Solid-Liquid Biphasic Hydroformylation of Olefins Catalyzed by Rhodium Carhonyl Complexes

Article abstract of DOI:10.1002/adsc.200303053

Some polymer-anchored alkenes have been hydroformylated by carrying out the reaction in a high-pressure reactor equipped with a suitably designed vial. The solid substrates are converted to the corresponding oxo-aldehydes in high yields. In all cases the regioselectivity was strongly shifted towards the linear aldehyde when the rhodium carbonyl complex was modified with xantphos (3:1 or 4:1 P/Rh molar ratio). Treatment with 5% of trifluoroacetine acid in dichloromethane at room temperature removed quantitatively the oxo-product from the polymer support, which can be purified and reused.

Full text of DOI:10.1002/adsc.200303053

FULL PAPERS
Solid-Liquid Biphasic Hydroformylation of Olefins Catalyzed by
Rhodium Carbonyl Complexes
M. Marchetti,a,* C. Botteghi,b S. Paganelli,b M. Taddeic
a
Sezione di Sassari dell×Istituto di Chimica Biomolecolare, trav. La Crucca, 3 Reg. Baldinca, 07040 Li Punti Sassari,
Italy
Fax: ( ‡ 39)-793-961-036, e-mail: mauro@ss.cnr.it.
b
¡
Dipartimento di Chimica, Universita Ca× Foscari Venezia, Calle Larga Santa Marta 2137, 30123 Venezia, Italy
E-mail: spag@unive.it.
c
¡
Dipartimento Farmaco Chimico Tecnologico, Universita degli Studi di Siena, Via A. Moro, 53100 Siena, Italy
E-mail: taddei.m@unisi.it.
Received: March 11, 2003; Accepted: July 16, 2003
Abstract: Some polymer-anchored alkenes have been molar ratio). Treatment with 5% of trifluoroacetic
hydroformylated by carrying out the reaction in a acid in dichloromethane at room temperature re-
high-pressure reactor equipped with a suitably de- moved quantitatively the oxo-product from the poly-
signed vial. The solid substrates are converted to the mer support, which can be purified and reused.
corresponding oxo-aldehydes in high yields. In all
cases the regioselectivity was strongly shifted towards Keywords: aldehydes; alkenes; hydroformylation;
the linear aldehyde when the rhodium carbonyl rhodium; solid-liquid biphasic catalysis; solid-phase
complex was modified with xantphos (3:1 or 4:1 P/Rh synthesis
*
Introduction
coordination of the catalytic species to a polymeric
matrix containing functional groups able to interact
with the transition metals;[4 7]
application of rhodium carbonyl complexes with
water-soluble ligands (mostly sodium salts of sulpho-
nated mono- or diphosphines) able to keep the
catalyst in water, so offering the outstanding possi-
bility of carrying out the process in an aqueous
biphasic system;[8,9]
application of rhodium carbonyl complexes with
suitably fluorinated ligands, which promote their
solubility in perfluorinated solvents where the reac-
tion occurs, while the oxo-products migrate in an
immiscible organic phase (flourous biphasic catalysis,
FBC);[10,11]
employment of carbon dioxide in supercritical phase
as the reaction medium and its release as a gas at the
end of the process;[12 14]
Hydroformylation of olefins is one of the most indus-
trially important reactions involving synthesis gas for
the production of aldehydes and derivatives (ca. 7 mil-
lions ton/year): the feature which characterizes this
process today relies on the fact that rhodium carbonyl
complexes, generally modified with ligands such as
phosphines and phosphites, are employed as catalysts to
an increasing extent because they provide high reaction
rates and selectivities for the formation of the desired
aldehyde.[1]
Rhodium derivatives, however, are very expensive
compounds: the price of this metal is currently 32.15 $/
g.[2] Moreover, since the rhodium world production
does not exceed 2 3 t/year, a number of successful
methods for recycling these catalysts have been de-
vised.
*
*
*
*
The oxo-process, however, is still afflicted by several
practical drawbacks, mainly the technical difficulty of
separating the aldehydes produced from the solvent and
use of ionic liquids as biphasic hydroformylation
media.[15 17]
from the soluble catalytically active complexes. To Another possibility for a smooth separation of the
overcome these problems, various ingenious methods products from the homogeneous catalyst is provided by
have been developed, some of which have reached hydroformylation of a polymer-anchored alkene, carry-
industrial maturity:
ing out the reaction in a solid-liquid biphasic system.
Only one example of this kind of catalytic process is
*
immobilization of the catalytically active metals or reported in the literature: the alkene 2-methyl-12-
metal derivatives on an inorganic support or ma- hydroxy-1-dodecene was attached to a polystyrene-
trix;[3]
grafted SynphaseTM crown through a linker formed by
Adv. Synth. Catal. 2003, 345, 1229 1236
DOI: 10.1002/adsc.200303053
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M. Marchetti et al.
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the trityl ether of p-hydroxybenzenesulphonic acid
In this context we have undertaken a study on the
hydroformylation in solid liquid biphasic systems with
(Scheme 1).[18]
The hydroformylation of this anchored olefin was the aim:
reported to proceed smoothly in the presence of i) to set up this catalytic process suitably to get high
Rh(CO)2(acac) in toluene at 40 60 8C and 40 75 atm
yield and reproducible results;
(CO/H2 ˆ 1); using a 30 mM catalytic solution of the ii) to indicate merits and limits of this reaction in
rhodium complex, 83% substrate conversion and 98%
regioselectivity towards the useful linear oxo-product
were claimed. This aldehyde, still linked to the poly-
meric support, was transformed into muscone by an
view of its application to the synthesis of bio-
logically active compounds.
intramolecular macrocyclization step. Alternatively, it Results and Discussion
can be removed from the polymer by treatment with
10% trifluoroacetic acid in dichloromethane.[18]
In the preparation of the substrates for hydroformyla-
Our research group is involved in the preparation of tion we have used a polymeric matrix formed by a
biologically active compounds by using the rhodium- styrene-divinylbenzene copolymer (99:1) containing
catalyzed hydroformylation as a key-step of the selected trityl chloride moieties as linkers. Before use the
synthetic schemes.[19 22] In these last years we have copolymer was treated with thionyl chloride in dichloro-
applied the aqueous two-phase oxo-reaction to olefinic methane in the presence of pyridine to regenerate all the
substrates containing functional groups using rhodium active sites; then it was allowed to swell by heating at
carbonyl complexes modified with easily accessible 508C for one hour in the same solvent.[27]
water-soluble ligands such as trisulphonated triphenyl-
Various alkenes containing suitable functions like
phosphine trisodium salt (TPPTS) or disulphonated hydroxy and carbonyl groups were linked to the
xantphos disodium salt, we have obtained outstanding polymeric matrix according to the following scheme
results producing aldehyde intermediates with high (Scheme 2).
yields.[23 24] Particularly interesting is the use of hydro-
In Figure 1 are depicted all the substrates used by us
philic proteins, such as seroalbumins, as rhodium for the biphasic solid-liquid hydroformylation:
ligands: these biopolymers form rather stable complexes Experimentally, the loading of the polymeric support
with rhodium carbonyl precursors, which display a very was carried out by reaction of the unsaturated alcohol or
high catalytic activity and exhibit peculiar selectivity acid with the trityl site in pyridine or diisopropylamine/
properties.[25 26]
pyridine in the temperature range 25 50 8C for 48 h.
The yields, determined after cleavage of the linked
hydroxy- or carboxyalkene with a 5% solution of
trifluoroacetic acid in dichloromethane, in all cases
were excellent ( > 99%). As p-hydroxystyrene is not
commercially available, the loading of the polymeric
matrix, in this case, was carried out by linking the p-
hydroxybenzaldehyde to the trityl moiety of the poly-
mer and then the aldehyde group was transformed into a
vinyl group by a Wittig reaction on the solid phase
(Scheme 3).[28]
When this reaction was carried out in the presence of
the triphenylmethylenephosphorane obtained by dehy-
drobromination of the corresponding phosphonium
bromide with sodium amide or butyllitium in THF, it
Scheme 1. First example of polymer-anchored alkene hydro-
formylation in a biphasic solid-liquid system.
Scheme 2. Linking of various functionalized alkenes to a polymeric matrix.
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Solid-Liquid Biphasic Hydroformylation of Olefins
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Figure 2. Special glass vial to be introduced into the high-
pressure reactor for solid-liquid biphasic hydroformylation
experiments.
Scheme 4. Intramolecular cyclization of 6-hydroxy-2-methyl-
hexanal.
Figure 1. Substrates for biphasic solid-liquid hydroformyla-
tion using the trityl-derivatized polymeric support.
Scheme 5. Reductive amination and reduction of oxo-alde-
hydes.
Scheme 3. Preparation of substrate 4 by Wittig reaction on
solid phase.
The oxo-reactions on the substrates 1 3 were carried
out using Rh(CO)2(acac) as the catalytic precursor at
substrate-to-catalyst molar ratio of 25 50; carrying out
the experiments in toluene at 40 100 8C and 20 60 atm
gave unsatisfactory results; only by using sodium (CO/H2 ˆ 1) very high conversions were obtained in
bis(trimethylsilyl)amide (NaHDMS) in THF, did we reasonable reaction times. Reaction conditions and
reach yields up to 95%.[28]
Some hydroformylation experiments were carried out
results are listed in Table 1.
The chemoselectivity of the hydroformylation in all
on the polymer-anchored 5-hexen-1-ol (2) following the runs was higher than 90% and in most cases nearly
practical advice of Tokahashi, Ebata and Dai.[18] Un- quantitative; sporadically up to 10% olefinic double
fortunately, we were not able to reproduce the good bond hydrogenation was noticed if the process was
results described in the literature: also when keeping an carried out at 1008C.
efficient contact between the solid and the liquid phase
The cleavage of the oxo-hydroxyaldehydes from the
by a vigorous stirring, the substrate conversions were polymer was rather difficult as these compounds are
very low ( ꢀ 20%). Moreover, the polymeric substrate sensitive to acidic conditions: for instance, 6-hydroxy-2-
showed, at the end of the reaction, to be extensively methylhexanal during the treatment with trifluoroacetic
decomposed due to the friction effect. Thus, we modi- acid (TFA) cyclized giving 3-methyloxepan-2-ol
fied the glass vial in a suitable way (as shown in Fig. 2) in (Scheme 4).
order to avoid this practical drawback.
To overcome this problem the oxo-aldehydes ob-
The new glass device consists of a ™traditional∫ vial tained were directly converted on the polymeric support
modified to be able to hold a glass basket having a into the corresponding alcohols by reduction with
porous septum as the bottom; the polymer-anchored NaBH4 in CH3OH/THF (1:1) or into N-phenylamines
substrate is positioned in the basket, which is partially by reductive amination in the presence of aniline using
immersed in the catalytic solution, whereas the mag- NaBH(OAc)3 as reduction agent in DMF (see Exper-
netic stirring bar is on the bottom of the vial. This imental Section) (Scheme 5)
method allows us to have an efficient stirring without
any mechanical stress of the substrate.
All these transformations were accomplished in
quantitative yields and after the cleavage with TFA
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M. Marchetti et al.
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1
the product mixtures were subjected to H NMR and derivatives:[1] for instance, the only experiment reported
GC-MS analysis. in the literature on an oxo-reaction of p-hydroxystyrene
For all the investigated substrates the regioselectiv- in the presence of HRh(CO)(PPh3)3 at 658C and 60 atm
ities of the oxo-process were rather low and the more (CO/H2 ˆ 1) afforded 99.6% regioselectivity towards
branched oxo-aldehyde was generally the most abun- the formation of 2-(p-hydroxyphenyl)propanal.[30]
dant isomer.
When the catalytic process on substrate 4 was effected
The regioselectivity was shifted towards the linear in the presence of the HRh(CO)(PPh3)3/xantphos (1:4)
oxo-product only by using xantphos,[1,29] a large bite system at 408C and 20 atm, the linear aldehyde is the
angle diphosphine ligand promoting the formation of only reaction product. The unexpected regioselectivity
straight chain aldehydes in the rhodium-catalyzed obtained in this reaction is not easy to explain, however,
hydroformylation, as an external ligand (xantphos/ it could be possible that steric hindering due to the
Rh ˆ 3:1) at low temperature and pressure (408C and polymeric matrix inhibits the insertion of the carbon
20 atm). [24] In the case of substrates 2 and 3 more than monoxide in the alpha position. It is noteworthy that 3-
80% of the corresponding linear hydroxy-aldehyde was (p-hydroxyphenyl)propanal represents a valuable pre-
produced.
cursor for the synthesis of several biologically interest-
Table 2 reports the most representative results ob- ing alkaloids, such as for instance, those belonging to the
tained in the solid-liquid biphasic hydroformylation of class of sceletium.[31,32]
p-hydroxystyrene (4): while the values of the chemo-
In Table 3 the results obtained in the solid-liquid
selectivity reproduce the excellent figures found in the hydroformylation of three unsaturated acids linked to
oxo-reaction on substrates 1 3, those of regioselectivity the polymeric matrix (5, 6 and 7) are collected. It is
are quite unexpected.
noteworthy that the chemoselectivity of the oxo-process
The prevailing aldehyde was always the linear one, is strongly dependent on the reaction temperature:
contrary to the results obtained in the homogeneous when the reaction was carried out on substrate 5 at
rhodium-catalyzed hydroformylation of styrene and 1008C, no aldehyde formation was observed, instead a
Table 1. Hydroformylation of polymer anchored unsaturated alcohols catalyzed by rhodium complexes.
Substrate Catalytic precursor
T [ 8C] Pressure Substrate/ Reaction Conversion Chemoselectivity Linear Branched
[atm]
catalyst
time [h] [%]
[%][a]
[%][a] [%]
1 (n ˆ 1) Rh(CO)2(acac)
1 (n ˆ 1) Rh(CO)2(acac)
100
60
50
50
20
50
50
60
50
20
20
60
50
20
25
25
25
50
25
25
25
25
25
25
25
25
12
24
48
48
12
24
24
48
48
12
24
96
> 99
98
95
90
99
99
99
90
95
99
99
99
45
30
65
50
45
50
52
64
85
30
23
82
55
70
35
50
55
50
48
36
15
70
77
18
1 (n ˆ 1) HRh(CO)(PPh3)3/xantphos 40
2 (n ˆ 4) Rh(CO)2(acac)
2 (n ˆ 4) Rh(CO)2(acac)
2 (n ˆ 4) Rh(CO)2(acac)
2 (n ˆ 4) Rh(CO)2(acac)
2 (n ˆ 4) Rh(CO)2(acac)/xantphos
100
100
80
60
40
99
> 99
> 99
98
> 99
99
> 99
85
> 99
2 (n ˆ 4) HRh(CO)(PPh3)3/xantphos 40
3 (n ˆ 8) Rh(CO)2(acac)
3 (n ˆ 8) Rh(CO)2(acac)
100
60
> 99
99
99
3 (n ˆ 8) HRh(CO)(PPh3)3/xantphos 40
Reaction conditions: substrate ˆ 500 mg (loading 1.47 mmol/g; substrate 0.7 mmol) solvent ˆ toluene, 20 mL; CO/H2 ˆ 1: 1;
xantphos/Rh ˆ 3: 1.
[a]
The only secondary product observed was the hydrogenated derivative of the substrate.
Table 2. Hydroformylation on solid phase of p-hydroxystyrene (4) catalyzed by rhodium complexes.
Catalytic precursor
T [ 8C] Pressure Substrate/ Reaction Conversion Aldehyde Linear Branched
[atm]
catalyst
time [h]
[%]
yield [%]
[%]
[%]
Rh(CO)2(acac)
Rh(CO)2(acac)
HRh(CO)(PPh3)3/xantphos
100
60
40
60
50
20
25
25
25
24
24
96
> 99
78
> 99
> 99
99
> 99
72
76
> 99
28
24
< 1
Reaction conditions: substrate ˆ 500 mg (loading 1.47 mmol/g; substrate 0.7 mmol); solvent ˆ toluene, 20 mL; CO/H2 ˆ 1: 1;
xantphos/Rh ˆ 4: 1.
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Table 3. Hydroformylation on solid phase of substrates 5 7, catalyzed by rhodium complexes.
Substrate Catalytic precursor
T [ 8C] Pressure Substrate/ Reaction Conversion Aldehyde Linear Branched
[atm]
catalyst
time [h] [%]
yield [%] [%]
[%]
5
5
5
6
6
6
7
7
Rh(CO)2(acac)
Rh(CO)2(acac)
HRh(CO)(PPh3)3/xantphos 40
Rh(CO)2(acac)
Rh(CO)2(acac)
HRh(CO)(PPh3)3/xantphos 40
Rh(CO)2(acac) 100
HRh(CO)(PPh3)3/xantphos 40
100
60
60
60
20
50
50
20
60
20
25
25
25
25
25
25
25
25
20
24
100
12
24
48
> 99[a]
> 99
> 99
> 99
92
> 99
> 99[a]
> 99
99
43
> 99
41
61
> 99
57
< 1
59
39
< 1
> 99
100
60
85[b]
92
> 99
22
48
> 99
> 99[c]
Reaction conditions: substrate ˆ 500 mg (loading 1.47 mmol/g; substrate 0.7 mmol); solvent ˆ toluene, 20 mL; CO/H2 ˆ 1: 1;
Xantphos/Rh ˆ 4: 1.
[a]
Complex mixture of unidentified products.
14% of pentanoic acid was detected.
Recovered as 2-azetidinecarboxylic acid.
[b]
[c]
Scheme 7. Formation of 2-azetidinecarboxylic acid.
Scheme 6. Preparation of 3-(2,3,4,9-tetrahydro-1H-b-carbo-
lin-1-yl)propionic acid.
aldehyde in nearly quantitative yields. However, we
were not able to separate this aldehyde from the
polymeric support: after cleavage with TFA in dichloro-
complex mixture of unidentified products was obtained, methane only 2-azetidinecarboxylic acid was isolated
very likely due to an extensive cleavage of the acrylic from the reaction mixture (Scheme 7).
acid from the polymer support. Carrying out the
The formation of this product is very likely due to an
reaction at 608C and 60 atm we noticed practically intramolecular reductive amination of the aldehyde
complete chemoselectivity, the two aldehydes being function with the amino group available after removal of
present in the reaction mixture in mainly a 1:1 molar the acetyl group by hydrogen under oxo-conditions.
ratio. Analogously to the results obtained with sub-
strates 1 4, the catalytic system HRh(CO)(PPh3)3/
xantphos (1:4) showed again an outstanding efficiency
in promoting the formation of the desired linear
Experimental Section
aldehydes in the hydroformylation of substrates 5 7.
In particular, the linear oxo-product deriving from the
substrate 5 can be useful in the preparation of valuable
building blocks to be employed in combinatorial
chemistry, for instance, to prepare peptide isosteres
which incorporate an electrophile, namely an aldehyde,
which can be coupled with a variety of nucleophiles.[33]
In this context we used the anchored 4-oxobutyric acid,
General Methods and Chemicals
IR spectra were measured with an FT-IR spectrometer Perkin
Elmer model 1720 as KBr disks or Nujol dispersions as
appropriate. Gas chromatography was performed with a
Perkin Elmer model 8500, mass spectra were recorded by
GC-MS model Helwett Packard GCD using the appropriate
1
columns and conditions. H NMR (300 MHz) and 13C NMR
obtained by hydroformylation of the substrate 5, to (75 MHz) spectra of CDCl3 solutions were recorded using a
Varian VXR 300 s spectrometer.
prepare the 3-(2,3,4,9-tetrahydro-1H-b-carbolin-1-yl)-
propionic acid in an easier way, compared with the
reported literature method.[34]
Furthermore, in the case of hydroformylation of
substrate 7, the unmodified carbonyl complex
Rh(CO)2(acac) did not ensure the desired high chemo-
selectivity, even at 608C, but produced a complex
mixture of unidentified compounds; lowering the reac-
tion temperature to 408C and using an excess of
Trityl chloride resin (loading 1.47 mmol/g) was purchased
from Calbiochem-Nova Biochem. Allyl alcohol, hex-5-en-1-ol,
dec-9-en-1-ol, p-hydroxybenzaldehyde, acrylic acid, 5-penten-
ic acid, acetylamidoacrylic acid, methyltriphenylphosphonium
bromide, bis(trimethylsilyl)amide, tryptamine, Rh(CO)2acac,
and HRh(CO)(PPh3)3 were purchased from Sigma-Aldrich
and used without further purification. Xantphos was prepared
as reported in the literature [29]
All non-catalytic reactions in solid phase were carried out by
.
xantphos were beneficial for the formation of the linear using the apparatus depicted in Figure 3.
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M. Marchetti et al.
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Hydroformylation Procedure
In a glass vessel containing a solution of the rhodium catalyst
(see Tables) in toluene (20 mL) were introduced, under a
nitrogen purge, 200 mg (ca. 0.3 mmol of unsaturated starting
product) of the polymeric substrate (1 7) put in the glass
basket previously described (see Figure 2). The vessel was
transferred into a 150-mL stainless steel reactor which was
pressurized with syngas to the desired pressure (see Tables)
and heated at 40 100 8C. The reaction was monitored at
selected times by cooling to room temperature, releasing the
gases and picking-up a sample of the polymer and performing
on it the p-anisaldehyde test.[36]
The reaction products deriving from substrates 2 7 were
cleaved from the polymeric matrix by using a 5% solution of
trifluoroacetic acid in dichloromethane for 30 minutes under
gentle stirring. The solution was neutralized by adding 0.5 g of
K2CO3 and then filtered. After the solvent evaporation, the
products were characterized by GC-MS and 1H NMR.
Figure 3. Apparatus to carry out solid phase reactions.
Preparation of Substrates 1 3 and 5 7
Oxo-Products Deriving from 2
Commercial trityl chloride resin (1.5 g) was activated using
thionyl chloride (2.4 mL, 32.3 mmol) and pyridine (3.15 mL) in
dichloromethane (15 mL). The reaction mixture was heated at
reflux for 3 hours, without stirring, and then transferred in the
glass reactor shown in Figure 3. The resin was filtered and
washed twice with dichloromethane and then allowed to swell
in dichloromethane (20 mL) for one hour. Dichloromethane
was filtered off and pyridine (20 mL) was added and the
mixture stirred by nitrogen bubbling for 10 minutes.
‡
7-Hydroxyheptanal: GC-MS (70 eV): m/e ˆ 130 [M] , 113, 101,
1
83, 56; H NMR (CDCl3): d ˆ 9.60 (t, J ˆ 1.5 Hz, 1H), 3.60
3.50 (m, 2H), 2.35 2.25 (m, 2H), 1.80 1.32 (m, 8H).
6-Hydroxy-2-methylhexanal (identified as 3-mehyloxepan-
2-ol): GC-MS (70 eV): m/e ˆ 130 [M] ; 113; 97, 84, 56; 1H NMR
‡
(CDCl3): d ˆ 4.35 (t, J ˆ 7.2 Hz, 1H), 3.40 3.30 (m, 2H), 1.75
1.25 (m, 7H), 0.9 (d, J ˆ 6.6 Hz, 3H); anal. calcd. For C7H14O2:
H 10.84, C 64.58; found: H 10.91, C 64.77.
After pyridine removal, the substrate of choice (44.0 mmol)
in pyridine (15 mL) was added to the resin and allowed to react
at 508C for 48 hours. The reaction was monitored as follows: a
sample of the polymer was collected and washed with
methanol and treated with a 5% solution of trifluoroacetic
acid in dichloromethane for 30 minutes under a gentle stirring.
Thesolution was neutralized byadding 0.5 g of K2CO3 and then
filtered. The solution was concentrated to small volume
(100 mL) and analyzed by TLC (glass plate) by using a mixture
of ethyl acetate/petroleum ether (2/8) as the eluent. The spots
were detected by spraying with a KMnO4 solution and heating
at 1808C, using pure starting products as reference.
Oxo-Products Deriving from 3
‡
11-Hydroxyundecanal: GC-MS (70 eV): m/e ˆ 169 [M OH] ,
157, 143, 111, 98, 82, 69, 55; 1H NMR (CDCl3): d ˆ 9.75 (t, J ˆ
1.6 Hz, 1H), 3.62 3.57 (m, 2H), 2.42 2.38 (m, 2H), 1.82 1.43
(m, 16H).
10-Hydroxy-2-methyldecanal: GC-MS (70 eV): m/e ˆ 169
‡
[M OH] , 157, 129, 124, 111, 98, 82, 69,58; 41; 1H NMR
À
(CDCl3): d ˆ 9.60 (d, J ˆ 1.5 Hz, 1H), 3.62 3.57 (m, 2H),
2.02 1.91 (m, 1H), 1.82 1.43 (m, 14H), 0.98 (d, J ˆ 6.2 Hz,
3H).
At the end of the reaction the functionalized polymer was
filtered and washed with dichloromethane (20 mL): the
reaction yields were, in all cases, quantitative.
Oxo-Products Deriving from 4
3-(p-Hydroxyphenyl)propanal: GC-MS (70 eV): m/e ˆ 150
‡
[M] , 121, 107, 94, 77; 1H NMR (CDCl3): d ˆ 9.85 (t, J ˆ
Preparation of Substrate 4 by a Modified Wittig
Reaction[35]
1.5 Hz, 1H), 6.96 (d, J ˆ 8.7 Hz, 2H), 6.86 (d, J ˆ 8.7 Hz, 2H),
2.95 2.80 (m, 2H), 2.61 2.55 (m, 2H).
2-(p-Hydroxyphenyl)propanal: GC-MS (70 eV): m/e ˆ 150
Sodium bis(trimethylsilyl)amide (251 mg, 1.37 mmol) was
added to a mixture of methyltriphenylphosponium bromide
(545 mg, 1.37 mmol) in anhydrous THF (15 mL) and vigo-
rously stirred under an inert atmosphere for 30 minutes. The
deep yellow mixture obtained was treated with a sample of p-
hydroxybenzaldehyde anchored to the trityl chloride resin
(200 mg; see procedure above described). After 20 hours the
polymer was filtered and washed twice with THF, twice with
dimethyl sulfoxide, twice with diethyl ether and then dried
under vacuum. The reaction yield was quantitative.
‡
[M] , 121, 103, 92, 77; 1H NMR (CDCl3): d ˆ 9.73 (d, J ˆ
1.8 Hz, 1H), 7.75 (d, J ˆ 8.2 Hz, 2H), 7.50 (d, J ˆ 8.2 Hz, 2H),
3.53 3.51 (m, 1H), 1.12 (d, J ˆ 6.5 Hz, 3H).
Oxo-Products Deriving from 5
1
4-Oxobutanoic acid: H NMR (CDCl3): d ˆ 9.5 (t, J ˆ 1.5 Hz,
1H), 3.7 3.6 (m, 2H), 2.8 2.7 (m, 2H).
1234
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Solid-Liquid Biphasic Hydroformylation of Olefins
FULL PAPERS
1
2-Methyl-3-oxopropanoic acid: H NMR (CDCl3): d ˆ 9.4
(m, 5H), 4.0 (s, 2H), 3.3 (m, 2H), 3.05 (m, 2H), 1.8 1.1 (m,
18H).
(d, J ˆ 1.5 Hz, 1H), 3.2 3.0 (m, 1H), 1.4 1.3 (m, 2H).
10-Phenylaminoundecan-1-ol: GC-MS (70 eV): m/e ˆ 248
‡
[M À CH3] , 246, 171, 157, 129; 1H NMR (CDCl3): d ˆ 7.1 6.9
(m, 5H), 3.3 (m, 2H), 3.05 (m, 2H), 1.8 1.1 (m, 15H), 1.02 (d,
Oxo-Products Deriving from 6
J ˆ 6.4 Hz, 3H).
6-Oxohexanoic acid: 1H NMR (CDCl3): d ˆ 9.78 (t, J ˆ 1.4 Hz,
1H), 6,75 (s, 1H), 2.45 2.40 (m, 2H), 2.39 2.29 (m, 2H), 1.78
1.70 (m, 2H), 1.41 1.17 (m, 2H).
Reductive Amination of the Oxo-Product Deriving
1
5-Oxo-4-methylpentanoic acid: H NMR (CDCl3): d ˆ 9.49
from the Hydroformylated 5 on a Solid Phase[34]
(d, J ˆ 1.6 Hz, 1H), 6.68 (s, 1H), 3.41 3.33 (m, 1H), 2.45 2.40
(m, 2H), 1.78 1.70 (m, 2H), 1.05 (d, J ˆ 7.4 Hz, 3H).
The hydroformylated polymer (200 mg, ca. 0.3 mmol of
aldehydes) was allowed to swell with a mixture of toluene/
dimethyl sulfoxide (1:1) for 1 h and then an excess of
tryptamine (20 equivs., 962 mg) and 0.2 mL of 10 N HCl were
added. The reaction mixture was stirred by nitrogen bubbling
at 508C for 72 h. The IR spectrum performed on a sample of
this polymer did not show the presence of the carbonyl group
anymore. The polymer was filtered, washed 3 times with
dimethyl sulfoxide (20 mL), 3 times with dichloromethane
(20 mL) and dried under vacuum.
Oxo-Product Deriving from 7
2-Acetylamino-4-oxobutanoic acid (identified as 2-azetidine-
carboxylic acid): 1H NMR (DMSO-d6): d ˆ 5.01 (s, 2H), 4.22
4.18 (m, 1H), 3.45 3.38 (m, 2H), 1.145 1,25 (m, 2H);
13C NMR (DMSO-d6): d ˆ 172.3, 52.5, 40.7, 17.3; anal. calcd.
for C4H7NO2: H 6.98, C 47.52, N 13.85; found: H7.00, C 47.73, N
13.98.
The cleavage of the product was carried out as previously
described. The yield was quantitative.
3-(2,3,4,9-Tetrahydro-1H-b-carbolin-1-yl)-propionic acid:
1H-NMR (CDCl3): d ˆ 10.83 (s, 1H), 9.0 (s, 1H), 8.05 (s, 1H),
7.61 7.04 (m, 4H), 3.82 3.68 (m, 1H), 3.35 3.02 (m, 4H),
2.65 1.80 (m, 4H); 13C-NMR (CDCl3): d ˆ 170.4, 138.6, 135.0,
125.2, 121.8, 119.8, 117.2, 112.5, 110.2, 46.4, 41.4, 37.6, 34.2, 28.9;
anal. calcd. for C14H16N2O2: H 6.60, C 68.83, N 11.47; found: H
6.62, C 68.99, N 11.52.
Reductive Amination of the Oxo-Products on a Solid
Phase
The oxo-products deriving from 1, due to their instability, were
not isolated following the above described procedure. Their
characterization was performed by transforming them into the
corresponding N-phenylamine derivatives.
The reductive amination was carried out on the oxo-
products deriving from substrates 1 and 3. The hydroformy-
lated polymer (200 mg, ca. 0.3 mmol of aldehydes) was allowed
to swell with a 1% AcOH solution in DMF for 1 h and then an
excess of NaBH(OAc)3 (4 equivs., 254 mg) and aniline (4
equivs., 0.1 mL) was added. The reaction mixture was stirred
by nitrogen bubbling at room temperature for 20 hours. The IR
spectrum performed on a sample of this polymer did not show
the presence of the carbonyl group anymore. The polymer was
filtered, washed with dichloromethane and dried under
vacuum.
Reduction of the Oxo-Products Deriving from
Substrate 2
The hydroformylated polymer (200 mg, ca. 0.3 mmol of
aldehydes) was allowed to swell with a mixture of tetrahy-
drofuran/methanol (1:1) for 1 h and then an excess of NaBH4
(10 equivs., 83 mg) was added. The reaction mixture was stirred
by nitrogen bubbling at room temperature for 5 h. The IR
spectrum performed on a sample of this polymer did not show
the presence of the carbonyl group anymore. The polymer was
filtered, washed 3 times with dichloromethane (20 mL) and
dried under vacuum.
The cleavage of the products was carried out as previously
described. The yields were in all cases quantitative.
The cleavage of the products was carried out as previously
described. The yield was quantitative.
‡
1,7-Heptandiol: GC-MS (70 eV): m/e ˆ 98 [M À 2(OH)] ,
Amines Deriving from 1
81, 68, 56, 41; 1H NMR (CDCl3): d ˆ 3.75 3.52 (m, 4H), 1.45
1.08 (m, 10H).
‡
N-Phenylaminobutan-1-ol: GC-MS (70 eV): m/e ˆ 165 [M] ,
149, 135, 121, 107, 55; 1H NMR (CDCl3): d ˆ 7.42 7.39 (m, 2H,
arom), 7.20 7.09 (m, 3H, arom), 4.75 (s, 2H), 3.78 3.60 (m,
2H), 3.22 3.16 (m, 2H), 1.82 1.61 (m, 4H).
2-Methyl-1,6-hexandiol: GC-MS (70 eV): m/e ˆ 102 [M À
‡
1
CH2OH] , 98, 72, 58; H NMR (CDCl3): d ˆ 3.75 3.52 (m,
2H), 3.40 3.30 (m, 2H), 1.90 1.81 (m, 1H), 1.60 1.06 (m,
6H), 0.9 (d, J ˆ 6,8 Hz, 3H).
2-Methyl-N-phenylaminopropan-1-ol: GC-MS (70 eV):
‡
m/e ˆ 165 [M] , 135, 112, 93, 55; 1H NMR (CDCl3): d ˆ 7.81
7.75 (m, 2H), 7.60 7.55 (m, 1H), 6.81 6.66 (m, 2H), 3.78 3.60
(m, 2H), 3.22 3.16 (m, 2H), 2.05 1.95 (m, 1H), 0.95 (d, J ˆ
6.2 Hz, 3H).
Acknowledgements
The authors are grateful to Mrs Barbara Sechi for the skillful
experimental assistance.
Amines Deriving from 3
11-Phenylaminoundecan-1-ol: GC-MS (70 eV): m/e ˆ 246
‡
1
[M À OH] , 218, 171, 157, 93; H NMR (CDCl3): d ˆ 7.1 6.9
Adv. Synth. Catal. 2003, 345, 1229 1236
asc.wiley-vch.de
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1235

M. Marchetti et al.
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¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2003, 345, 1229 1236