Rhodium-catalysed addition of organotrialkoxysilanes to α-substituted acrylic esters

Article abstract of DOI:10.1039/b606977k

The cationic rhodium complex [Rh(cod)₂][BF₄] effectively catalyses the 1,4-addition of organotrialkoxysilanes to α-substituted acrylic esters. The reactions are promoted by heating in an oil-bath or more conveniently in a microwave reactor allowing rapid access to a useful range of functionalised products including 2-alkyl succinates and α-amino acid derivatives. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b606977k

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Rhodium-catalysed addition of organotrialkoxysilanes to a-substituted
acrylic esters
a
a
b
a
Jonathan D. Hargrave, Jennifer Herbert, Gerwyn Bish and Christopher G. Frost*
Received 17th May 2006, Accepted 7th July 2006
First published as an Advance Article on the web 26th July 2006
DOI: 10.1039/b606977k
The cationic rhodium complex [Rh(cod)
2
][BF ] effectively catalyses the 1,4-addition of
4
organotrialkoxysilanes to a-substituted acrylic esters. The reactions are promoted by heating in an
oil-bath or more conveniently in a microwave reactor allowing rapid access to a useful range of
functionalised products including 2-alkyl succinates and a-amino acid derivatives.
Introduction
The transition-metal catalysed conjugate addition of organo-
metallics to activated alkenes is regarded as fundamental method-
1
ology for organic synthesis. Of particular importance is the
elegant rhodium-catalysed addition of organoboron reagents to
a,b-unsaturated carbonyl derivatives, pioneered by Hayashi and
2
Miyaura. This widely-used reaction can be carried out in aqueous
solvent and affords excellent enantioselectivities (>90% ee) across
a wide-range of substrates including a,b-unsaturated ketones,
3
esters, amides, phosphonates and sulfones. A successful catalytic
conjugate addition is dependent on an efficient transmetalation to
rhodium. Other organometallics that are known to participate in
the key transmetalation to rhodium include organotin, organosil-
Scheme 1 The rhodium-catalysed addition of organosilicon reagents.
icon, organozinc, organozirconium, organotitanium, organobis-
4
muth and organoindium reagents.
The utility of arylchlorosilanes in rhodium-catalysed conju-
gate additions has been reported. For example, the addition
of diphenyldichlorosilane 2 to cyclohexenone 1 is achieved in
The selective addition to a-substituted acrylic esters is more
difficult than cyclic enones. This can be attributed to their
lower reactivity and crucially, in the asymmetric process the
enantioselectivity is determined at the protonation step of an
the presence of a high-loading of cationic rhodium catalyst
5
(
Scheme 1). The reaction proceeds in water as solvent but
requires the addition of a large excess of fluoride salt for an
oxa-p-allylrhodium intermediate and not at the insertion step
efficient transformation to product 3. Oi and Inoue have reported
10
(
Fig. 1). Herein we report the utility of the silicon–rhodium
6
the additive-free conjugate addition of organotrialkoxysilanes.
transmetalation process as a means to promote the conjugate
addition of aryl nucleophiles to a-substituted acrylic esters. It was
found the addition of organotrialkoxysilanes can be promoted by
heating in an oil-bath or more conveniently in a microwave reactor
allowing rapid access to a useful range of functionalised products
including 2-alkyl succinates and a-amino acids.
The addition of phenyltrimethoxysilane 2a to cyclopentenone 4
in the presence of just 2 mol% of cationic rhodium complex
furnishes the product 5 in good yield. The conjugate addition of
organotrialkoxysilanes can also be accomplished using palladium
7
complexes. More recently, the rhodium-catalysed enantioselective
conjugate addition of organotrialkoxysilanes to a,b-unsaturated
8
carbonyl compounds has been disclosed. The use of organotri-
alkoxysilanes offers many of the advantages of boronic acids in
terms of commercial availability, ease of handling and stability to
air and moisture. Moreover, a number of straightforward synthetic
routes have been reported for their preparation including the
hydrosilylation of alkynes, the addition of Grignard reagents to
tetraethyl orthosilicate and the cross-coupling of triethoxysilane
9
with organohalides.
a
Department of Chemistry, University of Bath, Claverton Down, Bath,
BA2 7AY, UK. E-mail: c.g.frost@bath.ac.uk; Fax: +44 (0)1225 386231;
Tel: +44 (0)1225 386142
b
Pfizer Limited, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK
Fig. 1 The rhodium-catalysed addition to a-substituted acrylic esters.
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Results and discussion
The mechanism of the process as proposed by Oi and Inoue
is illustrated in Fig. 2 and closely relates to the mechanism of
the corresponding rhodium-catalysed addition of boronic acids
Initially, the conjugate addition of phenyltrimethoxysilane 2a to
dimethyl itaconate 6 was examined in the presence of different
rhodium complexes (Scheme 2).
2,6
described by Hayashi. It was noted that the reaction did not
occur in the absence of water, suggesting that the active silicon
species is likely to be an organosilanetriol I generated from the
hydrolysis of the organotrialkoxysilane. The organosilanetriol I,
would then transmetalate with the cationic catalyst II to generate
the organorhodium intermediate III and the side product, SiO .
2
Addition of the organorhodium species to substrate IV then leads
3
to an g -oxa-p-allylrhodium complex V that is protonated to afford
the product VI and the regenerated cationic catalyst. Alternatively,
Scheme 2 The rhodium-catalysed addition of phenyltrimethoxysilane.
the lack of reactivity in the absence of proton source could be
attributed to the g -oxa-p-allylrhodium complex V being inert to
3
transmetalation which would lead to the catalytic cycle stalling
at V.
The majority of organic reactions are heated using traditional
heat transfer equipment such as oil baths and heating blocks.
These heating techniques however are usually slower and do
not provide uniform heating. In contrast, microwaves provide
direct heating and radiation that passes through the reaction
vessel, hence heating only the reactants and solvent. Therefore
microwave irradiation provides fast heating rates and can enable
rapid optimisation of numerous organic transformations including
11
catalytic processes. Investigations into the effect of catalyst,
temperature and microwave irradiation on the rhodium-catalysed
addition reaction were studied (Table 1).
In initial experiments, no product was observed using neutral
rhodium catalysts such as [RhCl(coe)
2
]
2
or [RhCl(cod)] by
2
reaction in the microwave reactor or by standard heating (Table 1,
entries 1 and 2). This is in agreement with the previous report of Oi
and Inoue that notes the necessity of cationic rhodium complexes
to achieve an efficient transmetalation in the absence of added
6
base.
After heating for 24 hours in the presence of [Rh(cod)
substrate 6 was completely converted to product 7 (Table 1, entry
). During the microwave experiments the reaction times were
2
][BF
4
],
4
considerably shorter, and yet the reaction still proceeded to form
the product in excellent conversion. Subsequently, we found that
this was also true of the standard heating experiments (Table 1,
entries 7–9). It was therefore pleasing to note that in 50 minutes
both protocols afforded complete conversion to product. This is
significantly more efficient than previous literature examples that
are routinely run for 12–24 hours.
Fig. 2 Mechanism of rhodium-catalysed addition of organotrial-
koxysilanes.
To our surprise there was a marked difference in efficiency
using the cationic catalysts [Rh(cod)
Whereas the use of [Rh(cod) ][BF
sions to product in short reaction times, the complex with
PF counter ion was ineffective and led to protiodesilylation of
2
][PF
6
] and [Rh(cod)
2
][BF
4
].
2
4
] resulted in high conver-
Table 1 Optimisation of reaction parameters
6
the organotrialkoxysilane as the predominant reaction pathway
along with recovery of starting materials 2a and 6. Given that
a
b
Entry Conditions
[Rh catalyst]
Time/min Conversion (%)
[
Rh(cod)
2
][PF ] is an effective catalyst for the conjugate addition
6
1
2
3
4
5
6
7
8
9
0
A
A
A
A
A
B
B
B
B
[RhCl(coe)
[RhCl(cod)]
2
]
2
2
1440
1440
1440
1440
50
50
30
45
50
50
0
0
15
100
100
0
60
87
100
100
of organoboron reagents under identical reaction conditions the
organotrialkoxysilane is clearly detrimental to the action of the
catalyst. This may be due to the comparatively weak P–F bond
being hydrolysed in the presence of the organosilicon reagent
whereas the B–F bond in the BF counterion is stable. The partial
hydrolysis of PF has been observed previously in transition metal
complexes and this process generates HF in the reaction mixture.
Interestingly, the addition of a fluoride source to a reaction mixture
containing the [Rh(cod) ][BF ] catalyst leads to a decrease in the
amount of addition product 7a obtained.
[Rh(cod)
[Rh(cod)
[Rh(cod)
2
2
2
][PF
][BF
][BF
6
]
]
]
12
4
4
[RhCl(cod)]
2
13
[Rh(cod)
[Rh(cod)
[Rh(cod)
[Rh(cod)
2
2
2
2
][BF
][BF
][BF
][BF
4
4
4
4
]
]
]
]
4
6
14
c
1
B
a
◦
A Reactions were heated at 110 C in the presence of 3 mol% [Rh] in
dioxane–H
CEM Discover reactor set at a maximum temperature of 135 C (initial
power 110 W). Calculated from the H NMR. Using 1 mol% catalyst.
2
4
2
O (10 : 1). B Microwave experiments were performed in a
15
◦
b
1
c
The products from the addition process are of significant
utility in the development of pharmaceutical and agrochemical
3
236 | Org. Biomol. Chem., 2006, 4, 3235–3241
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1
6
intermediates. Therefore, the synthesis of a range of 2-substituted
in a microwave reactor provided the products in slightly lower
yields reflecting the lower reactivity of this substrate.
17
succinic esters was performed. For ease of operation and rapid
heating, the rhodium-catalysed addition was performed in capped
tubes under microwave irradiation. Using the optimal set of
reaction conditions, the scope of the organotrialkoxysilane was
examined. Pleasingly, in the addition to dimethyl itaconate 6, the
use of sterically and electronically diverse organotrialkoxysilanes
The catalytic conjugate addition of hydride is an established
19
process for the reduction of a,b-unsaturated carbonyl derivatives.
The transformation employs hydrogen donors such as hydrosi-
lanes or borohydride reagents as an alternative to hydrogen
gas. The reduction of a-substituted acrylic esters 6 and 8 with
triethoxysilane 2j occurred under identical conditions to the
arylations (Scheme 5). Again, for ease of operation and rapid
heating, the reduction was performed in capped tubes under
microwave irradiation to afford the products 10 and 11 in good
yields.
(
2a–i) resulted in excellent conversion and good isolated yields
of products 7a–i. The reaction is tolerant of the substitution
pattern and the electronic nature of the siloxane. All the reactions
proceeded in similar yields by heating in an oil bath or heating
◦
block at 110 C (Scheme 3).
Scheme 5 The rhodium-catalysed conjugate reduction.
Preliminary investigations into the enantioselective addition of
organotrialkoxysilanes to a-substituted acrylic esters focused on
the use of (R)-BINAP as the chiral ligand (Scheme 6). While
carrying out preliminary microwave experiments it was observed
that the ligand to metal ratio utilised had a dramatic effect on
the outcome of the reaction. Using the catalyst [Rh(cod)
2
][BF ] (3
4
◦
mol%), in the absence of ligand, at 135 C, complete conversion
of the starting acrylate 6 to product 7a was observed in 50
minutes (Table 2, entry 1). However upon the addition of (R)-
BINAP (3 mol%, 1 equivalent) to the reaction, a sharp decrease in
reactivity was observed, alongside a moderately low enantiomeric
excess of 24% ee (Table 2, entry 2). Upon altering the ligand
loading (4.5 mol%, 1.5 equivalents) a 55% conversion and 49%
enantiomeric excess was obtained, with higher ligand to rhodium
ratios giving no conversion to the desired product (Table 2,
entries 3 and 4). The application of sterically-hindered phenols as
alternative proton sources impeded the enantioselective reaction
as did the addition of fluoride sources such as KF (Table 2,
entry 9).
Scheme 3 The rhodium-catalysed addition of organotrialkoxysilanes.
With an efficient protocol established for the addition
to dimethyl itaconate 6 our attention turned to the a-
18
phthalimidoacrylic ester derivative 8. As shown in Scheme 4,
the arylation of 8 with selected organotrialkoxysilanes (2a–e) was
◦
performed by heating in an oil bath at 110 C for 18 hours. In
all cases the reaction proceeded in good yield to provide a useful
synthetic approach to unnatural amino acid derivatives 9a–e. The
corresponding reactions carried out under the standard conditions
Scheme 6 The enantioselective addition of phenyltrimethoxysilane.
Unfortunately, employing other enantiopure ligands such as
the monodentate phosphoramidite (S)-MONOPHOS proved
unsuccessful (Table 2, entry 6). This is consistent with the
previous report of Feringa et al. that demonstrated rhodium–
phosphoramidite complexes were unable to effect the conjugate
Scheme 4 The rhodium-catalysed addition to a-phthalimidoacrylic ester
derivatives.
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a
Table 2 Investigation into enantioselectivity
General procedure for the rhodium-catalysed conjugate addition of
organotrialkoxysilanes to a-substituted acrylic esters
b
c
Entry Ligand Ligand–[Rh] ee (%)
Conversion (%)
A suspension of dimethyl itaconate (0.5 mmol), organotrialkoxysi-
1
2
3
4
5
6
7
8
9
None
—
0
24
49
—
0
0
9
100
70
55
<2
0
0
100
0
lane (1.25 mmol), and [Rh(cod)
2
][BF ] (0.015 mmol, 3 mol%), in
4
(R)-BINAP
(R)-BINAP
(R)-BINAP
(R,R)-DUPHOS
1 : 1
3 : 2
2 : 1
3 : 2
dioxane (1 mL) and water (0.1 mL) was heated in a microwave reac-
◦
tor, under an inert atmosphere, at 135 C for 50 min (initial power
1
10 W). The solution was evaporated under reduced pressure and
(S)-MONOPHOS 3 : 2
(R,R)-DIOP 3 : 2
(R,R)-NORPHOS 3 : 2
re-dissolved in ethyl acetate (10 mL) and water (10 mL). The
phases were separated, and the aqueous phase extracted with ethyl
acetate (2 × 10 mL). The combined organics were washed with
0
—
d
(R)-BINAP
3 : 2
<5
a
brine, dried over MgSO , filtered and concentrated in vacuo. The
4
Microwave experiments were performed in a CEM Discover reactor set at
◦
b
a maximum temperature of 135 C (110 W). Determined by chiral HPLC
using a Daicel OD–H column at ambient temperature and a 98 : 2 hexane–
IPA solvent system with a flow rate of 1 mL min . Two peaks were found
at retention times of 19 and 23 minutes, correlating to the two product
enantiomers. Calculated from the H NMR. Using 2-methoxyphenol as
proton source.
crude material was purified by flash chromatography on silica gel
(eluent: petroleum ether–ethyl acetate). Alternatively, the reaction
−
1
◦
could be carried out by heating in an oil-bath at 110 C for the
c
1
d
indicated time.
Dimethyl 2-benzylsuccinate (7a). Title compound isolated as
a colourless oil (106 mg, 90%); R
f
(9 : 1, petroleum ether–ethyl
acetate) 0.2; H NMR (300 MHz, CDCl ) d 7.2–7.1(5H, m, Ar),
3.60 (3H, s, CH ), 3.57 (3H, s, CH ), 3.2–3.1 (2H, m, CH , CH),
.7–2.9 (2H, m, CH
), 2.34 (1H, dd, J = 4.8, 16.8 Hz, CH
NMR (75.5 MHz; CDCl ) 175.0, 172.6, 138.5, 129.4, 128.9, 127.4,
2.3, 52.1, 43.4, 38.1, 35.2. Further data were in accordance with
1
3
20
3
3
2
addition of organosiloxanes to cyclic enones. Disappointingly,
1
3
2
2
2
); C
other bidentate phosphorous ligands, such as (R,R)-DIOP and
3
(
R,R)-DUPHOS did not enhance the enantioselectivity (Table 2,
5
entries 5, 7 and 8). From these results we have established that
phosphine ligands retard the conjugate addition of organotri-
alkoxysilanes to a-substituted acrylic esters and given the modest
enantioselectivity observed we elected not to pursue this any
further.
21
previous results in the literature.
Dimethyl 2-((naphthalene-1-yl)methyl)succinate (7b). Title
◦
compound isolated as a white solid (120 mg, 84%), mp 96
C
22
◦
(
(
lit. 95.7 C); R
f
(9 : 1, petroleum ether–ethyl acetate) 0.16; IR
In summary, we have demonstrated that the cationic rhodium
−1
1
nujol, cm ) m 1719 (C=O), 1050 (C–O); H NMR (300 MHz,
complex [Rh(cod)
2
][BF ] effectively catalyses the conjugate addi-
4
CDCl
Ar), 7.69 (1H, d, J = 8.4 Hz, Ar), 7.46 (2H, m, Ar), 7.32 (1H, t,
J = 6.9 Hz, Ar), 7.21 (1H, d, J = 8.1 Hz, Ar), 3.61 (3H, s, OCH ),
.4–3.5(4H, m, CH , OCH ), 3.24 (1H, m, CH), 3.06 (1H, dd,
), 2.69 (1H, dd, J = 9.3, 17.1 Hz, CH ), 2.37
); C NMR (75.5 MHz; CDCl
3
) d 8.02 (1H, d, J = 8.7 Hz, Ar), 7.80 (1H, d, J = 9.3 Hz,
tion of organotrialkoxysilanes to a-substituted acrylic esters. This
methodology is very versatile offering the possibility of obtaining
a variety of novel 2-substituted succinate esters and unnatural a-
amino acid derivatives, simply by changing the functionality on
the starting organosilicon reagent.
3
3
2
3
J = 9.3, 13.5 Hz, CH
2
2
13
(
1
1H, dd, J = 5.1, 17.1 Hz, CH
2
3
)
72.6, 175.3, 134.6, 134.4, 132.1, 129.3, 128.1, 127.8, 126.7, 126.1,
1
25.7, 123.9, 52.4, 52.1, 42.5, 35.6, 35.5. Further data were in
21
accordance with previous results in the literature.
Experimental
Dimethyl 2-(4-butylbenzyl)succinate (7c). Title compound iso-
Commercially available solvents and reagents were obtained from
Sigma-Aldrich Company Ltd, Lancaster Synthesis Ltd, Fisher
Scientific Ltd and Strem Chemicals UK and were used without
further purification. Microwave experiments were performed using
a CEM Discover reactor. Solvents and reagents were deoxy-
genated where necessary by purging with nitrogen. Flash column
chromatography was carried out using Merck kieselgel 60 H
silica gel (particle size: 0.063–0.100 mm). Melting points were
determined using a B u¨ chi 535 melting point apparatus and are
uncorrected. Infra red spectra (4000 to 600 cm ) were recorded on
a Perkin Elmer (1600) FT spectrometer with internal calibration.
Fast Atom Bombardment (FAB) and Electron Impact (EI) mass
spectra were obtained using a Fisons VG Autospec Finnigan
MAT 8340 instrument at the University of Bath. Additional mass
spectra were run at the EPSRC National Mass Spectrometry
Service Centre at Swansea University. High Performance Liquid
Chromatography (HPLC) was performed on a Perkin Elmer
HPLC-IPM using a Chiralpak OD–H column by Daicel Chemical
Ind. Ltd. Elemental analyses were recorded on a Micromass
Autospec Spectrometer at the University of Bath.
lated as a colourless oil (126 mg, 86%); R
ethyl acetate) 0.19; IR (film, cm ) m 3459, 2858, 1740, 1614, 1594,
f
(9 : 1, petroleum ether–
−1
1
1
515, 1437, 1356, 1331, 1264, 1202, 1168, 837; H NMR (300 MHz,
CDCl
) d 7.0–7.05 (2H, d, J = 8.2 Hz, Ar), 6.97 (2H, d, J = 8.1 Hz,
Ar), 3.59 (3H, s, CH ), 3.54 (3H, s, CH ), 3.1–2.9 (2H, m, CH2,
CH), 2.7–2.9 (2H, m, CH ), 2.5 (2H, m, CH
), 2.3 (1H, dd, J =
.7, 16.7 Hz, CH2), 1.5 (2H, m, CH ), 1.25 (2H, m, CH ), 0.85
); C NMR (75.5 MHz; CDCl ) 175.2, 172.7,
44.70, 135.5, 134.9, 129.7, 129.2, 128.97, 52.3, 52.1, 43.4, 37.7,
3
3
3
2
2
4
2
2
13
(
1
3
3H, t, J = 7.3, CH
3
3
−
1
+
+
5.6, 34.3, 34.0, 22.6, 14.3; HRMS (EI ) [MH ] calcd for C17
H
24
4
O ,
m/z 293.1747; found m/z 293.1744; elemental analysis calcd (%)
: C 69.8, H 8.3, N 0; found: C 70.1, H 8.4, N 0%.
for C17
H
24
O
4
Dimethyl 2-(2-methylbenzyl)succinate (7d). Title compound
isolated as a colourless oil (104 mg, 83%); R (9 : 1, petroleum
ether–ethyl acetate) 0.2; IR (film, cm ) m 2953, 1736, 1638, 1605,
f
−
1
1
1437, 1353, 1264, 1206, 1162, 1006; H NMR (300 MHz, CDCl
7.1–7.0 (4H, m, Ar), 3.60 (3H, s, CH ), 3.57 (3H, s, CH ), 3.2–3.1
(2H, m, CH , CH), 2.7–2.6 (2H, m, CH
), 2.34 (1H, dd, J = 4.8,
16.8 Hz, CH ); C NMR (75.5 MHz; CDCl )
3
) d
3
3
2
2
1
3
2
), 2.2 (3H, s, CH
3
3
3
238 | Org. Biomol. Chem., 2006, 4, 3235–3241
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1
3
2
75.3, 172.6, 136.7, 130.9, 130.2, 127.2, 126.3, 52.3, 52.1, 42.1,
General procedure for the rhodium-catalysed conjugate addition of
organotrialkoxysilanes to a-amino acrylates
+
+
5.6, 35.4, 19.6; HRMS (EI ) [MH ]; calcd for C14
H
18
O
4
, m/z
51.1278; found m/z 251.1282.
A suspension of ethyl-a-phthalimidoacrylate (0.5 mmol), organo-
trialkoxysilane (1.25 mmol), and [Rh(cod)
2
][BF ] (0.015 mmol, 3
4
Dimethyl 2-(4-methoxybenzyl)succinate (7e). Title compound
isolated as a colourless oil (116 mg, 87%); R (9 : 1, petroleum
mol%), in dioxane (2 mL) and water (0.2 mL) was refluxed under
an inert atmosphere. After 24 hours the solution was evaporated
under reduced pressure and re-dissolved in ethyl acetate (10 mL)
and water (10 mL). The phases were separated, and the aqueous
phase extracted with ethyl acetate (2 × 10 mL). The combined
f
−
1
1
ether–ethyl acetate) 0.18; IR (film, cm ) m 2953, 1732 (C=O); H
NMR (300 MHz, CDCl
) d 7.0 (2H, d, J = 8.7 Hz, Ar), 6.76 (2H,
d, J = 8.7 Hz, Ar), 3.72 (3H, s, ArOCH ), 3.60 (3H, s, CH ),
.57 (3H, s, CH ), 2.8–3.1 (2H, m, CH , CH), 2.5–2.7 (2H, m,
CH ). Further data were in
), 2.33 (1H, dd, J = 5.1, 16.8 Hz, CH
accordance with previous results in the literature.
3
3
3
3
3
2
organics were washed with brine, dried over MgSO , filtered
4
2
2
21
and concentrated in vacuo. The crude material was purified by
flash chromatography on silica gel (eluent: petroleum ether–ethyl
acetate).
Dimethyl 2-((phenanthren-10-yl)methyl)succinate (7f). Title
◦
compound isolated as a white solid (150 mg, 89%), mp 94–97 C;
−
1
R
2
(
f
(9 : 1, petroleum ether–ethyl acetate) 0.15; IR (CDCl
3
1
, cm ) m
Ethyl 2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoate(9a). Title
923, 2726, 2671, 1719, 1460, 1377, 1305, 1151, 1076; H NMR
300 MHz, CDCl
) d 8.7–8.6 (1H, m, Ar), 8.55 (1H, d, J = 8.0 Hz,
Ar), 8.1–8.2 (1H, m, Ar), 7.75 (1H, dd, J = 1.3, 7.4 Hz, Ar),
.7–7.4 (5H, m, Ar), 3.65 (3H, s, CH ), 3.5–3.6 (1H, m, CH ), 3.5
3H, s, CH ), 3.25–3.4 (1H, m, CH), 3.1–3.2 (1H, m, CH ), 2.7
), 2.4 (1H, dd, J = 4.5, 11.9 Hz,
); C NMR (75.5 MHz; CDCl ) 175.3, 172.6, 132.8, 131.8,
compound isolated as a white solid (126 mg, 78%); R
f
(4 : 1,
1
petroleum ether–ethyl acetate) 0.42; H NMR (300 MHz, CDCl )
3
3
d 7.74–7.79 (2H, m, Ar), 7.66–7.70 (2H, m, Ar), 7.12–7.20 (5H, m,
Ph), 5.14 (1H, dd, J = 5.3, 10.9, NCH), 4.25 (2H, dq, J = 1.6,
7
(
3
2
7.2, CH
2
CH
3
), 3.49–3.64 (2H, m, CH
2
Ph), 1.26 (3H, t, J = 7.2,
3
2
(
1H, dd, J = 9.8, 7.8 Hz, CH
2
CH
3
). Further data were in accordance with previous results in
1
3
18
CH
2
3
the literature.
1
31.2, 131.1, 130.4, 128.6, 128.4, 127.3, 127.1, 126.8, 124.6, 123.7,
+
+
Ethyl 3-(naphthalen-1-yl)-2-(1,3-dioxoisoindolin-2-yl) propanoate
9b). Title compound isolated as a white solid (168 mg, 90%);
1
C
22.8, 52.4, 52.1, 42.0, 36.1, 35.6; HRMS (EI ) [MH ]; calcd for
, m/z 337.1434, found 337.1438.
(
21
H
20
O
4
◦
mp 233–234 C; R
f
(4 : 1, petroleum ether–ethyl acetate) 0.38; mp
◦
1
Dimethyl 2-allylsuccinate (7g). Title compound isolated as a
colourless oil (46 mg, 49%); R (9 : 1, petroleum ether–ethyl acetate)
.19; H NMR (300 MHz, CDCl ) d 5.6–5.7 (1H, m, CH), 5.05
),
), 3.0–2.9 (1H, m, CH), 2.65 (1H, dd, J = 9.08,
), 2.34 (2H, m, CH ), 2.2 (1H, m, CH). Further data
87–90 C; H NMR (300 MHz, CDCl
3
) d 8.10 (1H, d, J = 8.7,
Ar), 7.81 (1H, d, J = 8.7 Hz, Ar), 7.72–7.76 (2H, m, Ar), 7.65–7.69
(3H, m, Ar), 7.43–7.51 (2H, m, Ar), 7.22–7.26 (2H, m, Ar), 5.31
(1H, dd, J = 4.5, 11.3 Hz), 4.3 (2H, dq, J = 1.1, 7.2), 4.17 (1H,
dd, J = 4.5, 14.7 Hz), 3.9 (1H, dd, J = 11.3, 14.7), 1.28 (3H, t, J =
f
1
0
3
(
3
1H, d, J = 4.29 Hz, CH), 4.95 (1H, s, CH), 3.60 (3H, s, CH
3
.58 (3H, s, CH
.63 Hz, CH
3
1
3
7
2
2
7.2 Hz); C NMR (75.5 MHz, CDCl ) 167.7, 166.2, 132.8, 132.6,
3
21
were in accordance with previous results in the literature.
131.7, 130.5, 130.3, 127.7, 126.6, 126.0, 125.2, 124.5, 124.0, 122.2,
1
21.8, 60.9, 51.6, 30.6, 12.9. Further data were in accordance with
18
Dimethyl 2-(4-(trifluoromethyl)benzyl)succinate (7h). Title
compound isolated as a colourless oil (140 mg, 92%); R (4 :
previous results in the literature.
f
−
1
1
, petroleum ether–ethyl acetate) 0.37; IR (film, cm ) m 2955,
Ethyl 3-(4-butylphenyl)-2-(1,3-dioxoisoindolin-2-yl) propanoate
1
2259, 1925, 1732, 1619, 1585, 1548, 1438, 1418, 1324; H NMR
(9c). Title compound isolated as a colourless oil (120 mg, 63%);
R (4 : 1, petroleum ether–ethyl acetate) 0.41; IR (film, cm ) m 2930,
−
1
(300 MHz, CDCl
3
) d 7.47 (2H, d, J = 8.2 Hz, Ar), 7.2 (2H, d, J =
.9 Hz, Ar), 3.58 (3H, s, CH ), 3.57 (3H, s, CH ), 3.05–3.11 (2H,
, CH), 2.78 (1H, dd, J = 7.15, 13.1 Hz, CH ), 2.6 (1H, dd,
J = 8.2, 16.5 Hz, CH ), 2.34 (1H, dd, J = 5.2, 16.5 Hz, CH
NMR (75.5 MHz, CDCl ) 173.1, 170.9, 141.4, 127.8, 124.9, 121.3,
17.7, 50.9, 50.8, 41.7, 36.3, 33.9; HRMS (EI ) [MNH
·NH m/z 322.1261, found 322.1260.
f
1
7
3
3
1778, 1744 (C=O), 1719, 1614, 1515, 1467, 1445, 1388, 1243; H
NMR (300 MHz, CDCl
) d 7.6–7.7 (4H, m, Ar), 6.98 (2H, d, J =
8.08 Hz, Ar), 6.9 (2H, d, J = 8.08 Hz, Ar), 5.06 (1H, dd, J = 5.6,
10.89, NCH), 4.16 (2H, dq, J = 1.7, 7.1 Hz, CH CH ), 3.38–3.54
(2H, m, CHCH ), 1.35–1.45 (2H,
), 2.41 (2H, t, J = 7.56 Hz, CH
m, CH ), 1.1–1.2 (5H, m, CH CH
), 0.8 (3H, t, J = 7.27, CH
NMR (75.5 MHz, CDCl ) 169.3, 167.9, 141.7, 134.5, 134.4, 134.2,
32.0, 129.0, 128.9, 123.7, 62.3, 53.9, 35.5, 34.6, 33.8, 22.6, 14.5,
m, CH
2
2
3
1
3
2
2
);
C
3
2
3
+
+
1
4
]; calcd
2
2
1
3
for C14
H
15
O
4
F
3
4
2
3
2
3
); C
3
Dimethyl 2-(4-(biphenyl)benzyl)succinate (7i). Title compound
1
1
◦
isolated as a white solid (93 mg, 60%); mp 61–65 C; R
f
(4 : 1,
+
+
4.3; HRMS (EI ) [MH ]; calcd for C23
H
25NO , m/z 380.1856,
4
−
1
petroleum ether–ethyl acetate) 0.3; IR (KBr, cm ) m 3027 (C–H),
found 380.1856.
3
1
005 (C–H), 2954 (C–H), 2926 (C–H), 1761 (C=O), 1726 (C=O),
1
175 (C–O), 1153 (C–O); H NMR (300 MHz, CDCl
3
) d 7.42–7.50
Ethyl 2-(1,3-dioxoisoindolin-2-yl)-3-o-tolylpropanoate (9d). Title
compound isolated as a colourless oil (116 mg, 69%); R (4 : 1,
petroleum ether–ethyl acetate) 0.35; IR (film, cm ) m 2981, 1777,
(
7
(
2
4
1
4
4H, m, Ar), 7.3–7.38 (2H, m, Ar), 7.2–7.28 (1H, m, Ar), 7.14–
.16 (2H, m, Ar), 3.6 (3H, s, CH ), 3.56 (3H, s, CH ), 2.98–3.12
2H, m, CH ),
, CH), 2.68–2.76 (1H, dd, J = 8.2, 13.1 Hz, CH
.58–2.67 (1H, dd, J = 8.6, 16.1 Hz, CH ), 2.32–2.4 (1H, dd, J =
.8, 16.5 Hz, CH ); C NMR (75.5 MHz, CDCl ) 175.1, 172.7,
41.1, 140.0, 137.6, 129.8, 129.2, 127.6, 127.4, 127.0, 52.5, 52.4,
f
−
1
3
3
1
2
2
1743, 1715, 1631, 1494, 1467, 1423, 1388; H NMR (300 MHz,
2
CDCl
(4H, m, Ph), 5.09 (1H, dd, J = 5.3, 10.9, NCH), 4.1 (2H, dq, J =
1.9, 7.2, CH CH ), 3.4–3.64 (2H, m, CH Ph), 2.3 (3H, s, Ar–Me),
), C NMR (75.5 MHz, CDCl ) 169.4,
3
) d 7.74–7.79 (2H, m, Ar), 7.66–7.70 (2H, m, Ar), 6.9–7.1
1
3
2
3
2
3
2
+
+
13
3.4, 37.7, 35.3; HRMS (EI ) [MNH
4
]; calcd for C19
H
20
O
4
·NH
4
1.26 (3H, t, J = 7.2, CH
3
3
m/z 330.1700, found 330.1700.
167.9, 136.9, 135.2, 134.5, 131.9, 130.9, 130.0, 127.4, 126.3, 123.8,
This journal is © The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 3235–3241 | 3239

View Article Online
+
1
C
20.70, 62.4, 52.1, 32.7, 19.6, 14.5; HRMS (EI+) [MH ]; calcd for
, m/z 338.1387, found 338.1381.
Netherlands, 2001, ch. 6; N. Krause and A. Hoffman-roder, Synthesis,
2
001, 171.
20
H
19NO
4
2
3
For reviews see: T. Hayashi, Synlett, 2001, 879; T. Hayashi and
K. Yamasaki, Chem. Rev., 2003, 103, 2829; K. Fagnou and M.
Lautens, Chem. Rev., 2003, 103, 169; M. Sakai, H. Hayashi and N.
Miyaura, Organometallics, 1997, 16, 4229; Y. Takaya, M. Osgawara,
T. Hayashi, M. Sakai and N. Miyaura, J. Am. Chem. Soc., 1998, 120,
Ethyl 3-(4-methoxyphenyl)-2-(1,3-dioxoisoindolin-2-yl)propanoate
9e). Title compound isolated as a colourless oil (140 mg, 79%);
(
1
H NMR (300 MHz, CDCl
2H, m, Ar), 7.07 (2H, d, J = 8.7 Hz, 2,6-Ar–CH), 6.71 (2H, d, J =
.7 Hz, 3,5-Ar–CH), 5.09 (1H, dd, J = 5.6, 10.7 Hz, NCH), 4.25
2H, dq, J = 1.9, 7.2 Hz, CH CH ), 3.70 (3H, s, OMe), 3.43–3.58
2H, m, CHCH ), 1.26 (3H, t, J 7.2 Hz, CH ). Further data were
3
) d 7.75–7.81 (2H, m, Ar), 7.65–7.72
5
579.
(
8
(
(
For representative examples see: T. Hayashi, K. Ueyama, N. Tokunaga
and K. Yoshida, J. Am. Chem. Soc., 2003, 125, 11508; R. Shintani, K.
Okamoto and T. Hayashi, T., Org. Lett., 2005, 7, 4757; R. Itooka, Y.
Iguchi and N. Miyaura, J. Org. Chem., 2003, 68, 6000; K. M. Belyk,
C. D. Beguin, M. Palucki, N. Grinberg, J. DaSilva, D. Askin and N.
Yasuda, Tetrahedron Lett., 2004, 45, 3265; J.-F. Paquin, C. Defieber,
C. R. J. Stephenson and E. M. Carreira, J. Am. Chem. Soc., 2005, 127,
10850 and references therein.
2
3
2
3
18
in accordance with previous results in the literature.
General procedure for the rhodium-catalysed conjugate addition of
triethoxysilane
4
S. Oi, M. Moro, H. Ito, Y. Honma, S. Miyano and Y. Inoue, Tetrahedron,
2
002, 58, 91; T. Hayashi, K. Ueyama, N. Tokunaga and K. Yoshida,
J. Am. Chem. Soc., 2003, 125, 11508; R. Shintani, N. Tokunaga, H.
Doi and T. Hayashi, J. Am. Chem. Soc., 2004, 126, 6240; T. S. Huang
and C. J. Li, Org. Lett., 2001, 3, 2037; A. Kakuuchi, T. Taguchi
and Y. Hanzawa, Tetrahedron, 2004, 60, 5051; S. Oi, T. Sato and Y.
Inoue, Tetrahedron Lett., 2004, 45, 5051; T. Hayashi, N. Tokunaga,
K. Yoshida and J. W. Han, J. Am. Chem. Soc., 2002, 124, 12102;
K. Yoshida and T. Hayashi, J. Am. Chem. Soc., 2003, 125, 2872; M.
Murata, R. Shimazaki, M. Ishikura, S. Watanabe and Y. Masuda,
Synthesis, 2002, 717; S. Venkatraman and C.-J. Li, Tetrahedron Lett.,
A suspension of a-substituted acrylic ester (0.5 mmol), triethoxysi-
lane (205 mg, 1.25 mmol), and [Rh(cod)
2
][BF ] (0.015 mmol, 3
4
mol%), in dioxane (1 mL) and water (0.1 mL) was heated in
◦
a microwave reactor, under an inert atmosphere, at 135 C for
5
0 min (initial power 110 W). The solution was evaporated under
reduced pressure and re-dissolved in ethyl acetate (10 mL) and
water (10 mL). The phases were separated, and the aqueous
phase extracted with ethyl acetate (2 × 10 mL). The combined
2
5
001, 42, 781; T. Miura and M. Murakami, Chem. Commun., 2005,
676.
organics were washed with brine, dried over MgSO , filtered
4
5
6
T. S. Huang and C. J. Li, Chem. Commun., 2001, 2348.
S. Oi, Y. Honma and Y. Inoue, Org. Lett., 2002, 4, 667.
7 T. Hishikata, Y. Yamamoto and N. Miyaura, Chem. Lett., 2003,
and concentrated in vacuo. The crude material was purified by
flash chromatography on silica gel (eluent: petroleum ether–ethyl
acetate).
3
6
2, 752; S. E. Denmark and N. Amishiro, J. Org. Chem., 2003, 68,
997; T. Hishikata, Y. Yamamoto, I. D. Gridnev and N. Miyaura,
Organometallics, 2005, 24, 5025.
Dimethyl 2-methylsuccinate (10). Title compound isolated as a
8
9
S. Oi, Y. Honma and Y. Inoue, Org. Lett., 2003, 5, 97; Y. Otomaru and
T. Hayashi, Tetrahedron: Asymmetry, 2004, 15, 2647; S. Oi, A. Taira,
Y. Honma, T. Sato and Y. Inoue, Tetrahedron: Asymmetry, 2006, 17,
colourless oil (57 mg, 71%); R (9 : 1, petroleum ether–ethyl acetate)
f
−
1
1
0
.19; IR (film, cm ) m 3425, 1734 (C=O); H NMR (300 MHz,
CDCl ) d 3.63 (3H, s, CH ), 3.61 (3H, s, CH ), 2.82–2.92 (1H, m,
), 2.35 (1H, dd, J = 6.07,
); C NMR (75.5 MHz,
5
98.
3
3
3
A. S. Manoso and P. DeShong, J. Org. Chem., 2001, 66, 7449; W. M.
Seganish and P. DeShong, J. Org. Chem., 2004, 69, 6790; A. S.
Manoso and P. DeShong, J. Org. Chem., 2004, 69, 8305 and references
therein.
CH), 2.7 (1H, dd, J = 8.06, 8.40, CH
2
1
3
1
0.4, CH
2
), 1.12 (3H, d, J = 7.1, CH
) 176.1, 172.7, 52.5, 52.4, 37.9, 36.0, 17.4; MS (EI+) [MH ];
, m/z 160.0730, found 160.0302.
3
+
CDCl
3
1
1
0 For examples of rhodium-catalysed additions/enantioselective proto-
calcd for C
7
H
12
O
4
nations, see: M. T. Reetz, D. Moulin and A. Gosberg, Org. Lett.,
2
001, 3, 4083; C. J. Chapman, K. J. Wadsworth and C. G. Frost,
Ethyl 2-(1,3-dioxoisoindolin-2-yl)propanoate (11). Title com-
pound isolated as a white solid, alongside trace amounts of
J. Organomet. Chem., 2003, 680, 206; L. Navarre, S. Darses and
J.-P. Genet, Angew. Chem., Int. Ed., 2004, 43, 719; M. P. Sibi, H.
Tadamidani and K. Patil, Org. Lett., 2005, 7, 2571; T. Nishimura, S.
Hirabayashi, Y. Yasuhara and T. Hayashi, J. Am. Chem. Soc., 2006, 128,
inseparable ethyl-a-phthalimidoacrylate; R
ether–ethyl acetate) 0.41; IR (nujol, cm ) m 2922, 2853, 1783,
f
(4 : 1, petroleum
−
1
2
556.
1
1
716, 1611, 1464, 1385, 1303, 1262, 1233, 1201, 1152, 1099, 1082,
1 D. Adam, Nature, 2003, 421, 571; Microwaves in Organic Synthesis,
ed. A. Loupy, Wiley-VCH, Weinheim, Germany, 2002; C. O. Kappe,
Angew. Chem., Int. Ed., 2004, 43, 6250; B. L. Hayes, Aldrichimica Acta,
1
064, 1021, 1008, 934, 883, 799, 761, 719; H NMR (300 MHz,
CDCl
3
) d 7.87 (2H, dd, J = 3.0, 5.3 Hz, Ar), 7.74 (2H, dd, J =
.0, 5.3 Hz, Ar), 4.97 (1H, q, J = 7.2 Hz, CH), 4.21 (2H, dq, J =
.3, 7.2 Hz, CH ), 1.24 (3H, t,
), 1.70 (3H, d, J = 7.2 Hz, CHCH
CH ); C NMR (75.5 MHz, CDCl ) 170.1, 167.8,
34.5, 132.3, 123.9, 62.2, 48.0, 15.7, 14.5.
2
004, 37, 66; C. Gabriel, S. Gabriel, E. H. Grant, B. S. J. Halstead
3
1
and D. M. P. Mingos, Chem. Soc. Rev., 1998, 27, 213; S. Caddick,
Tetrahedron, 1995, 51, 10403.
2
3
1
3
J = 7.2 Hz, CH
2
3
3
12 M. Pucheault, S. Darses and J.-P. Genet, Eur. J. Org. Chem., 2002, 3552.
1
3 J. E. Huheey, E. A. Keitner and R. L. Keitner, Inorganic Chemistry:
Principles of Structure and Reactivity, Harper-Collins, New York, 4th
edn, 1993.
1
1
4 S. J. Thompson, P. M. Bailey, C. White and P. M. Maitlis, Angew. Chem.,
Int. Ed. Engl., 1976, 15, 490; C. White, S. J. Thompson and P. M.
Maitlis, J. Organomet. Chem., 1977, 134, 319; R. Fernandez-Galan,
B. R. Manzano, A. Otero, M. Lanfranchi and M. A. Pellinghelli, Inorg.
Acknowledgements
We are grateful to the EPSRC (DTA) and Pfizer Limited (CASE
award to JH) for funding. The EPSRC Mass Spectrometry Service
at the University of Wales Swansea is also thanked for their
assistance.
Chem., 1994, 33, 2309.
1
15 With KF as additive a 35% conversion was observed by H NMR.
1
6 M. C. Fournie-Zaluski, A. Coulaud, R. Bouboutou, P. Chaillet, J.
Devin, G. Waksman, J. Costentin and B. P. Roques, J. Med. Chem.,
1
2
985, 28, 1158; W. M. Moore and C. A. Spilburg, Biochemistry, 1986,
5, 5189; P. Buhlmayer, A. Caselli, W. Fuhrer, R. Goschke, V. Rasetti,
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