Highly regioselective rhodium-catalysed hydroformylation of unsaturated Esters: The first practical method for quaternary selective carbonylation

Article abstract of DOI:10.1002/chem.200600914

Highly regioselective hydroformylation of unsaturated esters can be achieved when a highly reactive, ligand-modified, rhodium catalyst is employed near ambient temperatures (15-50°C) and pressures over 30 bar. The use of 1,3,5,7-tetramethyl-2,4,8-trioxa-6-phosphaadamantane shows distinct advantages over other commonly applied phosphanes in terms of reaction rate, and regio- and chemoselectivity. Hydroformylation of a range 1,1-di- and 1,1,2-trisubstituted unsaturated esters yields quaternary aldehydes that are forbidden products according to Keulemans Rule. The aldehydes can be reductively aminated with molecular hydrogen to give β-amino acid esters in high yield. The overall green chemical process involves converting terminal alkynes into unusual β-amino acid esters with only water generated as an essential byproduct. This catalytic system has also been applied to the hydroformylation of simple 1,2-disubstitued unsaturated esters, which have been hydroformylated with excellent α-selectivity and good chemo-selectivity for the first time.

Full text of DOI:10.1002/chem.200600914

FULL PAPER
DOI: 10.1002/chem.200600914
7978
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Chem. Eur. J. 2006, 12, 7978 – 7986

FULL PAPER
Highly Regioselective Rhodium-Catalysed Hydroformylation of Unsaturated
Esters: The First Practical Method for Quaternary Selective Carbonylation
Matthew L. Clarke* and Geoffrey J. Roff[a]
Abstract: Highly regioselective hydro-
formylation of unsaturated esters can
be achieved when a highly reactive,
ligand-modified, rhodium catalyst is
employed near ambient temperatures
(15–508C) and pressures over 30 bar.
The use of 1,3,5,7-tetramethyl-2,4,8-
1,1-di- and 1,1,2-trisubstituted unsatu-
rated esters yields quaternary alde-
hydes that are forbidden products ac-
cording to Keulemans Rule. The alde-
hydes can be reductively aminated with
molecular hydrogen to give b-amino
acid esters in high yield. The overall
green chemical process involves con-
verting terminal alkynes into unusual
b-amino acid esters with only water
generated as an essential byproduct.
This catalytic system has also been ap-
plied to the hydroformylation of simple
1,2-disubstitued unsaturated esters,
which have been hydroformylated with
excellent a-selectivity and good chemo-
selectivity for the first time.
trioxa-6-phosphaadamantane
shows
distinct advantages over other com-
monly applied phosphanes in terms of
reaction rate, and regio- and chemose-
lectivity. Hydroformylation of a range
Keywords: aldehydes · atom effi-
ciency · homogeneous catalysis ·
hydroformylation · rhodium
Introduction
Low-molecular-weight, densely functionalised aldehydes
are very important building blocks, in particular for the syn-
thesis of secondary amines. Secondary amines are an ex-
tremely common motif in compounds of pharmaceutical in-
terest, with reductive amination the workhorse for their
preparation. This research project was therefore aimed to-
wards preparing these building blocks in a highly efficient
manner from commodity chemicals (terminal alkynes) with
no harmful waste products. The proposed route is shown in
Scheme 1 and utilises the potentially 100% atom-efficient
One of the challenges facing the chemical industry is to
retain the capacity to synthesise complex molecules, while
significantly reducing the environmental impact of the syn-
thetic procedures required. The development of selective
procedures that do not generate waste products is therefore
an important objective that should give process chemists an
improved arsenal of clean methodology. Hydroformylation
of alkenes is an excellent example of a potentially 100%
atom efficient reaction, and has been extensively used in the
industrial synthesis of simple linear aldehydes (production is
estimated at ~7 million tonnes per annum).[1–4] Enantioselec-
tive hydroformylation of some commodity alkenes, such as
styrene, vinyl acetate and allyl cyanide, has also been an
active topic of research in both academia and industry, with
some notable advances in recent years.[5–13] However, despite
these precedents, hydroformylation is underused in organic
syntheses, with little known about how more complex sub-
strates perform in this reaction.[14–16]
Scheme 1. Palladium-catalysed alkoxycarbonylation followed by hydro-
formylation.
a-selective alkoxycarbonylation of terminal alkynes devel-
oped by Drent and co-workers for methyl methacrylate syn-
thesis from propyne,[17] coupled with the unexplored (poten-
tially 100% atom efficient) hydroformylation of the result-
ing 1,1-disubstituted esters (Scheme 1).
[a] Dr. M. L. Clarke, Dr. G. J. Roff
School of Chemistry, University of St. Andrews
EaSTChem, St. Andrews, Fife, KY16 9ST (UK)
Fax : (+44)1334-463-850
E-mail: mc28@st-andrews.ac.uk
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7979

M. L. Clarke and G. J. Roff
There are two possible regiochemical outcomes from this
reaction, a quaternary or linear aldehyde, with the linear
product being predicted based on the prevailing dogma in
hydroformylation chemistry. The low probability of forming
quaternary aldehydes using this methodology is emphasised
by the widely quoted Keulemans rule that states: “in hydro-
formylation, formyl groups are not produced at quaternary
carbon centres”.[15,16,18,19] However, an inspection of the liter-
ature suggested to us that this empirical rule was more of a
general observation. In particular, there are a couple of iso-
lated examples of chelation controlled quaternary selective
hydroformylation reactions.[20–23] In these examples, the pref-
erential formation of a quaternary rhodium alkyl species sta-
bilised by a second chelate interaction seems the most likely
explanation for the selectivity observed. More relevantly,
Alper and co-workers had shown that hydroformylation of
to hold some advantage in the hydroformylation of methyl
atropate in two preliminary reactions under unoptimised
conditions. This observation led us to thoroughly investigate
the effect of ligands, solvents, temperature, pressure, and
substrate in hydroformylation of unsaturated esters, and
here we describe how these studies have led to a practical
procedure for the synthesis of quaternary substituted alde-
hydes, and enabled high-yielding a-selective hydroformyla-
tion of 1,2-substituted unsaturated esters for the first time.
If the hydroformylation of tert-butyl methacrylate (2a) is
performed at high temperatures and low pressure the prod-
ucts were found to be predominantly linear (Table 1 and
Scheme 2). Using the cage phosphane catalyst 1a, tert-butyl
Table 1. Hydroformylation of methyl methacrylate and tert-butyl meth-
acrylate.
methyl methacrylate using [Rh
(cod)(h6-C6H5-BPh3)] and
G
Alkene
Ligand
Conversion [%][a]
Q/L[a]
1/3.2
1/12.0
1/18.0
1/5.1
1/2.9
1/5.0
1/38.0
11.3/1
1.3/1
1/0.6
14.8/1
54/1
11/1
45/1
11/1
50/1
Conditions[b]
dppb (cod=cyclooctadiene, dppb=1,2-bis(diphenylphos-
phano)benzene) as ligand gave a 54% yield of the quaterna-
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
PPh3
PPh3
BINAP
BINAP
BISBI
BISBI
(PhO)3P
PPh3
1b
1b
1a
PPh3
1b
1a
1a
1a
95
51
23
25
91
25
95
99
99
95
98
99
A
B
B
C
C
B
B
D
D
E
D
F
ry aldehyde, Me2C
N
N
ty.[24] This report in particular gave us some hope that a gen-
eral procedure for quaternary selective hydroformylation of
unsaturated esters could be realised if the correct catalyst
and reaction conditions could be found.
Results and Discussion
99
F
F
F
F
99[c]
99[d]
99[e]
Research described in our preliminary communication dem-
onstrated that quaternary regioselectivity could be obtained
providing very reactive rhodium catalysts derived from
bulky monophosphite ligands, 1b were employed. However,
[a] Determined by proton NMR spectroscopy. [b] Reaction conditions:
A) 1008C, 18 bar, 20 h; B) 1008C, 8 bar, 20 h; C)1008C, 18 bar, 40 h; D)
508C, 50 bar, 70 h; E) 408C, 40 bar, 30 h; F) 508C, 50 bar, 20 h. [c] THF
used as reaction solvent. [d] DCM used as reaction solvent. [e] 97% iso-
lated yield.
Scheme 2. The hydroformylation of methyl and tert-butyl methacrylate.
methacrylate was hydroformylated at 508C under 50 bar of
syngas with high quaternary/linear selectivity. Recently,
Reetz and Li have carried out hydroformylation of tert-butyl
methacrylate, using mixtures of monodentate phosphorus li-
gands, although no other substrates were reported.[27] Their
results show that the majority of ligands give poor selectivity
but several combinations of ligand give similarly excellent
regioselectivity.
Hydroformylation of the methyl ester (2b) gave even
higher selectivity to the quaternary aldehyde. The use of al-
ternative solvents to toluene gave decreased regioselectivity.
Since methyl methacrylate is a nonviscous liquid and to
regioselectivity (between 1.7:1 and 13:1) and chemical yield
were not quite high enough to be a practical method for
synthesis.[25] In an initially unrelated project, we collaborated
with the Pringle group to show the remarkably high activity
of phenylphosphatrioxaadamantanes (1a) in rhodium-cata-
lysed hydroformylation of hex-1-ene.[26] This paper also
notes that this easily prepared, air-stable phosphane seemed
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Chem. Eur. J. 2006, 12, 7978 – 7986

Homogeneous Catalysis
FULL PAPER
demonstrate the full power of this catalytic system, we hy-
droformylated neat methyl methacrylate using a substrate/
catalyst ratio of 10000 to obtain excellent regioselectivity
and almost complete conversion. Analysis of the reaction
mixture reveals quaternary aldehyde (95%), linear aldehyde
(1.5%) hydrogenated product (1.5%) with only 2% of the
methyl methacrylate present.
A thorough examination of the effect of ligands, tempera-
ture and pressure in the hydroformylation of methyl atro-
pate (3) and esters 4–7 has been carried out (Tables 2 and 3
below). Substrates 3, 5 and 6 were readily prepared by me-
thoxycarbonylation of the alkynes. Once again, rhodium
complexes of 1a gave by far most impressive results with re-
spect to both regio and chemoselectivity.
monodentate ligands performed badly in this reaction giving
relatively low conversions or favouring hydrogenation. Bi-
dentate ligands tested showed very little reactivity.
To demonstrate the scope of this new process, a series of
other 1,1-disubstituted alkenes were hydroformylated with
high regioselectivity (Scheme 4; Table 3). The hydrogenation
byproduct was again a problem in the hydroformylation of
dimethyl itaconate (4). However, this was essentially elimi-
nated by using phosphane 1a as ligand.
For reaction of methyl atropate at 1008C, (Scheme 3;
Table 2; entries 11–14), the amount of linear product re-
duces dramatically with an increase in pressure and the
Scheme 4. Hydroformylation of a range of other 1,2-disubstituted unsatu-
rated esters (see Table 3 footnotes for reaction conditions).
Table 3. Hydroformylation of 1,1-disubstituted alkenes.
Substrate
Conditions[a]
Conversion [%][b]
(% hydrog)
Q/L[b]
AHCTREUNG
Scheme 3. Hydroformylation of methyl atropate, 3.
A
B
C
99 (20)
99 (16)
99 (3)[c]
>100/1
10/1
Table 2. Hydroformylation of methyl atropate.
92/1
Entry Ligand
T
[8C]
P
t
Aldehyde
[bar] [h] [%][a]
(% hydrog)
Q/L[a]
D
C
99
5.3/1
11/1
ACHTREUNG
30[d]
AHCTREUNG
1
2
3
4
5
6
7
8
1b
PPh3
30
50
50
50
50
50
50
50
50
50
50
50
5
90 45 (55)
20 30 (46)
20 52 (7)
20 21 (22)
>50/1
6/1
6.4/1
20/1
4.0/1
23/1
>100/1
>100/1
1.5/1
1/1
1/>100
1/28
1/5.3
1.6/1
16/1
44/1
>100/1
>100/1
42/1
D
E
>99
6.6/1
22/1
>99 (8)[e]
A
(CF3)2C6H3)3P 50
A
B
C
94[f]
54[g]
82[h]
56/1
6.2/1
48/1
50
50
50
50
50
50
50
100
100 10
100 25
100 50
75
50
30
15
50
50
G
20
5 (79)
ACHTREUNG
20 47 (19)
dppe
dppb
xantphos
BINAP
1a
1a
1a
1a
1a
1a
1a
1a
1a
20
20
20
20
1 (16)
6 (14)
5
6
[a] Reaction conditions: 0.2% [Rh(acac)(CO)2], toluene, A) PPh3 (1%),
G
508C, 50 bar, 20 h; B) 1b (1%), 508C, 50 bar, 20 h; C) 1a (1%), 508C,
50 bar, 20 h; D) 1a (1%) 758C, 75 bar, 70 h; E) 1a (1%), 508C, 50 bar,
70 h. [b] Determined by proton NMR spectroscopy. [c] 93% isolated
yield. [d] 70% isomerisation product detected. [e] 69% isolated yield.
[f] 6% isomerisation product detected. [g] 45% isomerisation detected.
[h] 18% isomerisation detected, 62% isolated yield.
9
10
11
12
13
14
15
16
17
18
19
20
70 45 (55)
40 60 (30)
24 70 (30)
24 76 (24)
24 87 (13)
20 90 (10)
90 92[b] (8)
70 55 (1)
66 86 (14)
20 86 (14)
50
50
50
50
25
60
A different problem arose in the hydroformylation of
methyl a-butylacrylate (5) and the diester 7. The reactions
were sluggish and extensive isomerisation to the trisubstitut-
ed ester seemed to have taken place. This suggested the pos-
sibility that the reaction of 5 proceeds by the hydroformyla-
tion of the more stable trisubstituted alkene (8) to the same
quaternary product (9; Scheme 5). When the reaction was
stopped after several hours, NMR spectroscopy showed only
aldehyde and trisubstituted alkene 8 to be present lending
strong support to this proposal. Direct hydroformylation of
the trisubstituted alkene was examined by isolating a pure
sample of 8 after three hours of treatment with the Rh cata-
lyst and syngas.
1a
41/1
[a] Determined by proton NMR spectroscopy; starting material is the
only other chemical making up mass balance. [b] 91% isolated yield.
[c] (4-anis)3P=(4-MeO-C6H4)3P.
amount of hydrogenation is also reduced. In experiments in
which the pressure was kept constant (entries 14–18), the
amount of linear product and hydrogenation decreased with
decreasing temperature. Under optimal conditions hydroge-
nation was suppressed to 8% with essentially complete qua-
ternary selectivity (entry 17). All other commonly applied
Trisubstituted alkenes (Scheme 6; Table 4) are especially
problematic substrates for hydroformylation. Breit and co-
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7981

M. L. Clarke and G. J. Roff
The results show that an ester group has such a strong
effect at directing hydroformylation, that disfavoured qua-
ternary aldehydes can be produced with excellent selectivity.
The reason this has not been exploited successfully in the
past is that the directing effect is somewhat temperature,
pressure and ligand dependant and, in particular, is negligi-
ble when higher temperatures are employed. Most catalytic
systems are ineffective at the temperatures used in this
study, with the remarkable difference between other ligands
and 1a evident in Table 2. Finally, it should be noted that
the substrates employed are very readily hydrogenated
under hydroformylation conditions. The use of ligand 1a in-
hibits hydrogenation.
Scheme 5. Proposed isomerisation-hydroformylation.
Inspection of the literature reveals that high-yielding re-
gioselective hydroformylation of 1,2-disubsituted unsaturat-
ed esters (Scheme 7) has not been possible to date, despite
Scheme 6. Hydroformylation of trisubstituted alkenes (see Table 4 foot-
notes for reaction conditions).
Table 4. Hydroformylation of trisubstituted alkenes.
Substrate
Conditions[a]
Conversion [%][b]
a/b[b]
A
0
ND
B
99
10.1/1
A
B
16
12/1
7.5/1
78[c]
Scheme 7. Hydroformylation of 1,2-substituted unsaturated esters (see
Table 5 footnotes for reaction conditions).
A
B
48
23/1
48/1
99[d]
hydroformylation being the cheapest, cleanest route to the
fundamental building blocks. We therefore investigated sev-
eral of these substrates using the new catalyst system and re-
action conditions.
[a] Reaction conditions: A)508C, 50 bar, 70 h; B)758C, 75 bar, 70 h.
[b] Determined by proton NMR spectroscopy. [c] 70% isolated yield,
3% hydrogenation. [d] 69% isolated yield.
A practical process for hydroformylation of methyl croto-
nate (13) has been elusive as phosphane-modified catalysts
generally give b-products under the conditions required to
achieve full conversion and also suffer from very significant
hydrogenation byproduct.[29,30] Our studies, under relatively
mild conditions, revealed a high degree of hydrogenation
when PPh3 was used as the ligand (Scheme 7 and Table 5).
workers have developed a remarkably active hydroformyla-
tion catalyst that gave incredibly high TOF (TOF=turnover
frequency) for most substrates.[28] However, hydroformyla-
tion of (À)-a-pinene gave only 13% conversion to the dia-
stereomerically pure linear aldehyde after 16 h emphasising
the sluggish nature of the substrates. Methyl tiglate (12) has
been reported to barely react unless high temperatures are
employed and yields below 50% are observed.[29] It was
therefore pleasing to observe that using modified conditions
of 75 bar and 758C, conversion of 12 to quaternary aldehyde
could be achieved using this catalytic system (Table 4).
When alkene 8, previously implicated in hydroformylation
of 5, was examined good quaternary selectivity was ob-
served. A particularly surprising substrate is 11. In addition
to the quaternary aldehyde being disfavoured by Keule-
manꢁs rule, it is well established that hydroformylation reac-
tions are normally directed to benzylic positions.[15] Howev-
er, there is a clear regioselective preference for the quater-
nary aldehyde. No reaction occurred when 10 was the sub-
strate suggesting that only the 1,1,2-trisubstituted alkenes
would react and tetrasubstituted alkenes would most likely
be unreactive.
Table 5. Hydroformylation of 1-substituted alkenes.
Substrate
Ligand
Conditions[a]
Conversion [%][b]
(% hydrog)
a/b[b]
AHCTREUNG
13
13
13
14
15
15
15
15
16
PPh3
1a
1a
1a
1b
PPh3
1a
1a
C
C
D
D
C
C
C
E
C
99 (35)
99 (5)[c]
99 (3)
>100/1
>100/1
>100/1
52/1
5.1/1
5.6/1
6.0/1
13.8/1
5.9/1
99 (5)
99 (14)
95 (26)
99 (16)
89 (4)
1a
99 (12)[d]
[a] Reaction conditions: A) 158C, 50 bar, 20 h; B) 158C, 50 bar, 70 h; C)
508C, 50 bar, 24 h; D) 408C, 75 bar, 90 h, 5:1 CO/H2 syngas used; E)
308C, 80 bar, 60 h, 5:1 CO/H2 syngas used. [b] Determined by proton
NMR spectroscopy. [c] 94% isolated yield. [d] 64% isolated yield.
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Homogeneous Catalysis
FULL PAPER
The influence of the cage phosphane 1a is dramatic, almost
eliminating hydrogenation and retaining near-perfect regio-
selectivity. Similarly excellent results were obtained in the
hydroformylation of 14. Hydroformylation of methyl croto-
nate, being a nonviscous liquid was attempted without sol-
vent with substrate/catalyst ratio of 10000. Regioselectivity
remained essentially perfect, but more significant hydroge-
nation (17%) was detected. Hydroformylation of methyl
cinnamate (15) was also investigated, although studies by
Botteghi and Paganelli had shown that the hydrogenation
byproduct was more significant than the desired aldehydes
with regioselectivity also poor (best a-selectivity: 11% alde-
hydes with a/b=2:1).[31] Our investigation into the a-selec-
tive hydroformylation clearly demonstrates that Rh catalysts
of the cage phosphane used in conjunction with 50 bar
syngas and lower temperature can reduce the amount of hy-
drogenation byproduct and deliver excellent a-regioselectiv-
ity. The regioselectivity could be further increased and hy-
drogenation further suppressed by using syngas rich in CO
(5:1 CO/H2). Figure 1 shows that this substrate also displays
a strong temperature dependence on chemo- and regioselec-
tivity. The analogous cinnamate 16 showed similar selectivity
and conversion.
Scheme 8. Reductive amination by imine hydrogenation of one of the
quaternary aldehydes.
Conclusion
Aldehydes are fundamental building blocks for organic syn-
thesis. The majority of the aldehydes produced in this paper
have been difficult to access in an efficient manner. In the
case in which their preparation by hydroformylation has
been attempted before, very discouraging results were ob-
tained. We have demonstrated that using phenylphospha-
trioxaadamantane as a ligand, a range of unsaturated esters
can be hydroformylated with high conversion and regiose-
lectivity to favour the less common a-substituted aldehyde.
Keulemanꢁs rule has often been quoted to explain why qua-
ternary aldehydes are not observed in hydroformylation.
This paper shows that not only can this class of aldehyde be
detected in hydroformylation chemistry, but that methoxy-
carbonylation followed by hydroformylation represent a
clean and practical method for quaternary aldehyde synthe-
sis. Our studies have clearly indicated the necessity for
lower reaction temperatures and higher syngas pressure to
facilitate such regioselectivity and to reduce the amount of
hydrogenation byproducts. It has been demonstrated that b-
amino acid derivatives are available in high yield from the
aldehydes, thus completing the overall process of synthesis-
ing useful chemical building blocks from simple alkynes.
Figure 1. The effect of temperature on regio- and chemoselectivity of hy-
droformylation of methyl cinnamate.
Reductive amination: b-Amino acids are valuable building
blocks in the synthesis of peptidomimetics,[32] therapeutic
agents and biologically active compounds.[33,34] Our overall
scheme would amount to the conversion of a terminal
alkyne into b-amino acid derivative with high yield and only
water produced as a necessary byproduct. The catalysts
should be removed in the aqueous extraction of the amine
salt. To confirm the feasibility of the reductive amination re-
action, the aldehyde 18 was readily converted to imine 19
(Scheme 8). The crude imine was hydrogenated in the pres-
Experimental Section
General: All chemicals and solvents were obtained through commercial
sources. Gases were obtained though BOC. Solvents were removed by
rotary evaporation on a Heidolph labrota 4000. Flash column chromatog-
raphy was performed using Davsil silica gel 35–70u 60 A (Fluorochem).
NMR were recorded on Bruker Avance 300 instruments. Proton signal
multiplicities are given as s (singlet), d (doublet), t (triplet), q (quartet),
m (multiplet) or multiples thereof. Infrared spectra were recorded on a
Perkin–Elmer Spectrum GX FT-IR system. Liquids were analysed as
films, solids were analysed as KBr discs or nujol mull. Mass spectra were
recorded on Waters Micromass LCT fitted with lockspray for accurate
mass (ESI) or GCT (CI) instruments. Hydroformylation experiments
were carried out in small glass vessels inside stainless steel autoclaves,
heated in oil baths and stirred magnetically. The ligands MeCgPPh (1a),
phosphite 1b, 1,2-bis(diphenylphosphano)ethane (dppe), 1,2-bis(diphe-
nylphosphano)benzene (dppb), 2,2’-bis[(diphenylphosphano)methyl]-1,1’-
biphenyl (BISBI), (1,1’-binaphthalene)-2,2’-diylbis(diphenylphosphane)
ence of [{Ir(cod)Cl}2] and dppf (dppf=1,1’-bis(diphenyl-
A
phosphano)ferrocene) to a high yield of the amino ester 20.
This result suggests that the quaternary aldehydes produced
should be readily reductively aminated using hydrogen, al-
though the direct one-pot route to such compounds via hy-
droaminomethylation failed to give us the desired com-
pound.[35]
(BINAP),
and
9,9-dimethyl-4,5-bis(diphenylphosphano)xanthene,
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7983

M. L. Clarke and G. J. Roff
(XANTPHOS) were obtained from Strem. The products here have been
prepared or detected before by other less efficient methods.[25,30,35–49]
General procedure—alkoxycarbonylation of alkynes:[25] para-Toluenesul-
(CH3)3), 9.57 ppm (s, 1H; CHO); 13C NMR (75 MHz, CDCl3): d=19.6
((CH3)2), 27.9 (C
C
G
1743 (C=Oester), 2721, 2825 cmÀ1 (C Haldehyde).
À
fonic acid (1.5%) and alkyne were added to solution of Pd(OAc)2
G
Hydroformylation of methyl methacrylate (2b): The general procedure
(0.05%), Ph2PyP (1.5%) in dry methanol. The mixture was transferred
to an autoclave and stirred under 40 bar COat 60 8C for 4 h. NMR spec-
troscopy showed complete conversion in each case. The mixture was di-
luted with diethyl ether, was washed with saturated NH4Cl and water,
was dried (MgSO4) and was concentrated. The residue was distilled
under vacuum to give the desired products in around 60% yield (care
had to be taken not sublime any Ph2PPy, hence the isolated yields are sig-
nificantly below the conversion).
Methyl atropate (3): 1H NMR (300 MHz, CDCl3): d=3.74 (s, 3H;
CO2CH3), 5.81 (s, 1H; CH2), 6.29 (s, 1H; CH2), 7.26–7.38 ppm (m, 5H;
ArH); 13C NMR (75 MHz, CDCl3): d=52.2 (CO2CH3), 126.9 (C=CH2),
128.1128.2, 128.3 (ArCH), 136.7 (ArC), 141.3 (C=CH2), 167.3 ppm
(CO2CH3); MS (ES+): m/z: 185 [M+Na]+; IR (film): n˜ =1615 (C=C),
1723 cmÀ1 (C=O).
2-Methylenehexanoic acid methyl ester(4) : 1H NMR (300 MHz, CDCl3):
d=0.90 (d, J=7.2 Hz, 3H; CH3), 1.25–1.50 (m, 4H; (CH2)2), 2.28 (t, J=
8.4 Hz, 2H; CH2), 3.73 (s, 3H; CO2CH3), 5.51 (s, 1H; =CH2), 6.11 ppm
(s, 1H; =CH2); 13C NMR (75 MHz, CDCl3): d=13.8 (CH3), 22.3, 30.5,
31.6 (CH2), 51.6 (CO2CH3), 124.4 (C=CH2), 140.8 ppm (C=CH2),
CO2CH3; MS (ESÀ): m/z: 127 [MÀCH3]À; IR (film): n˜ =1632 (C=C),
1723 cmÀ1 (C=O).
was followed with [Rh(acac)(CO)2] (2 mg, 0.0078 mmol), 1a (11.3 mg,
A
0.039 mmol), methyl methacrylate (0.42 mL, 3.88 mmol) and toluene
(2 mL). The mixture was stirred under 50 bar syngas at 508C for 24 h.
Flash column chromatography (SiO2, hexane/EtOAc 4:1) yielded 490 mg
1
(97%) of a pale yellow oil; H NMR (300 MHz, CDCl3): d=1.40 (s, 6H;
(CH3)2), 3.78 (s, 3H; CO2CH3), 9.70 ppm (s, 1H; CHO); 13C NMR
(75 MHz, CDCl3): d=19.7 ((CH3)2), 52.5 (CO2CH3), 53.8 (C), 173.2
(CO2CH3), 199.0 ppm (CHO); MS (ES+): m/z: 131 [M+H]+; IR (film):
n˜ =1727 (C=Oaldehyde), 1739 (C=Oester), 2725, 2844 cmÀ1 (C Haldehyde).
À
Hydroformylation of methyl atropate (3): The general procedure was fol-
lowed with [Rh(acac)(CO)2] (1 mg, 0.0039 mmol), 1a (5.6 mg,
E
0.019 mmol), methyl atropate (314 mg, 1.94 mmol) and toluene (1 mL).
The mixture was stirred under 50 bar syngas at 308C for 90 h. Flash
column chromatography (SiO2, hexane/EtOAc 4:1) yielded 340 mg
(91%) of a pale yellow oil. 1H NMR (300 MHz, CDCl3): d=1.71 (s, 3H;
CH3), 3.82 (s, 3H; CO2CH3), 7.21–7.49 (m, 5H; ArH), 9.88 ppm (s, 1H;
CHO); 13C NMR (75 MHz, CDCl3): d=18.2 (CH3), 53.2 (CO2CH3), 62.5
(C), 127.3, 128.6, 129.6, 136.8 (ArC), 172.5 (CO2CH3), 197.0 ppm (CHO);
MS (CI): m/z: 193 [M+H]+; HRMS (CI): m/z calcd for C11H13O3:
193.0865; found: 193.0868 [M+H]+; IR (film): n˜ =1446, 1495 (C=CPh),
1720 (C=Oaldehyde), 1749 (C=Oester), 2727, 2844 cmÀ1 (C Haldehyde).
À
5-Cyano-2-methylenepentanoic acid methyl ester(5)
:
1H NMR
Hydroformylation of dimethyl itaconate (4): The general procedure was
(300 MHz, CDCl3): d=1.80 (quin, J=7.7 Hz, 2H; CH2CH2CH2), 2.30 (t,
J=7.2 Hz, 2H; CH2CN), 2.43 (td, J=7.7, 1.0 Hz, 2H; CH2C=C), 5.6 (q,
J=1.2 Hz, 1H; C=CH2), 6.16 ppm (d, J=1.2 Hz, 1H; C=CH2); 13C NMR
(75 MHz, CDCl3): d=16.5, 24.2, 31.0 (CH2), 52.0 (CO2CH3), 119.3 (CN),
126.6 (C=CH2), 138.3 (C=CH2), 167.0 ppm (CO2CH3); MS (ES+): m/z:
176 [M+Na]+; IR (film): n˜ =1632 (C=C), 1720 (C=O), 2247 cmÀ1 (CN).
followed with [Rh(acac)(CO)2] (2 mg, 0.0078 mmol), 1a (11.3 mg,
U
0.039 mmol), dimethyl itaconate (614 mg, 3.88 mmol) and toluene
(2 mL). The mixture was stirred under 50 bar syngas at 508C for 24 h.
Flash column chromatography (SiO2, hexane/EtOAc 4:1) yielded 679 mg
(93%) of a pale yellow oil. 1H NMR (300 MHz, CDCl3): d=1.30 (s, 3H;
CH3), 2.80 (s, 2H; CH2), 3.57 (s, 3H; CH2CO2CH3), 3.71 (s, 3H;
CO2CH3), 9.84 ppm (s, 1H; CHO); 13C NMR (75 MHz, CDCl3): d=19.6
(CH3), 38.5 (CH2), 52.0, 52.7 (CO2CH3), 54.6 (C), 171.1, 172.4 (CO2CH3),
199.1 ppm (CHO); MS (ES+): m/z: 189 [M+Na]+; HRMS (ES+): m/z
calcd for C8H12O5: 189.0763; found: 189.0757 [M+H]+; IR (film): n˜ =
Synthesis of diester(7) : Tri-n-butylphosphane (723 ml, 0.0029 mol) was
added to stirring solution of methylacrylate (10.46 mL, 0.116 mol) and
hydroquinone (64 mg, 0.58 mmol) in tert-butanol (20 mL). The mixture
was heated under reflux for 4 h before treating with 2m HCl (20 mL) and
extracting with diethyl ether. The combined organics were dried
(MgSO4) and concentrated. Column chromatography (hexane/EtOAc
1718–1746 (br; C=O), 2735, 2852 cmÀ1 (C Haldehyde).
À
Hydroformylation of methyl a-butylacrylate (5): The general procedure
1
4:1) yielded 5.76 g (58%) of a clear oil; H NMR (300 MHz, CDCl3): d=
was followed with [Rh(acac)(CO)2] (2 mg, 0.0078 mmol), 1a (11.3 mg,
A
2.40–2.60 (m, 4H; 2CH2), 3.60 (s, 3H; CO2CH3), 3.69 (3s, H; CO2CH3),
5.53 (1s, H; C=CH2), 6.12 ppm (s, 1H; C=CH2); 13C NMR (75 MHz,
CDCl3): d=27.3, 32.8 (CH2), 51.5, 51.8 (CO2CH3), 125.9 (C=CH2), 138
(C=CH2), 167.0, 173.0 ppm (CO2CH3) ; MS (ES+): m/z: 175 [M+H]+;
IR (film): n˜ =1639 (C=C), 1718 cmÀ1 (C=O).
0.039 mmol), methyl a-butylacrylate (0.415 mL, 3.88 mmol) and toluene
(2 mL). The mixture was stirred under 75 bar syngas at 758C for 70 h.
1H NMR (300 MHz, CDCl3): d=0.83 (t, J=7.2 Hz, 3H; CH3CH2), 1.05–
1.31 (7m, H; CH3, CH2CH2), 1.57–1.86 (m, 2H; CH2), 3.69 (s, 3H;
CO2CH3), 9.64 ppm (s, 1H; CHO); 13C NMR (75 MHz, CDCl3): d=13.8
(CH3), 22.9, 26.3, 34.2 (CH2), 52.3 (CO2CH3), 57.7 (C), 172.8 (CO2CH3),
199.7 ppm (CHO); MS (ES+): m/z: 173 [M+H]+; HRMS (ES+): m/z
calcd for C9H16O3: 173.1177; found: 173.1170 [M+H]+; IR (film): n˜ =
Synthesis of a-methyl methylcinnamate (9): A mixture of a-methylcin-
namic acid (4.05 g, 25.0 mmol) and para-toluenesulfonic acid (481 mg,
0.25 mmol) in methanol (50 mL) was heated under reflux for 5 h. The
cooled solution was diluted with diethyl ether, was washed with NaHCO3
and brine, and was dried (MgSO4) before concentrating to a white solid
1722 (C=Oaldehyde), 1748 (C=Oester), 2733, 2864 cmÀ1 (C Haldehyde).
À
Hydroformylation of 5-cyano-2-methylenepentanoic acid methyl ester
1
(3.30 g, 69%). H NMR (300 MHz, CDCl3): d=2.15 (s, 3H; CH3), 3.84 (s,
(6): The general procedure was followed with [Rh(acac)(CO)2] (2 mg,
E
3H; CO2CH3), 7.29–7.46 (m, 5H; ArH), 7.72 ppm (s, 1H; CHO);
13C NMR (75 MHz, CDCl3): d=14.1 (CH3), 52.1 (CO2CH3), 128.3, 128.4,
129.7 (ArC), 135.9 (C=CH), 139.0 (C=CH), 169.1 ppm (CO2CH3); MS
(ES+): m/z: 199 [M+Na]+; IR (nujol): n˜ =1633 (C=C), 1719 cmÀ1 (C=
O).
0.0078 mmol), 1a (11.3 mg, 0.039 mmol), 5-cyano-2-methylenepentanoic
acid methyl ester (594 mg, 3.88 mmol) and toluene (2 mL). The mixture
was stirred under 50 bar syngas at 508C for 70 h. Flash column chroma-
tography (SiO2, hexane/EtOAc 4:1) yielded 492 mg (69%) of a clear oil.
1H NMR (300 MHz, CDCl3): d=1.29 (s, 3H; CH3), 1.48–1.65 (m, 2H;
CH2), 1.68–1.99 (m, 2H; CH2), 2.32 (t, J=7.2 Hz, 2H; CH2), 3.2 (s, 3H;
CO2CH3), 9.62 ppm (s, 1H; CHO); 13C NMR (75 MHz, CDCl3): d=17.8
(CH3), 17.9, 21.0, 33.0 (CH2), 53.1 (CO2CH3), 57.6 C), 119.4 (CN), 172.4
(CO2CH3), 198.8 ppm (CHO); MS (ES+): m/z: 184 [M+H]+; HRMS
(ES+): m/z calcd for C9H13NO3: 184.0973; found: 184.0981 [M+H]+; IR
General procedure—rhodium-catalysed hydroformylation using phenyl-
phosphatrioxaadamantane 1a as a ligand: [Rh(acac)(CO)2] (0.2%) and
G
phosphane (1%) were placed in a clean dry Schlenk tube. The air was
displaced with nitrogen and toluene added. The alkene was added and
the mixture transferred to an autoclave and stirred under syngas (1:1).
The conversion was measured from NMR spectroscopy and isolated
yields were obtained through flash chromatography.
ꢀ
(film): n˜ =1721 (C=Oaldehyde), 1746 (C=Oester), 2247 (C N), 2737,
2846 cmÀ1 (C Haldehyde).
À
Hydroformylation of tert-butyl methacrylate (2a): The general procedure
Hydroformylation of 2-methylenepentanedioic acid dimethyl ester (7):
was followed using [Rh(acac)(CO)2] (2 mg, 0.0078 mmol), 1a (11.3 mg,
N
The general procedure was followed with [Rh(acac)(CO)2] (1 mg,
N
0.039 mmol), tert-butyl methacrylate (0.63 mL, 3.88 mmol) and toluene
(2 mL). The mixture was stirred under 50 bar syngas at 508C for 70 h;
1H NMR (300 MHz, CDCl3): d=1.24 (s, 6H; (CH3)2), 1.40 (s, 9H;
0.0039 mmol), 1a (5.6 mg, 0.019 mmol), 2-methylenepentanedioic acid di-
methyl ester (334 mg, 1.94 mmol) and toluene (1 mL). The mixture was
stirred under 50 bar syngas at 508C for 24 h. Flash column chromatogra-
7984
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 7978 – 7986

Homogeneous Catalysis
FULL PAPER
phy (SiO2, hexane/EtOAc 4:1) yielded 260 mg (62%) of a pale yellow
oil. H NMR (300 MHz, CDCl3): d=1.31 (s, 3H; CH3), 2.03–2.46 (m, 4H;
The mixture was stirred under 50 bar syngas at 508C for 24 h. Aldehyde:
1H NMR (300 MHz, CDCl3): d=3.15 (dd, J=5.1, 6.7 Hz, 2H; CH2), 3.57
(m, 1H; CH), 3.64 (s, 3H; CO2CH3), 7.08–7.24 (m, 5H; ArH), 9.66 ppm
1
(CH2)2), 3.66 (s, 3H; CH2CO2CH3), 3.77 (s, 3H; CO2CH3), 9.70 ppm (s,
1H; CHO); 13C NMR (75 MHz, CDCl3): d=17.2 (CH3), 28.5, 29.0 (CH2),
51.8, 52.6 (CO2CH3), 60.4 (C), 172.1, 172.9 (CO2CH3), 198.5 ppm (CHO);
MS (ES+): m/z: 203 [M+H]+; HRMS (ES+): m/z calcd for C9H14O5:
203.0919; found: 203.0928 [M+H]+; IR (film): n˜ =1717–1740 (br; C=O),
1
(d, J=2.1 Hz, 1H; CHO); Enol: H NMR (300 MHz, CDCl3): d=3.33 (s,
2H; CH2), 3.64 (s, 3H; CO2CH3), 6.97 (dt, J=12.5, 1.0 Hz, 1H; CHOH),
7.08–7.24 (m, 5H; ArH), 11.40 ppm (d, J=12.8 Hz, 1H; CHOH);
13C NMR (Both tautomers, 75 MHz, CDCl3): d=32.2, 33.1, 51.4, 52.6,
60.2, 104.4, 126.2, 126.9, 128.3, 128.4, 128.6, 128.7, 137.4, 140.4, 161.8,
196.4 ppm; MS (ES+): m/z: 193 [M+H]+; IR (film): n˜ =1446, 1495 (C=
À
2735, 2848 cmÀ1 (C Haldehyde).
À
Hydroformylation of a-methyl methylcinnamate (11): The general proce-
C
Ph), 1668 (C=Cenol), 1717 (C=Oaldehyde), 1739 (C=Oester), 3334 cmÀ1 (O
dure was followed with [Rh(acac)(CO)2] (1 mg, 0.0039 mmol), 1a
E
Henol).
(5.6 mg, 0.019 mmol), a-methyl methylcinnamate (341 mg, 3.88 mmol)
and toluene (2 mL). The mixture was stirred under 75 bar syngas at 758C
for 70 h. Flash column chromatography (SiO2, hexane/EtOAc 4:1) yield-
ed 279 mg (70%) of a clear oil. 1H NMR (300 MHz, CDCl3): d=1.20 (s,
3H; CH3), 2.99, 3.18 (2d, J=13.8 Hz, 2H; CH2), 3.65 (s, 3H; CO2CH3),
6.99–7.22 (m, 5H; ArH), 9.70 ppm (s, 1H; CHO); 13C NMR (75 MHz,
CDCl3): d=17.4 (CH3), 40.7 (CH2), 52.8 (CO2CH3), 59.3 (C), 127.5,
128.8, 130.4, 135.8 (ArC), 172.6 (CO2CH3), 199.8 ppm (CHO); MS (ES+
): m/z: 207 [M+H]+; HRMS (ES+): m/z calcd for C12H14O3: 207.1021;
found: 207.1027; IR (film): n˜ =1454, 1497 (C=CPh), 1720 (C=Oaldehyde),
Hydroformylation of methyl 4-chlorocinnamate (16): The general proce-
dure was followed with [Rh(acac)(CO)2] (1 mg, 0.0039 mmol), 1a
G
(5.6 mg, 0.019 mmol), methyl 4-chlorocinnamate (381 mg, 1.94 mmol) and
toluene (1 mL). The mixture was stirred under 50 bar syngas at 508C for
24 h. Workup yielded 283 mg (64%) of a pale yellow oil. Aldehyde:
1H NMR (300 MHz, CDCl3): d=3.10 (m, 2H; CH2), 3.58 (m, 1H; CH),
3.64 (s, 3H; CO2CH3), 6.97–7.20 (m, 4H; ArH), 9.67 ppm (d, J=1.5 Hz,
1H; CHO); Enol: 1H NMR (300 MHz, CDCl3): d=3.30 (s, 2H; CH2),
3.66 (s, 3H; CO2CH3), 6.97–7.20 (m, 5H; ArH, CHOH), 11.39 ppm (d,
J=12.6 Hz, 1H; CHOH); 13C NMR (both tautomers, 75 MHz, CDCl3):
d=31.3, 32.6, 51.6, 52.6, 60.1, 104.0, 128.4, 128.8, 129.8, 130.3, 131.6,
132.8, 136.0, 138.5, 161.9, 172.3, 195.8 ppm; MS (ES+): m/z: 227
1742 (C=Oester), 2729, 2843 cmÀ1 (C Haldehyde).
À
Hydroformylation of methyl tiglate (12): The general procedure was fol-
lowed with [Rh(acac)(CO)2] (2 mg, 0.0078 mmol), 1a(11.3 mg,
N
[M+H]+; HRMS (ES+): m/z calcd for C11H12ClO3: 227.0475; found:
0.039 mmol), methyl tiglate (0.46 mL, 3.88 mmol) and toluene (2 mL).
The mixture was stirred under 75 bar syngas at 758C for 70 h. Flash
column chromatography (SiO2, hexane/EtOAc 4:1) yielded 384 mg
(69%) of a pale yellow oil. 1H NMR (300 MHz, CDCl3): d=0.82 (t, J=
7.5 Hz, 3H; CH3), 1.22 (s, 3H; CH3), 1.65–1.94 (m, 2H; CH2), 3.69 (s,
3H; CO2CH3), 9.64 ppm (s, 1H; CHO); 13C NMR (75 MHz, CDCl3): d=
9.0 (CH2CH3), 16.5 (CH3), 27.8 (CH2), 52.7 (CO2CH3), 58.5 (C), 173.1
(CO2CH3), 200.2 ppm (CHO); MS (ES+): m/z: 145 [M+H]+; IR (film):
+
À
227.0482 [M+H] ; IR (film): n˜ =804 (C Cl), 1670 (C=Cenol), 1723 (C=
Oaldehyde), 3449 cmÀ1 (O Henol).
À
Synthesis of b-amino acid ester20 : A mixture of aldehyde 18 (520 mg,
4 mmol) and benzylamine (471 mg, 4.4 mmol) were stirred in toluene at
508C overnight. The mixture was concentrated under high vacuum to the
crude imine 19; 1H NMR (300 MHz, CDCl3): d=1.52 (s, 6H; ((CH3)2),
3.81 (s, 3H; CO2CH3), 4.74 (s, 2H; CH2), 7.27–7.36 (m, 5H; ArH),
7.97 ppm (t, J=1.3 Hz, 1H; CHO).
n˜ =1722 (C=Oaldehyde), 1750 (C=Oester), 2739, 2843 cmÀ1 (C Haldehyde).
À
A mixture of [Ir(COD)Cl]2 (5.4 mg, 0.008 mmol) and 1,1’-bis(diphenyl-
A
Hydroformylation of methyl crotonate (13): The general procedure was
phosphano)ferrocene (dppf; 11.1 mg, 0.02 mmol) was stirred in methanol
(2 mL) for 5 min before adding to the crude imine. The mixture was stir-
red under 60 bar H2 at 508C for 24 h. The mixture was concentrated and
partitioned between ether and 0.5m HCl. The acidic layer was made
basic and extracted three times into diethyl ether. The combined organics
were dried (MgSO4) and concentrated to give 749 mg (85%) of a clear
oil. This was converted quantitatively to the hydrochloride salt 20 by
treatment with 2m HCl in diethyl ether and collecting the precipitate.
1H NMR (300 MHz, D2O): d=1.14 (s, 6H; (CH3)2), 3.06 (s, 2H; CH2),
3.56 (s, 3H; CO2CH3), 4.19 (s, 2H; CH2Ph), 7.36 (s, 2H; ArH), 7.41 ppm
(s, 3H; ArH); (75 MHz, D2O): d=22.6 ((CH3)2), 41.0 (C), 51.7 (CH2),
52.8 (CH2), 52.9 (CO2CH3), 129.2, 129.6, 130.2 (ArCH), 129.8 (ArC),
177.6 ppm (CO2CH3); MS (ES+): m/z: 222 [M+H]+; IR (film): n˜ =1743
followed with [Rh(acac)(CO)2] (2 mg, 0.0078 mmol), 1a (11.3 mg,
A
0.039 mmol), methyl crotonate (0.41 mL, 3.88 mmol) and toluene (2 mL).
The mixture was stirred under 50 bar syngas at 508C for 24 h. Flash
column chromatography (SiO2, hexane/EtOAc 4:1) yielded 475 mg
(94%) of a yellow oil. Aldehyde: 1H NMR (300 MHz, CDCl3): d=0.91
(t, J=7.4 Hz, 3H; CH3), 2.03 (quin, J=7.4 Hz, 2H; CH2), 3.15 (td, J=
2.3, 7.2 Hz, 1H; CH), 3.71 (s, 3H; CO2CH3), 9.64 ppm (d, J=2.3 Hz, 1H;
CHO); 13C NMR (75 MHz, CDCl3): d=12.0 (CH3), 20.5 (CH2), 52.7
(CO2CH3), 60.1 (CH), 170.3 (CO2CH3), 197.7 ppm (CHO); Enol:
1H NMR (300 MHz, CDCl3): d=0.95 (t, J=7.4 Hz, 3H; CH3), 2.03 (qd,
J=1.0, 7.4 Hz, 2H; CH2), 3.71 (s, 3H; CO2CH3), 6.94 (dt, J=12.5,
1.0 Hz, 1H; CHOH), 11.26 ppm (d, J=12.5 Hz, 1H; CHOH); 13C NMR
(75 MHz, CDCl3): d=14.9 (CH3), 21.0 (CH2), 51.8 (CO2CH3), 106.8 (C),
160.6 (CHOH), 173.2 ppm (CO2CH3); MS (ESÀ): m/z: 129 [MÀH]À;
HRMS (ESÀ): m/z calcd for C6H9O3: 129.0552; found: 129.0549
[MÀH]À; IR (film): n˜ =1671 (C=Cenol), 1720 (C=Oaldehyde), 1740 (C=Oester),
(C=O), 3433 cmÀ1 (N H).
À
3337 cmÀ1 (O Henol).
À
Hydroformylation of methyl trans-2-pentenoate (14): The general proce-
dure was followed with [Rh(acac)(CO)2] (1 mg, 0.0039 mmol), 1a
A
Acknowledgements
(5.6 mg, 0.019 mmol), methyl trans-2-pentenoate (221 mg, 1.94 mmol)
and toluene (1 mL). The mixture was stirred under 75 bar syngas (5:1
CO/H2) at 408C for 90 h. Aldehyde: 1H NMR (300 MHz, CDCl3): d=
0.88 (t, J=7.4 Hz, 3H; CH3), 1.31–1.60 (m, 2H; CH2), 1.78 (t, J=7.2 Hz,
2H; CH2), 3.22 (td, J=7.2, 2.3 Hz, 1H; CH), 3.71 (s, 3H; CO2CH3),
9.63 ppm (d, J=2.6 Hz, 1H; CHO); Enol: 1H NMR (300 MHz, CDCl3):
d=0.81 (t, J=7.2 Hz, 3H; CH3), 1.31–1.60 (m, 2H; CH2), 1.96 (t, J=
7.4 Hz, 2H; CH2), 3.71 (s, 3H; CO2CH3), 6.93 (dt, J=12.5, 0.8 Hz, 1H;
CHOH), 11.31 ppm (d, J=12.3 Hz, 1H; CHOH); 13C NMR (both tauto-
mers, 75 MHz, CDCl3): d=13.5, 13.7, 20.3, 22.8, 28.7, 29.3, 51.4, 52.4,
58.2, 104.6, 160.8, 168.6, 172.9, 197.3 ppm; MS (ESÀ): m/z: 144 [MÀH]À;
HRMS (ESÀ): m/z calcd for C7H11O3: 143.0708; found: 143.0708
We are extremely grateful to the Leverhulme Trust for their financial
support and to Johnson Matthey for loan of Rh salts. The authors also
thank Professor Paul Pringle for the gift of a sample of 1a in the early
stages of this work: we are the latest of many catalysis groups to benefit
from his teamꢁs commitment to the study of unusual phosphane ligands.
[1] F. Ungvary, Coord. Chem. Rev. 2004, 248, 867.
[2] F. Ungvary, Coord. Chem. Rev. 2003, 241, 295.
[3] P. W. N. M. van Leeuwen, C. Claver, Rhodium Catalysed Hydrofor-
mylation, 2000, Kluwer Academic, Dordrecht, Chapter 8.
[4] P. C. J. Kamer, P. W. N. M. van Leeuwen, J. N. H. Reek, Acc. Chem.
Res. 2001, 34, 895.
[MÀH]À; IR (film): n˜ =1737 (C=Oaldehyde), 3464 cmÀ1 (O Henol).
À
Hydroformylation of methyl cinnamate (15): The general procedure was
followed with [Rh
0.039 mmol), methyl cinnamate (629 mg, 3.88 mmol) and toluene (2 mL).
A
[5] F. Agbossou, J. F. Carpentier, A. Mortreaux, Chem. Rev. 1995, 95,
2485.
Chem. Eur. J. 2006, 12, 7978 – 7986
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7985

M. L. Clarke and G. J. Roff
[6] M. Dieguez, O. Pamies, C. Claver, Tetrahedron: Asymmetry 2004,
15, 2113.
[28] B. Breit, R. Winde, T. Mackewitz, R. Paciello, K. Harms, Chem.
Eur. J. 2001, 7, 3106.
[7] C. J. Cobley, K. Gardner, J. Klosin, C. Praquin, C. Hill, G. T. White-
ker, A. Zanotti-Gerosa, J. L. Petersen, K. A. Abboud, J. Org. Chem.
2004, 69, 4031.
[8] C. J. Cobley, J. Klosin, C. Qin, G. T. Whiteker, Org. Lett. 2004, 6,
3277.
[9] S. Breeden, D. J. Cole-Hamilton, D. F. Foster, G. J. Schwarz, M.
Wills, Angew. Chem. 2000, 112, 4272; Angew. Chem. Int. Ed. 2000,
39, 4106.
[29] M. Tanaka, T. Hayashi, I. Ogata, Bull. Chem. Soc. Jpn. 1977, 50,
2351.
[30] J. Weber, P. Lappe, H. Springer, EP 417597, 1991.
[31] C. Botteghi, S. Paganelli, J. Organomet. Chem. 1993, 451, C18.
[32] D. Steer, R. A. Lew, P. Perlmutter, A. I. Smith, M.-I. Aguilar, Curr.
Med. Chem. 2002, 9, 811.
[33] A. F. Abdel-Magid, J. H. Cohen, C. A. Maryanoff, Curr. Med. Chem.
1999, 6, 955.
[10] J. E. Babin, G. T. Whiteker, 1993, WO93/03839.
[11] K. Nozaki, N. Sakai, T. Nanno, T. Higashijima, S. Mano, T. Horiuchi,
H. Takaya, J. Am. Chem. Soc. 1997, 119, 4413.
[12] M. Dieguez, O. Pamies, A. Ruiz, S. Castillon, C. Claver, Chem. Eur.
J. 2001, 7, 3086.
[34] E. Juaristi, H. Lopez-Ruiz, Curr. Med. Chem. 1999, 6, 983.
[35] Hydroformylation of methyl methacrylate and methyl atropate was
performed in the presence of benzylamine. Only the imine formed
in the case of methyl methacrylate, whereas benzylamine added in a
Michael fashion to methyl atropate. No reduced secondary amine
products were detected even in the presence of an iridium based hy-
drogenation catalyst.
[13] M. M. H. Lambers-Verstappen, J. G. De Vries, Adv. Synth. Catal.
2003, 345, 478.
[14] C. Botteghi, R. Ganzerla, M. Lenarda, G. Moretti, J. Mol. Catal.
1987, 40, 129.
[15] M. L. Clarke, Curr. Org. Chem. 2005, 9, 701.
[16] B. Breit, W. Seiche, Synthesis 2001, 1.
[36] J. Barluenga, A. Ballesteros, R. Bernardo De La Rua, J. Santamaria,
E. Rubio, M. Tomas, J. Am. Chem. Soc. 2003, 125, 1834.
[37] C. J. Albisettir, D. C. England, M. J. Hogsed, R. M. Joyce, J. Am.
Chem. Soc. 1956, 78, 472.
[17] E. Drent, P. Arnoldy, P. H. M. Budzelaar, J. Organomet. Chem.
1993, 455, 247.
[18] P. W. N. M. van Leeuwen, C. F. Roobeek, J. Organomet. Chem. 1983,
258, 343.
[19] A. I. M. Keuelemans, A. Kwantes, T. van Bavel, Recl. Trav. Chim.
Pays-Bas 1948, 67, 298.
[20] S. Gladiali, L. Pinna, Tetrahedron: Asymmetry 1990, 1, 693.
[21] C. Botteghi, G. Chelucci, G. D. Ponte, M. Marchetti, S. Paganelli, J.
Org. Chem. 1994, 59, 7125.
[22] C. Botteghi, M. Marchetti, S. Paganelli, B. Sechi, J. Mol. Catal. A
1997, 118, 173.
[23] I. J. Krauss, C. C.-Y. Wang, J. L. Leighton, J. Am. Chem. Soc. 2001,
123, 11514.
[24] a) C. W. Lee, H. Alper, J. Org. Chem. 1995, 60, 499 and references
therein; b) earlier papers on hydroformylation of methyl methacry-
late generally showed b-selectivity: G. Parrinello and J. K. Stille, J.
Am. Chem. Soc. 1987, 109, 7122; c) K. Prokai-Tatrai, S. Toros, B.
Heil, J. Organomet. Chem. 1987, 332, 331.
[38] H.-J. Cristau, A. Coulombeau, A. Genevois-Borella, F. Sanchez,
J.-L. Pirat, J. Organomet. Chem. 2002, 643–644, 381.
[39] J. D. McClure, J. Org. Chem. 1970, 35, 3045.
[40] D.-I. Kato, K. Miyamoto, H. Ohta, Tetrahedron: Asymmetry 2004,
15, 2965.
[41] T. Chiba, J.-I. Sakaki, T. Takahashi, A. Kamiyama, C. Kaneko, M.
Sato, J. Chem. Soc. Perkin Trans. 1 1987, 1845.
[42] L. Kollar, G. Consiglio, P. Pino, Chimia 1986, 40, 428.
[43] T.-A. Mitsudo, N. Suzuki, K.A. Kobayashi, T. Kondo, J. Mol. Catal.
A 1999, 137, 253.
[44] C. D. Monica, N. Maulucci, F. De Riccardis, I. Izzo, Tetrahedron:
Asymmetry 2003, 14, 3371.
[45] W. Keim, D. Vogt, H. Waffenschmidt, P. Wasserscheid, J. Catal.
1999, 186, 481.
[46] C. Botteghi, S. Paganelli, J. Organomet. Chem. 1991, 417, C41.
[47] C. P. Reddy, S. Tanimoto, Synthesis 1987, 575.
[48] T. Hosokawa, T. Kamiike, S.-L. Murahashi, M. Shimada, T. Sugafuji,
Tetrahedron Lett. 2002, 43, 9323.
[25] M. L. Clarke, Tetrahedron Lett. 2004, 45, 4043.
[26] R. A. Baber, M. L. Clarke, K. Heslop, A. Marr, A. G. Orpen, P. G.
Pringle, A. M. Ward, D. A. Zambrano-Williams, Dalton Trans. 2005,
1079.
[49] K. Ikeda, K. Achiwa, M. Sekiya, Tetrahedron Lett. 1983, 24, 913.
[27] M. T. Reetz, X. Li, Angew. Chem. 2005, 117, 3022; Angew. Chem.
Int. Ed. 2005, 44, 2962.
Received: June 27, 2006
Published online: September 22, 2006
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