Rhodium catalysed hydroformylation of unsaturated esters

Article abstract of DOI:10.1016/j.tetlet.2004.03.168

Rhodium catalysed hydroformylation of unsaturated esters has been studied. A pronounced temperature dependence was observed on the regioselectivity and catalytic activity for these reactions, and under the appropriate conditions, it is possible to obtain preferentially either linear or quaternary products. A quaternary selective hydroformylation of methyl atropate to give 1,3-aldehydic esters has also been developed.

Full text of DOI:10.1016/j.tetlet.2004.03.168

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4043–4045
q
Rhodium catalysed hydroformylation of unsaturated esters
Matthew L. Clarke*
School of Chemistry, University of St. Andrews, St. Andrews, Fife, KY16 9ST, UK
Received 5 February 2004; revised 16 March 2004; accepted 26 March 2004
Abstract—Rhodium catalysed hydroformylation of unsaturated esters has been studied. A pronounced temperature dependence was
observed on the regioselectivity and catalytic activity for these reactions, and under the appropriate conditions, it is possible to
obtain preferentially either linear or quaternary products. A quaternary selective hydroformylation of methyl atropate to give 1,3-
aldehydic esters has also been developed.
Ó 2004 Elsevier Ltd. All rights reserved.
3
1
,3-Difunctional and 1,4-difunctional carbonyl com-
centres’. However, a review of the literature shows that
Alper and co-workers have already made some progress
in this regard. Hydroformylation of methyl methacry-
pounds are useful intermediates in organic synthesis and
pharmaceutical chemistry. A potentially attractive and
atom efficient strategy that could produce a wide range
of these compounds is alkoxycarbonylation of terminal
alkynes, followed by regioselective hydroformylation.
The resulting aldehydes should be readily transformable
by reductive amination/reduction/oxidation into a range
of compounds including amino-alcohols, c-butyrolac-
tones and diacids. Hydroformylation is well established
as an important reaction for bulk chemical synthesis,
but in recent years there has been growing interest in the
application of this reaction as a functional group toler-
ant, completely atom efficient C–C bond forming reac-
6
late (MMA) in the presence of [Rh(COD)(g -Ph-BPh
dppb gave a 54% yield of the quaternary aldehyde
3
)]/
4
Me C(CHO)(CO Me) with a 9:1 selectivity. An earlier
2
2
paper showed a pronounced temperature and pressure
effect on the regioselectivity of MMA hydroformylation:
at high pressure and lower temperatures, high selectivity
for quaternary Me C-(CHO)(CO Me) could be ob-
2
2
tained using [Rh(PPh
3
)
3
(CO)H] as catalyst. Unfortu-
nately, at these lower temperatures (40–60 °C), catalytic
activity is compromised. The aim of this study was to
5
understand further the factors affecting rate and selec-
tivity in hydroformylation of the more highly substi-
tuted unsaturated esters, which have recently become
more accessible using palladium catalysed alkoxycarb-
onylation. It was envisaged that highly reactive phos-
phite based catalysts might promote a high yielding
regioselective reaction.
1
tion for selective organic synthesis.
Acrylates have been found to be amongst the least
reactive substrates in hydroformylation, and conse-
quently studies which demonstrate their high-yielding,
selective transformation into 1,3- and 1,4-difunctional
2
compounds are relatively scarce. Furthermore, the
formation of potentially valuable chiral 1,3-aldehydic
esters from 2-substituted 2-propenoate esters is further
In order to discover the ideal ligand and conditions for
hydroformylation of unsaturated esters, a range of
ligands was screened in the hydroformylation of tert-
1
disadvantaged by defying the widely quoted Keulemans
2b
(empirical) rule, which states that ‘in hydroformylation,
formyl groups are not produced at quaternary carbon
butyl methacrylate (Scheme 1). Representative results
are shown in Table 1. At 100 °C, the linear aldehyde is
formed preferentially, but high selectivity is only ob-
tained at low pressures. Phosphine ligands (including the
6
normally highly linear selective BISBI ligand) fail to
Keywords: Hydroformylation; Alkoxycarbonylation; Regioselective
C–C bond formation; Quaternary carbons; Phosphite; Rhodium.
give either acceptable yields or regioselectivity in this
reaction. The use of triphenylphosphite as the ligand
gives a near perfect conversion to the linear product
(Table 1; entry 7). The use of the bulky phosphite,
q
Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2004.03.168
*
Tel.: +44-1334-463-829; fax: +44-1334-463-808; e-mail: mc28@
st-andrews.ac.uk
7
tdtbpp at 40 °C and 40 bar reverses the selectivity in
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.168

4044
M. L. Clarke / Tetrahedron Letters 45 (2004) 4043–4045
Table 1. Rhodium catalysed hydroformylation of tert-butyl methacrylate
Entry
Ligand
Conversion (%)
1b/1a
Temperature (°C)
Pressure (bar)
Time (h)
1
2
3
4
5
6
7
8
Ph
Ph
3
P
P
95
51
23
25
91
25
95
95
3.2/1
12.0/1
18.0/1
5.1/1
2.9/1
5.0/1
38.0/1
0.6/1
100
100
100
100
100
100
100
40
18
8
20
20
20
40
40
20
20
30
3
BINAP
BINAP
BISBI
8
18
18
8
BISBI
(PhO)
tdtbpp
3
P
8
40
Reactions were carried out in a 100 mL stainless steel autoclave under the conditions described in the Table 1 and Scheme 1. Conversion, GC yields
and selectivity were measured using a GC equipped with a FID detector and are measured against biphenyl (20 mol%) added as an internal standard.
1
The identity of the products and the product distributions were further confirmed by H NMR integration and EI and CI mass spectrometry.
The phosphite based catalysts were used for hydro-
PPh2
PPh2
formylation of atropate esters 2a and 3a (Scheme 3).
These substrates were even less reactive than tert-butyl
methacrylate and required longer reaction times for
complete conversion. A small amount (ꢀ10%) of
hydrogenation product was also detected in these reac-
tions. However, at lower temperature and higher pres-
sure, it proved possible to form a quaternary carbon
centre selectively using rhodium catalysed hydroformyl-
ation (Table 2; entry 1, synthesis of 5a). Some of this
material was purified using flash chromatography and
showed the expected spectroscopic data for the pure
O
P
PPh2
PPh2
3
BISBI
BINAP
tdtbpp
2
% Ligand
CHO
CHO
CO2But
0
.33% [Rh(acac)(CO)2]
CO2But
CO But
2
1b
Me
H2 / CO (1:1), toluene
1
a
Scheme 1. Ligands used in the hydroformylation of tert-butyl acrylate.
11;
regioisomer 5a.
In addition, at 100 °C and low pres-
sure, it was possible to form the linear aldehyde with
good selectivity (12:1) using the conditions in Table 2;
entry 2. The bulky isopropyl ester proved extremely
unreactive in this reaction (higher temperatures than
favour of the quaternary aldehyde 1a (Table 1; entry 8,
Scheme 1).
Since styrenes tend to favour branched selectivity in
8
1
00 °C were not attempted since tropolate esters are
rhodium catalysed hydroformylation, it was envisaged
that hydroformylation of hitherto unstudied atropate
esters might show selectivity for the quaternary aldehyde
known to polymerise at elevated temperatures). The use
of the catalyst system based on tdtbpp did not appear to
give any product at all in this case (not shown in Table
5
a. These compounds are potentially useful intermedi-
2
).
ates for a range of compounds (including, for example,
amino-alcohols Ph(Me)C(CH OH)(CH NHR) that
2
2
In order to investigate the role of the phenyl group in
allowing access to the quaternary aldehydes, the hydro-
formylation of 2-n-butyl acrylic acid methyl ester, 4a
have been investigated as b-adrenoceptor blocking
agents).
9
(
prepared using the Drent methoxycarbonylation reac-
The atropate type esters 2a and 3a were prepared using
the catalyst system designed by Drent et al. for car-
tion) was also attempted using the triphenylphosphite
based catalyst system (Table 2; entries 5–7). As can be
seen, sufficient quaternary selectivity or conversions in
these reactions could not be obtained under the condi-
tions studied. The presence of an aryl group may
therefore be advantageous in these reactions.
10
bonylation of propyne. This catalyst gave essentially
complete conversion and regioselectivity towards iso-
mers 2a and 3a. Some material was unavoidably lost
during removal from the autoclave and during vacuum
distillation thus giving ꢀ60% yields of pure material
(
Scheme 2).
In conclusion, it has been shown that regioselective
methoxycarbonylation of phenylacetylene followed by
regioselective hydroformylation constitutes a valid
method to construct 1,3-dicarbonyl compounds bearing
a quaternary carbon centre (and thus contradicting
Keulemans rule). Under alternative reaction conditions,
it is also possible to prepare 1,4-dicarbonyl compounds
of high regioisomeric purity.
O
0
.05% [Pd(OAc)2]
O
R1
OR2
1.5% Ph2Py
R1
OR2
1
.5% p-tolSO3H
R1
2
o
R OH, 60 C, 40 bar CO
2b-4b not
2
a-4a
detected
Yield (Conversion
to alkene)
1
2
2
a: R = Ph, R = Me, 65% (>95)
1
2
i
3
a: R = Ph, R = Pr, 56% (>95)
1
n
2
4
a: R
= Bu, R = Me, 63% (>95)
Scheme 2. Synthesis of unsaturated esters 2a–4a using palladium
catalysed alkoxycarbonylation of alkynes.
Experimental procedures and selected spectroscopic and characteri-
sation data are available in the supplementary material.

M. L. Clarke / Tetrahedron Letters 45 (2004) 4043–4045
Table 2. Hydroformylation of unsaturated esters 2a–4a
4045
Entry
Alkene
Ligand
Conversion
(
b/a
Pressure (bar)
Time (h)
Temperature
(°C)
% hydrog. product) (a ¼ quaternary product)
1
2
3
4
5
6
7
2a
2a
3a
3a
4a
4a
4a
tdtbpp
tdtbpp
>98 (13)
>98 (13)
9 (n.d.)
1/13
12.2/1
1/2
35
12
40
8
70
40
20
20
20
40
70
45
100
40
(PhO)
(PhO)
(PhO)
(PhO)
3
3
3
3
P
P
P
P
24 (n.d.)
49 (<5%)
15 (n.d.)
33 (n.d.)
12/1
11/1
1/3.7
1/1.7
100
100
40
8
32
32
tdtbpp
50
Reactions were carried out in a 100 mL stainless steel autoclave under the conditions described in the Table 2 and Scheme 3. Conversion, GC yield
and selectivity were measured using a GC equipped with a FID detector and are measured against biphenyl (20 mol%) added as an internal standard.
1
Product identities and distributions were further confirmed by H NMR integration and EI and CI mass spectrometry.
only example of hydroformylation of tert-butyl acrylate:
Consiglio, G.; Kollar, L.; Kolliker, R. J. Organomet.
Chem. 1990, 396, 375; (c) Parrinello, G.; Stille, J. K. J. Am.
Chem. Soc. 1987, 109, 7122; (d) Chelation controlled
formation of branched aldehydes: Gladiali, S.; Pinna, L.
Tetrahedron: Asymmetry 1991, 2, 62.
2
% L
CHO
CHO
CO2R2
0
.33% [Rh(acac)(CO)2]
R1
R1
CO2R2
R1
2
CO R
2
H2 / CO (1:1), toluene
5
a-7a
5b-7b
a: R 11 = Ph, R2 = Me
2
3
4
1
2
2
i
5a/5b: R = Ph, R = Me
a: R = Ph, R = Pr
1
2
i
1
n
Bu, R2 = Me
6a/6b: R = Ph, R = Pr
a: R
=
3. This ‘rule’ is often described in textbooks: for example,
Chapter 4 in Colquhoun, H. M.; Thompson, D. J.; Trigg,
M. V. In Carbonylation: Direct Synthesis of Carbonyl
Compounds; Plenum: New York, 1991; Original Reference:
Keulemans, A. I. M.; Kwantes, A.; Van Bavel, T. Recl.
Trav. Chim. Pays-Bas 1948, 67, 298.
1
n
2
7
a/7b: R = Bu, R = Me
CHO
Ph
CO2Me
5
a
4
5
. Lee, C. W.; Alper, H. J. Org. Chem. 1995, 60, 499.
. Pittman, C. U., Jr; Honnick, W. D.; Yang, J. J. J. Org.
Chem. 1980, 45, 684.
Scheme 3. Hydroformylation of esters 2a–4a.
6
7
. Casey, C. P.; Paulsen, E. L.; Beuttenmueller, E. W.; Proft,
B. R.; Petrovich, L. M.; Matter, B. A.; Powell, D. R. J.
Am. Chem. Soc. 1997, 119, 11817.
. (a) van Leeuwen, P. W. N. M.; Rooboeek, C. F.
J. Organomet. Chem. 1983, 258, 343; (b) van Rooy, A.;
Orji, E. N.; van Leewen, P. W. N. M. Organometallics
Acknowledgements
The author would like to thank Professor Paul Pringle
for his support of this work, and Dr. G. C. Lloyd-Jones
for the use of his GC instrument.
1
995, 14, 34.
8
. (a) Breit, B. J. Chem. Soc., Chem. Commun. 1996, 2071; (b)
Sakai, N.; Mano, S.; Nozaki, K.; Takaya, H. J. Am.
Chem. Soc. 1993, 115, 7033; (c) Baber, R. A.; Clarke, M.
L.; Orpen, A. G.; Ratcliffe, D. A. J. Organomet. Chem
References and notes
2
003, 667, 112.
1
. (a) Breit, B. Acc. Chem. Res. 2003, 36, 264; (b) Lambers-
Verstappen, M. M. H.; deVries, J. G. Adv. Synth. Catal.
9. Knabe, J.; Bladauf, J.; Bucheit, W. Arch. Pharm. G. E.
1985, 318, 832.
2
003, 345, 478; (c) Botteghi, C.; Pagnelli, S.; Moratti, F.;
10. (a) Drent, E.; Arnoldy, P.; Budzelaar, P. H. M. J. Orga-
nomet. Chem. 1993, 455, 247, and references therein.; (b)
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dron Lett. 2002, 43, 753.
11. The synthesis of the ethyl ester has been previously
reported by a multi-step procedure: Domagal, J. M.; Bach,
R. D.; Wemple, J. J. Am. Chem. Soc. 1976, 98, 1975.
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Korda, A.; Shay, W. R. J. Org. Chem. 1991, 56, 2024;
(e)Rhodium Catalysed Hydroformylation; Claver, C., Van
Leeuwen, P. W. N. M., Eds.; Kluwer, 2002.
2
. (a) Hu, Y.; Chen, W.; Banet Osuna, A. M.; Iggo, J. A.;
Xiao, J. J. Chem. Soc., Chem. Commun. 2002, 788; (b) The