Enantioselective palladium-catalysed conjugate addition of arylsiloxanes

Article abstract of DOI:10.1039/b616969d

The complex formed from Pd(CH₃CN)₄(BF ₄)₂ and (R,R)-MeDUPHOS is a highly enantioselective catalyst for the asymmetric conjugate addition of aryltriethylsiloxanes to a variety of unsaturated ketones, lactones and

Full text of DOI:10.1039/b616969d

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Enantioselective palladium-catalysed conjugate addition of
arylsiloxanes{
Francesca Gini, Bart Hessen, Ben L. Feringa and Adriaan J. Minnaard*
Received (in Cambridge, UK) 21st November 2006, Accepted 9th January 2007
First published as an Advance Article on the web 18th January 2007
DOI: 10.1039/b616969d
desired 1,4-addition product 3a in 94% ee although the isolated
The complex formed from Pd(CH3CN)4(BF4)2 and
(R,R)-MeDUPHOS is a highly enantioselective catalyst for
the asymmetric conjugate addition of aryltriethylsiloxanes to a
variety of unsaturated ketones, lactones and lactams.
yield turned out to be only 30%. The corresponding Heck-type
product was not formed at all but by GC analysis considerable
amounts of cyclohexanone and phenol were detected again,
besides 3a. The palladium complex catalysed the disproportiona-
tion by reduction and oxidation of the starting material as shown
by the outcome of the reaction carried out in the absence of
PhSi(OEt)3: 60% conversion into phenol and cyclohexanone was
achieved after overnight reaction. The oxidation of 1a to phenol
using palladium complexes is well known,12 but the reduction of
a,b-unsaturated enones instead is rare.13
The asymmetric transition-metal catalysed conjugate addition of
organometallic reagents is of great importance for the formation of
enantiopure b-substituted carbonyl compounds.1 With respect to
the addition of aryl and alkenyl groups, the rhodium-catalysed
asymmetric addition of boronic acids pioneered by Hayashi and
Miyaura2 shows excellent enantioselectivities with a variety of
ligands.3 In studies based on earlier work of Miyaura et al.,4 our
group showed recently that the corresponding palladium-catalysed
addition of arylboronic acids provides a versatile alternative.5
As an alternative to boronic acids,6 organosilicon compounds
have attracted much attention in recent years due to their low
toxicity and high stability to both air and moisture. Especially
aryltriethoxysilanes are low-cost and can be readily prepared
nowadays in one step by a Barbier-type reaction of the
corresponding aryl bromide and tetraethoxysilane at room
temperature.7 In contrast to arylboronic acids,8 arylsiloxanes are
easily purified by distillation or chromatography. Transmetalation,
however, is considerably more difficult compared to arylboronic
reagents, requiring highly efficient catalysts.
The carbon–silicon bond of arylsiloxanes is known to be very
stable and this slows down the transmetalation step hence allowing
the side reaction to occur.14 Additives able to coordinate to Si can
increase the reactivity of arylsiloxanes. Fluoride is well known to
be an efficient activator. Among the fluoride sources tested the
most efficient one proved to be ZnF2.15 The addition of
2 equivalent to the reaction in a dioxane–water mixture (10 : 1)
at 100 uC gave full conversion in 2 h affording the desired product
3a in 70% isolated yield and 97% ee. The efficiency of ZnF2
compared to other fluoride sources might depend on its ability to
act as a double activator: F2 increases the reactivity of the
organosiloxane while Zn2+ coordinates to the oxygen of the
carbonyl group, thereby increasing the reactivity of the enone.
Despite this major improvement still around 10% of phenol and
cyclohexanone were observed by GC analysis.
The role of water according to the proposed catalytic cycle10a is
the hydrolysis of the Pd–C bond in the final step of the cycle
leading to the formation of the conjugate addition product and
regeneration of the active catalyst. A second role is the hydrolysis
of the aryltrialkoxysilane to the arylsilanol which is considered to
be the actual reagent.9e Variation of the reaction conditions led to
the following observation. When the reaction was carried out at
100 uC with a lower dioxane : water ratio (4 : 1), full conversion to
the conjugate addition product was achieved in 30 minutes with
, 5% of side products and an excellent ee of 98%. In this reaction
medium, even at a reaction temperature as low as 50 uC, and in the
presence of only 1 equiv. of ZnF2, the conjugate addition product
was obtained with complete enantioselectivity (. 99%) in 75%
isolated yield, virtually without side products16 (entry 1, Table 1).
The catalyst loading could be decreased to 2 mol% affording the
desired product in an overnight reaction without decrease in the ee.
The use of 5 mol% (R,R)-MeBPE (Scheme 1) afforded comparable
results but the conjugate addition product was obtained in 90% ee.
With these optimized conditions established, the scope of the
reaction was examined (Table 1, Scheme 2). The steric hindrance
of the arylsiloxane has an important influence on the reactivity,
A number of examples of rhodium-catalysed enantioselective
conjugate addition of aryl- and alkenylsilanes have been reported
in the literature.9 Both the groups of Miyaura and Denmark
reported achiral palladium complexes that catalyse the conjugate
addition of arylsiloxanes.10 The enantioselective addition of
aryltrifluorosilanes has been reported as well.11 The corresponding
enantioselective reaction using palladium(II) catalysts, however,
has been elusive until now.
Herein we report the highly enantioselective conjugate addition
of aryltriethoxysilanes using a Pd(II)–MeDUPHOS catalyst.
Initially, we studied the conjugate addition of phenyltriethylsi-
loxane 2a to 2-cyclohexenone 1a applying the conditions we
developed earlier for the conjugate addition of arylboronic acids:
5 mol% of Pd(CF3COO)2 and 5.5 mol% of (R,R)-MeDUPHOS in
dioxane–water (10 : 1) at 100 uC. After 24 h, 90% conversion of
starting material 1a into a mixture of cyclohexanone and phenol
was observed, without any traces of conjugate addition product.
To our delight, the use of Pd(CH3CN)4(BF4)2 instead afforded the
Stratingh Institute, University of Groningen, Nijenborgh 4, 9747 AG,
Groningen, The Netherlands. E-mail: A.J.Minnaard@rug.nl;
Fax: +31 503634296; Tel: +31 503634258
{ Electronic supplementary information (ESI) available: Detailed experi-
mental procedures, 1H- and 13C-NMR and analytical data for all
compounds reported. See DOI: 10.1039/b616969d
710 | Chem. Commun., 2007, 710–712
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Table 1 The use of substituted arylsiloxanes in the addition to
a,b-unsaturated compounds
Conv.b
Entrya Aryl siloxane Substrate (%)
Yieldc
(%) (3)
eed
(%)
1e
2g
3
2a
2b
2c
2d
2e
2f
2a
2a
2a
2a
2a
2a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1d
1e
1f
100
15
75f (3a) 99 (R)
nd (3b)
60 (3c)
64 (3d)
70 (3e)
70 (3f)
80 (3g)
84 (3h)
nd (3i)
20 (3i)
40 (3j)
60 (3k)
nd
100
100
100
100
100
100
40
100
100
100
96 (+)
98 (R)
95 (+)
96 (+)
90 (R)
99 (R)
90 (S)
88 (S)
78 (+)
94 (+)
Scheme 2 a,b-unsaturated compounds and arylsiloxanes investigated.
4e
5
6
7
8
9
Next, the scope of the reaction in terms of substrates was
investigated. 2-Cyclopentenone afforded full conversion exclusively
to the conjugate addition product with 90% ee. The reaction
carried out with 2-cycloheptenone and 2E-octenone in contrast
gave disappointing results: the main compound obtained with the
reaction conditions optimized for 1a was the corresponding
saturated ketone. All attempts to increase the ratio toward the
1,4-addition product failed and acyclic substrates in general gave
mainly conjugate reduction product.
10g
11
12
a
Reaction
conditions:
Pd(CH3CN)4(BF4)2
(5
mol%),
(R,R)-MeDUPHOS (5.5 mol%), dioxane : H2O 5 4 : 1, ZnF2 (1 eq.),
b
ArSi(OEt)3 (2 eq.), 50 uC, 18 h. By GC analysis with n-dodecane
as internal standard or by TLC analysis. After purification with
c
d
column chromatography. Determined by HPLC (see Experimental
e
Section). 5 h. The yield of this reaction is lowered due to the
f
Dihydropyridone 1c, an important building block for alkaloid
synthesis, showed excellent reactivity and afforded the 1,4-addition
product with complete enantioselectivity (entry 8).18 Lactone 1d
gave only 40% conversion when the reaction was carried out at
50 uC but increasing the temperature to 100 uC led to full
conversion and the same high enantioselectivity (entries 9 and 10).
Unfortunately, only 20% yield of 3i was obtained.19 Enone 1e,
prepared using RCM according to Hoveyda et al.,20 gave full
conversion to the desired product 3j with 78% ee but only 40%
isolated yield was obtained probably due to volatility of the
product and instability of the starting material, as observed
previously.
g
volatility of the product. 100 uC.
e.g. o-MePhSi(OEt)3 afforded only 15% conversion even when the
temperature was raised to 100 uC. The corresponding m- and
p-tolylsiloxane gave full conversion with excellent enantioselec-
tivities of 96% and 98% (entries 3 and 4).
Electron withdrawing groups on the arylsiloxane are tolerated
and the reaction with p-ClPhSi(OEt)3 afforded full conversion to
the desired product in 95% ee (entry 5). This contrasts the result
obtained in the conjugate addition of arylboronic acids,5 where
boronic acids with electron withdrawing groups gave incomplete
conversion although with excellent enantioselectivity. Also an
arylsiloxane bearing an electron donating group showed very
good reactivity and enantioselectivity: the reaction with
p-MeOPhSi(OEt)3 afforded complete conversion into the 1,4-
product in 96% ee (entry 6).17
The enantioselective conjugate addition of alkyl and aryl
nucleophiles to a,b-unsaturated lactams has not been studied
extensively but leads to 4-substituted-2-piperidinones that are
important synthons for natural products. The asymmetric addition
of alkyl groups has been accomplished using dialkylzinc and
trialkylaluminium reagents21 whereas the complementary addition
of aryl groups has been achieved using the Rh-catalysed addition
of arylboronic acids.22 We were very pleased to observe that the
use of 1f as a substrate in the reaction with PhSi(OEt)3 gave full
conversion overnight, affording the 1,4-addition product 3k with
an excellent 94% ee in 60% yield.
In conclusion, the first palladium-catalysed enantioselective
conjugate addition of aryltrialkylsiloxanes is described. The
catalyst, generated in situ from Pd(CH3CN)4(BF4)2 and
(R,R)-MeDUPHOS, is efficient and excellent enantioselectivities
are obtained for a series of substrates and aryltriethylsiloxanes.
Aryltriethylsiloxanes are non-toxic, stable compounds, easy to
handle and readily prepared or commercially available. The
presented method could therefore be a versatile alternative to the
corresponding rhodium- and palladium-catalysed addition of
boronic acids.
Scheme 1
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(c) T. Nishikata, Y. Yamamoto and N. Miyaura, Organometallics, 2004,
23, 4317.
Notes and references
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12 R. J. Theissen, J. Org. Chem., 1971, 6, 752.
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K. Tomioka and Y. Nagaoka, in Comprehensive Asymmetric Catalysis,
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York, 1999, vol. 3, ch. 31; (c) N. Krause and A. Hoffmann-Roder,
Synthesis, 2001, 171; (d) M. P. Sibi and S. Mayem, Tetrahedron, 2000,
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2 (a) M. Sakai, H. Hayashi and N. Miyaura, Organometallics, 1997, 16,
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N. Miyaura, J. Am. Chem. Soc., 1998, 120, 5579.
3 Modern Rhodium-Catalysed Organic Reactions, ed. P. A. Evans, Wiley-
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4 T. Nishikata, Y. Yamamoto and N. Miyaura, Angew. Chem., Int. Ed.,
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5 F. Gini, B. Hessen and A. J. Minnaard, Org. Lett., 2005, 7, 5309.
6 Boronic Acids: Preparation and Application in Organic Synthesis and
Medicine, ed. D. G. Hall, Wiley-VCH, Weinheim, 2005.
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W. M. Seganish and P. DeShong, J. Org. Chem., 2004, 69, 8305; (b)
A. S.-Y. Lee, Y.-T. Chang, S.-F. Chu and K.-W. Tsao, Tetrahedron
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13 An example of the Pd/DuPHOS-catalysed enantioselective reduction of
3-methyl-2-cyclohexenone has been reported before, see: (a) D. Drago
and P. S. Pregosin, Organometallics, 2002, 21, 1208. Very recently a
procedure for Pd/BINAP catalysed enantioselective conjugate reduc-
tions has been reported, see: (b) Y. Tsuchiya, Y. Hamashima and
M. Sodeoka, Org. Lett., 2006, 8, 4851. The conversion of 1a into phenol
and cyclohexanone catalysed by Pd(OAc)2 has been observed before,
see: (c) M. Hayashi, K. Yamada and S. Nakayama, J. Chem. Soc.,
Perkin Trans. 1, 2000, 1501. For non-enantioselective conjugate
reduction, see: (d) A. Haskel and E. Keinan, in Handbook of
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Wiley & Sons, New York, 2002, vol. 2, ch. VII 2.3, pp. 2767–2782.
14 For a study of nucleophilic activation in cross-coupling reactions of
silanolates, see: S. E. Denmark and J. D. Baird, Chem. Eur. J., 2006, 12,
4954 and references therein.
15 The use of ZnF2 has previously been reported in the palladium-catalysed
monoarylation of nitriles: L. Wu and J. F. Hartwig, J. Am. Chem. Soc.,
2005, 127, 15824. See also Ref. 4.
8 To avoid boroxine formation and to increase reactivity, boronic acids
can be converted either to their corresponding potassium trifluorobo-
rates or sodium trihydroxyborates. This requires, however, an additional
step. (a) G. A. Molander and R. Figueroa, Aldrichim. Acta, 2005, 38, 49;
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Chem. Soc., 2001, 123, 10774. For the conjugate addition of
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2002, 4, 667; (f) J. D. Hargrave, J. Herbert, G. Bish and C. G. Frost,
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16 The same reaction carried out in the absence of ZnF2 afforded only 60%
conversion to phenol and cyclohexanone.
17 Also in the addition of substituted arylsiloxanes the side reaction leading
to the formation of phenol and cyclohexanone could not be completely
suppressed and traces of these products were detected by GC.
18 For a recent example of enantioselective Rh-catalysed conjugate
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B. L. Feringa and A. J. Minnaard, Org. Lett., 2005, 7, 2433.
19 The presence of the corresponding saturated lactone in the crude
mixture was confirmed by GC-MS analysis. NMR suggested the
presence of the product derived from the ring opening of the conjugate
addition product 3i by ethanol present in the reaction mixture.
20 M. K. Brown, S. J. Degrado and A. H. Hoveyda, Angew. Chem., Int.
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712 | Chem. Commun., 2007, 710–712
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