 ꢂC.
4. Experimental
A reaction temperature of 70 ꢂC seemed to be a good
compromise between enantioselectivity and isolated
yield of the substitution product 2. Although the elimi-
nation was slightly preferred at this temperature, vinyl-
naphthalene 4 could be easily recycled to benzylic
substrate 1.
1H and 13C NMR spectra were recorded on a Bruker
AC-250 MHz spectrometer in CDCl3 with tetrameth-
ylsilane as an internal standard. Coupling constants
are reported in hertz. All reactions involving palladium
catalysis were carried out using Schlenk techniques un-
der an argon atmosphere. Dimethylsulfoxide (DMSO)
was dried over CaH2 and distilled prior to use. Pd(dba)2
(dba denotes dibenzylideneacetone)16 and acetates 1a
and 1b2 were prepared according to reported
procedures.
Finally, an asymmetric induction of 90% was obtained
conducting the palladium-catalyzed substitution with a
slow addition (over 6.5 h) of the nucleophile to the sub-
Table 2. Effect of the temperature and addition conditions (Eq. 3)
Entry
T (ꢂC)
2b
3b (%)
4b (%)
Substitution/elimination ratio
Yield (%)
Ee (%)
1a
2a
3b
4a
50
70
70
90
26
24
11
4
82
87
90
74
0
7
45
42
64
27
37/63
43/57
15/85
55/45
0
29
a Rapid addition of the substrate/catalyst solution to the nucleophile solution.
b Slow addition of the nucleophile solution to the substrate/catalyst solution.

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M. Assie et al. / Tetrahedron: Asymmetry 16 (2005) 1183–1187
1186
CHE2
KOAc
(R)-3b
MeO
KCHE2
(R)-2b
- KOAc
Pd(II)L*
OAc
OAc
- Pd(0)L*
Pd(0)L*
MeO
MeO
(S)-1b
- Pd(0)L*
- Pd(0)L*
Pd(0)L*
MeO
4b
OAc
Pd(II)L*
OAc
Pd(0)L*
KCHE2
MeO
MeO
- KOAc
(R)-1b
CHE2
- Pd(0)L*
KOAc
(S)-3b
MeO
(S)-2b
Figure 2. Asymmetric induction process.
2
A typical experimental procedure is as follows (Table 1,
entry 8): acetate 1b (244 mg, 1 mmol) in 1 mL of DMSO
was added under an argon to a mixture of Pd(dba)2
3J = 7.9 Hz, CH2–CO2CH3); 2.73 (dd, 1H, J = 15.2Hz
and 3J = 7.3 Hz, CH2–CO2CH3); 3.38–3.52(m, 1H,
CH3–CH); 3.60 (s, 3H, OCH3); 7.34–7.48 (m, 3H, Ar);
7.65 (s, 1H, Ar); 7.76–7.80 (m, 3H, Ar). 13C NMR
(CDCl3, 62.9 MHz): 172.9, 143.2, 133.7, 132.4, 128.3,
127.8, 127.7, 126.1, 125.6, 125.5, 125.0, 51.7, 42.7,
36.7, 21.9.
(11.5 mg,
0.02mmol)
and
( R,R)-iPr-DUPHOS
(12.6 mg, 0.03 mmol) in 1 mL of DMSO. After 0.25 h
stirring, this solution was added to a suspension of
potassium dimethylmalonate (340 mg, 2mmol, from
tBuOK and dimethylmalonate) in 2mL of DMSO.
The reaction mixture was stirred at 70 ꢂC for 48 h, then
diluted with ethyl acetate (20 mL) and the organic phase
washed with 2 · 10 mL of water. The aqueous phases
were extracted with ethyl acetate (2 · 10 mL) and the
combined organic phases were dried over MgSO4 and
concentrated. The crude product was purified by flash
chromatography (silica, heptane/ethyl acetate: 90/10
then 80/20) to give 2b (75 mg, 24%, ee = 87%), 3b
(17 mg, 7%) and 4b (78 mg, 42%). The two enantiomers
of 2b were resolved by HPLC analysis with a chiral sta-
tionary-phase column Chiracel OD-H [hexane/isopropa-
nol 99/1, 0.5 mL minÀ1, t = 34.4 min (enantiomer R),
37.2min (enantiomer S)].
Methyl 3-(6-methoxy-naphthalen-2-yl)butanoate 3b was
obtained as a white solid. Mp: 69 ꢂC. Rf 0.28 (heptane/
EtOAc 90/10). IR (CHCl3): mmax 1732cm À1; mp:
69 ꢂC. HRMS: calcd for C16H18O3 258.1250. Found:
258.1249. 1H NMR (CDCl3, 250 MHz): 1,37 (d, 3H,
3J = 6.8 Hz, CH3–CH); 2.61 (dd, H, J = 15.1 Hz and
2
2
3J = 8.3 Hz, CH2–CO2CH3); 2.71 (dd, H, J = 15.1 Hz
and 3J = 6.8 Hz, CH2–CO2CH3); 3.31–3.49 (m, 1H,
CH3–CH); 3.61 (s, 3H, OCH3); 3.90 (s, 3H, OCH3);
3
7.10–7.15 (m, 2H, Ar); 7.32 (d, 1H, Ar, J = 8.3 Hz);
7.57 (s, 1H, Ar); 7.68 (d, 2H, Ar, 3J = 8.3 Hz). 13C
NMR (CDCl3, 62.9 MHz): 173.0, 157.4, 140.9, 133.4,
129.2, 129.1, 127.1, 126.0, 124.8, 118.8, 105.6, 55.3,
51.6, 42.8, 36.4, 21.9.
Compounds 2a and 2b have already been characterized.2
2-Vinylnaphthalene 4a and 6-methoxy-2-vinylnaphtha-
lene 4b are commercially available products.
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(CHCl3): mmax 1732cm À1. HRMS: calcd for C15H16O3
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2
3J = 6.7 Hz, CH3–CH); 2.62 (dd, 1H, J = 15.2Hz and

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