Hydroformylation Reactions with Recyclable Rhodium-Complexed Dendrimers on a Resin

Article abstract of DOI:10.1021/ja0303384

Rhodium-complexed dendrimers supported on a resin were evaluated as catalysts for the hydroformylation of aryl olefins and vinyl esters. The results showed the reactions proceeded very efficiently at room temperature with excellent yields. Outstanding selectivity for the branched aldehydes was also observed in all cases. The dendritic catalysts can be recycled by simple filtration and reused even up to the tenth cycle without loss of activity and selectivity. These results represent a dramatic improvement over those previously described for rhodium-catalyzed (dendrimer and nondendrimer based) hydroformylation reactions.

Full text of DOI:10.1021/ja0303384

Published on Web 10/01/2003
Hydroformylation Reactions with Recyclable
Rhodium-Complexed Dendrimers on a Resin
Shui-Ming Lu and Howard Alper*
Contribution from the Centre for Catalysis Research and InnoVation, Department of Chemistry,
UniVersity of Ottawa, 10 Marie Curie, Ottawa, Ontario, Canada, K1N 6N5
Received June 3, 2003; E-mail: halper@uottawa.ca
Abstract: Rhodium-complexed dendrimers supported on a resin were evaluated as catalysts for the
hydroformylation of aryl olefins and vinyl esters. The results showed the reactions proceeded very efficiently
at room temperature with excellent yields. Outstanding selectivity for the branched aldehydes was also
observed in all cases. The dendritic catalysts can be recycled by simple filtration and reused even up to
the tenth cycle without loss of activity and selectivity. These results represent a dramatic improvement
over those previously described for rhodium-catalyzed (dendrimer and nondendrimer based) hydroformy-
lation reactions.
Introduction
ity under mild conditions, ease of separation from the product,
and reuse as many times as possible without too much of a
The hydroformylation of olefins, which produces linear and
branched aldehydes under carbon monoxide and hydrogen, is
one of the most thoroughly investigated reactions in homoge-
neous catalysis.1 From the fine chemistry viewpoint, the
branched aldehydes are more important as they provide valuable
intermediates for the pharmaceutical industry. For example,
ibuprofen and naproxen, being two nonsteroidal antiinflamma-
tory drugs,2 can be obtained by the hydroformylation of
4-isobutylstyrene and 2-vinyl-6-methoxynaphthalene, respec-
tively, followed by oxidation of the resulting branched-chain
aldehydes.3
decrease in efficiency.6 Introduction of a dendritic template
between the support and catalyst is particularly attractive in this
regard.
Dendrimers have attracted an increasing attention due to their
special properties and functions.7 An important application of
dendrimers is the use of their complexes as catalysts.6,8 Soluble
dendrimers were widely utilized for a variety of catalytic
reactions.9 However, there have been only a few examples
concerning heterogeneous dendritic catalysts.10 For instance,
(5) (a) Leadbeater, N. E.; Marco, M. Chem. ReV. 2002, 102, 3217-3274. (b)
McNamara, C. A.; Dixon, M. J.; Bradley, M. Chem. ReV. 2002, 102, 3275-
3300. (c) de Miguel, Y. R.; Brule, E.; Margue, R. G. J. Chem. Soc., Perkin
Trans. 1 2001, 3085-3094. (d) Sandee, A. J.; Reek, J. N. H.; Kamer, P.
C. J.; van Leeuwen, P. W. N. M. J. Am. Chem. Soc. 2001, 123, 8468-
8476. (e) de Miguel, Y. R. J. Chem. Soc., Perkin Trans, 1 2000, 4213-
4221. (f) Lindner, E.; Schneller, T.; Auer, F.; Mayer, H. A. Angew. Chem.,
Int. Ed. 1999, 38, 2154-2174. (g) Nozaki, K.; Itoi, Y.; Shibahara, F.;
Shirakawa, E.; Ohta, T.; Takaya, H.; Hiyama, T. J. Am. Chem. Soc. 1998,
120, 4051-4052.
Although homogeneous catalytic processes often display high
activity and selectivity, in most cases, the catalyst-product
separation is usually nontrivial. In addition, the metal catalysts
and ligands can be very expensive. These limit the practical
application of many excellent catalytic systems.1f,4 Immobiliza-
tion of homogeneous catalysts on a solid support is one of the
possible ways to prepare well-defined catalytic systems.5
Unfortunately, along with the advantages of the heterogeneous
catalysts, a significant loss of the catalytic activity and selectivity
is often observed. From a catalytic point of view, the ideal
catalyst should combine the advantages of both homogeneous
and heterogeneous catalysis including high activity and selectiv-
(6) (a) Astruc, D.; Chardac, F. Chem. ReV. 2001, 101, 2991-3023. (b)
Oosterom, G. E.; Reek, J. N. H.; Kamer, P. C. J.; van Leeuwen, P. W. N.
M. Angew. Chem., Int. Ed. 2001, 40, 1828-1849.
(7) For selected references on dendrimers, see: (a) Minard-Basquin, C.; Wenja,
T.; Hohner, A.; Raedler, J. O.; Muellen, K. J. Am. Chem. Soc. 2003, 125,
5832-5838. (b) Diez-Barra, E.; Garcia-Martinez, J.-C.; del Rey, R.;
Rodriguez-Lopez, J.; Giacalone, F.; Segura, J. L.; Martin, N. J. Org. Chem.
2003, 68, 3178-3183. (c) Percec, V.; Gloddle, M.; Bera, T. K.; Miura,
Y.; Shiyanovskaya, I.; Singer, K. D.; Balagurusamy, V. S. K.; Heiney, P.
A.; Schnell. I.; Rapp, A.; Spiess, H.-W.; Hudson, S. D.; Duan, H. Nature
2002, 419, 384-387. (d) Wimmer, N.; Marano, R. J.; Kearns, P. S.;
Rakoczy, E. P.; Toth, I. Bioorg. Med. Chem. Lett. 2002, 12, 2635-2637.
(e) Gray, S. M.; Frechet, J. M. J. Chem. ReV. 2001, 101, 3819-3867. (f)
Newkome, G. R.; Moorefield, C. N.; Vogtle, F. Dendritic Molecules:
Concepts, Synthesis, PerspectiVes; VCH: Weinheim, 1996.
(8) (a) Saudam, C.; Balzani, V.; Gorka, M.; Lee, S.-K.; Maestri, M.; Vicinelli,
V.; Vogtle, F. J. Am. Chem. Soc. 2003, 125, 4424-4425. (b) Esposito, A.;
Delort, E.; Lagnoux, D.; Djojo, F.; Reymond, J.-L. Angew. Chem., Int.
Ed. 2003, 42, 1381-1383. (c) Malkoch, M.; Hallman, K.; Lutsenko, S.;
Hult, A.; Malmstroem, E.; Moberg, C. J. Org. Chem. 2002, 67, 8197-
8202. (d) van Heerbeek, R.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.;
Reek, J. N. H. Chem. ReV. 2002, 102, 3717-3756. (e) Twyman, L. J.;
King, A. S. H.; Martin, I. K. Chem. Soc. ReV. 2002, 31, 69-82. (f) Knapen,
J. W. J.; van der Made, A. W.; de Wilde, J. C.; van Leeuwen, P. W. N.
M.; Wijkens, P.; Grove, D. M.; van Koten, G. Nature 1994, 372, 659-
663.
(1) (a) Breit, B. Acc. Chem. Res. 2003, 36, 264-275. (b) Bohnen, H.-W.;
Cornils, B. AdV. Catal. 2002, 47, 1-64. (c) Ungvary, F. Coord. Chem.
ReV. 2002, 228, 61-82. (d) Ungvary, F. Coord. Chem. ReV. 2001, 213,
1-50. (e) Breit, B.; Seiche, W. Synthesis 2001, 1-36. (f) van Leeuwen,
P. W. N. M. Rhodium Catalyzed Hydroformylation; Kluwer: Dordrecht,
2000. (g) Herrmann, W. A.; Cornils, B. Angew. Chem., Int. Ed. Engl. 1997,
36, 1048-1067.
(2) (a) Nonsteroidal Antiinflammatory Drugs; Lewis, A. J., Furst, D. E., Eds.;
Dekker: New York, 1994. (b) Riev, J.-P.; Boucherle, A.; Coursse, H.;
Mouzin, G. Tetrahedron 1986, 42, 4095-4131.
(3) (a) Reuben, B. G.; Wittcoff, H. A. Pharmaceutical Chemicals in Perspec-
tiVe; John Wiley: New York, 1989. (b) Riley, D. P.; Getman, D. P.; Beck,
G. R.; Heintz, R. M. J. Org. Chem. 1987, 52, 287-290.
(4) (a) Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem., Int. Ed. Engl. 1997,
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617-618.
9
13126
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10.1021/ja0303384 CCC: $25.00 © 2003 American Chemical Society

Recyclable Rhodium-Complexed Dendrimers on Resin
A R T I C L E S
Figure 1. Retrosynthetic analysis: solid-phase synthesis of rhodium-complexed dendrimers on a resin.
Rhee has employed dendrimers supported on silica for the
addition of diethylzine to benzaldehyde.10a Palladium dendrimers
on polystyrene catalyze Heck reactions as reported by Portnoy.10b
Recently, we described the immobilization of dendritic ligands
on a resin in which the ligands were placed on the outer11a and
inner11b arms of dendrimers and used for hydroformylation
reactions. The environment of complexed ligands on the arms
played an important role in this transformation. In contrast to
the known heterogeneous catalysts, our systems showed good
activity and selectivity. These results inspired us to explore the
synthesis of heterogeneous dendritic catalysts having both
interior and exterior functional groups for metal coordination
and their applications for hydroformylation reactions. We now
report the interesting and useful results from this investigation.
Results and Discussion
Preparation of Rhodium-Complexed Dendrimers on a
Resin. Solid-phase synthesis was used for the construction of
dendrimers.11 In comparison to the traditional solution chemistry
suffering from difficulties associated with long reaction time
and nontrivial purification,12 the solid-phase method enables the
use of excess reagents to drive the reaction to completion,
turning purification steps into the simple washing of resin.13
The dendrimers were prepared starting from the building block
3, which contains a reactive carboxyl moiety and four Fmoc-
protected amino groups, allowing the carboxyl moiety of one
molecule to be applied for the attachment to the deprotected
amino group of another moiety and rapid growth of dendritic
assemblies (Figure 1).
The coupling reaction of 3,5-diaminobenzoic acid with
glycine tert-butyl ester in the presence of 1-hydroxybenzotria-
zole (HOBT) and dicyclohexylcarbodiimide (DCC) afforded
tert-butyl ester derivative 1, which reacted with di-Fmoc-lysine
using 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HBTU) as the coupling reagent to give
(9) (a) Ropartz, L.; Morris, R. E.; Foster, D. F.; Cole-Hamilton, D. J. Chem.
Commun. 2001, 361-362. (b) Petrucci-Samija, M.; Guillemette, V.;
Dasgupta, M.; Kakkar, A. K. J. Am. Chem. Soc. 1999, 121, 1968-1969.
(c) Oosterom, G. E.; Steffens, S.; Reek, J. N. H.; Kamer, P. C. J.; van
Leeuwen, P. W. N. M. Top. Catal. 2002, 19, 61-73. (d) Reetz, M. T.;
Lohmer, G.; Schwickard, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 1526-
1529. (e) Chow, H.-F.; Make, C. C. J. Org. Chem. 1997, 62, 5116-5127.
(f) Kleij, A. W.; Gebbink, J. M. K.; van der Nieuwenhuijzen, P. A. J.;
Kooijman, H.; Lutz, M.; Spek, A. L.; van Koten, G. Organometallics 2001,
20, 634-647. (g) Bolm, C.; Derrien, N.; Seger, A. Chem. Commun. 1999,
2087-2088. (h) Bhyrappa, P.; Young, J. K.; Moore, J. S.; Suslick, K. S.
J. Am. Chem. Soc. 1996, 118, 5708-5711.
(10) (a) Chung, Y.-M.; Rhee, H.-K. Chem. Commun. 2002, 238-239. (b) Dahan,
A.; Portnoy, M. Org. Lett. 2003, 5, 1197-1200. (c) Dahan, A.; Portnoy,
M. Chem. Commun. 2002, 2700-2701. (d) Sellner, H.; Rheiner, P. B.;
Seebach, D. HelV. Chim. Acta 2002, 85, 352-387. (e) Sellner, H.; Seebach,
D. Angew. Chem., Int. Ed. 1999, 38, 1918-1920. (f) Sellner, H.;
Karjalainen, J. K.; Seebach, D. Chem.sEur. J. 2001, 7, 2873-2887. (g)
Reetz, M. T.; Giebel, D. Angew. Chem., Int. Ed. 2000, 39, 2498-2501.
(h) Bourque, S. C.; Maltais, F.; Xiao, W.-J.; Tardif, O.; Alper, H.; Arya,
P.; Manzer, L. E. J. Am. Chem. Soc. 1999, 121, 3035-3038. (i) Bourque,
S. C.; Alper, H.; Manzer, L. E.; Arya, P. J. Am. Chem. Soc. 2000, 122,
956-957. (j) Alper, H.; Arya, P.; Bourque, S. C.; Jefferson, G. R.; Manzer,
L. E. Can. J. Chem. 2000, 78, 920-924. (k) Antebi, S.; Arya, P.; Manzer,
L. E.; Alper, H. J. Org. Chem. 2002, 67, 6623-6631.
(12) Bosmas, A. W.; Janssen, H. M.; Meijer, E. M. Chem. ReV. 1999, 99, 1665-
1688.
(13) (a) Solid-Phase Organic Synthesis; Burgess, K., Eds.; Wiley-Interscience:
New York, 1999. (b) Dorwald, F. Z. Organic Synthesis on Solid Phase-
Supports, Linker, Reactions; Wiley-VCH: New York, 2000.
(11) (a) Arya, P.; Rao, N. V.; Singkhonrat, J.; Alper, H.; Bourque, S. C.; Manzer,
L. E. J. Org. Chem. 2000, 65, 1881-1886. (b) Arya, P.; Panda, G.; Rao,
N. V.; Alper, H.; Bourque, S. C.; Manzer, L. E. J. Am. Soc. Chem. 2001,
123, 2889-2890.
9
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A R T I C L E S
Lu and Alper
Scheme 1. Synthesis of Building Block 3
pseudopeptide tert-butyl ester 2. Deprotection of tert-butyl group
of compound 2 with trifluoroacetic acid afforded the building
block 3 in 95% yield (Scheme 1).
at room temperature for 2 h, at which time there was 30%
conversion to aldehydes (Table 1, entry 1). Increasing the
reaction time to 6 and 10 h gave 83% and 90% conversions,
respectively (Table 1, entries 2 and 3). Performing the reaction
under the same conditions for 16 h resulted in 96% conversion
to product (Table 1, entry 4). However, a >99% conversion of
styrene to aldehydes was observed when prolonging the reaction
time to 22 h at room temperature (branched:linear ) 36:1; Table
1, entry 5).
Solid-phase synthesis of rhodium-complexed dendrimers G1
and G2 was carried out on Fmoc-Rink amide MBHA resin
(Novabiochem, loading: 0.54 mmol/g). Treatment of the Fmoc-
protected resin with 20% piperidine in dimethylformamide gave
free amino resin, which reacted with the carboxyl group of the
building block 3 in the presence of HBTU affording dendrimer
4. An 86% coupling yield was determined by the cleavage and
purification of the known amount of the resin. The second-
generation dendrimer 5 was synthesized from dendrimer 4 in a
similar manner by repeating the required steps.
The dendrimers on a resin were phosphonated prior to
complexation with rhodium. Diphenylphosphinomethanol, pre-
pared in situ from paraformaldehyde and diphenylphosphine,
reacted with each terminal amino group of dendrimers. The
resulting phosphonated dendrimers were characterized by 31P
solid-state NMR. A chemical shift of -28 ppm for the various
generations compared well with the published value of -28
ppm9d,10h,i,k,11 for the polyaminophosphonated dendrimers (load-
ing of phosphine groups: G1, 2.01 mmol/g; G2, 2.63 mmol/
g).
The phosphonated dendrimers on a resin were complexed by
simply stirring with chloro(dicarbonyl)rhodium(I) dimer in
degassed dichloromethane at room temperature for 3 h under
argon. The resulting complexed dendrimers were characterized
by 31P solid-state NMR (complexed δ ) 25 ppm, uncomplexed
δ ) -28 ppm). The ICP results showed the rhodium contents
of G1 and G2 are 0.74 mmol/g and 0.83 mmol/g, respectively
(Scheme 2).
Optimization of Hydroformylation Reaction Conditions.
The hydroformylation reactions were optimized by using styrene
as a model substrate and G1 as the catalyst. The effects of the
reaction time, temperature, pressure of carbon monoxide and
hydrogen, and solvent were investigated; the results are listed
in Table 1. Table 1 showed that the reaction time played an
important role in this transformation (Table 1, entries 1-5).
The reaction was carried out by treating 2 mmol of styrene with
500 psi of carbon monoxide and 500 psi of hydrogen in the
presence of catalyst G1 in 10 mL of anhydrous dichloromethane
Clearly, the reaction temperature and the total pressure of
carbon monoxide and hydrogen also affected the hydroformy-
lation of styrene. Treatment of styrene with catalyst G1 at 500
psi of carbon monoxide and 500 psi of hydrogen in dichlo-
romethane at 45 °C and 65 °C for 22 h afforded 18:1 and 13:1
ratios of branched-to-linear aldehydes (>99% conversions),
respectively (Table 1, entries 6 and 7). The results are in
accordance with our previous observation that high temperature
decreased the selectivity for the branched aldehyde.10h,11a
Increasing the total pressure favored hydroformylation to give
the branched aldehydes (Table 1, entries 8-11). A 38:1 ratio
of branched-to-linear aldehydes was obtained under 600 psi of
carbon monoxide and 600 psi of hydrogen (Table 1, entry 8).
When the total pressure was changed to 800 and 600 psi, the
ratios of branched-to-linear aldehydes were reduced to 34:1 and
32:1, respectively (Table 1, entries 9 and 10). A decrease in
the conversion occurred when hydroformylation proceeded at
a total pressure of 400 psi (branched:linear ) 32:1; Table 1,
entry 11). These results indicate the selectivity may be due to
thermodynamic effects (linear aldehydes pack more efficiently).
The solvent was another key factor for successful hydro-
formylation. Dichloromethane proved to be the best solvent for
this transformation, and the reaction also worked well in
chloroform, benzene, toluene, and ethyl acetate with >99%
conversions, but a slight decrease in selectivity for the branched
aldehydes was observed (Table 1, entries 12-15). Other
solvents, such as tetrahydrofuran, ether, and hexane, gave >80%
conversions (Table 1, entries 16-18). Apparently, no solvent
is as effective as dichloromethane.
Hydroformylation of Aryl Olefins and Vinyl Esters.
Rhodium-complexed dendrimers were assessed as catalysts for
the hydroformylation of styrene, 4-isobutylstyrene, 4-vinylani-
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Recyclable Rhodium-Complexed Dendrimers on Resin
A R T I C L E S
Scheme 2. Solid-Phase Synthesis of Rhodium-Complexed Dendrimers on a Resina
a (a) (i) 20% piperidine, DMF; (ii) 4 equiv of 3, 4 equiv of HBTU, 8 equiv of DIPEA, DMF, 16 h. (b) 20% piperidine, DMF; (ii) 16 equiv of 3, 16 equiv
of HBTU, 24 equiv of DIPEA, DMF, 24 h. (c) (i) 15 equiv of Ph2PCH2OH with respect to NH2, prepared from (HCHO)n and Ph2PH in degassed toluene,
70 °C 2 h, stirred rt 16 h; (ii) 0.25 equiv of [Rh(CO)2Cl]2 with respect to PPh2, CH2Cl2, rt, 3 h. (d) repeat steps in part c.
Table 1. Hydroformylation of Styrene with Rhodium-Complexed
temperature for 22 h. The results, summarized in Tables 2-8
of the Supporting Information, indicate that the room temper-
Dendrimers under Different Reaction Conditionsa
ature hydroformylation reactions give quantitative conversion
to aldehydes, with a remarkable preference for the branched-
chain products using G1 and G2 as the catalysts (styrene, 36
( 3:1; 4-isobutylstyrene, 33.5 ( 2.5:1; 4-vinylanisole, 45 (
c
pressure
(psi)
temp
(°C)
time
(h)
conversionb
(%)
selectivity
B:L ratio
3:1; 2-vinyl-6-methoxynaphthalene, 38 ( 4:1; vinyl benzoate,
32 ( 1:1; vinyl acetate, 21.5 ( 1.5:1; dimethyl vinylphospho-
nate, 43.5 ( 1.5:1). Both catalysts are easily recovered by simple
filtration and reusable for at least six more cycles without loss
of activity and regioselectivity. For example, hydroformylation
of styrene using the catalyst G1 exhibited >99% conversion to
aldehydes (the ratios of branched-to-linear aldehydes ranged
from 36:1 to 33:1) up to the seventh cycle. The conversion to
the aldehydes decreased to 95% for the eighth cycle, but
prolonging the reaction time to 32 h gave >99% conversion
for the ninth cycle. Catalyst G2 was found to be more reactive
than catalyst G1 for the hydroformylation of styrene, the ratios
of branched-to-linear aldehydes ranging from 39:1 to 36:1 with
>99% conversions observed, even up to the tenth cycle, without
loss of activity and selectivity (Table 2, Supporting Information).
entry
solvent
CH2Cl2
1
2
3
4
5
6
7
8
9
1000
1000
1000
1000
1000
1000
1000
1200
800
25
25
25
25
25
45
65
25
25
25
25
25
25
25
25
25
25
25
2
6
30
83
90
32:1
34:1
34:1
35:1
36:1
18:1
13:1
38:1
34:1
32:1
32:1
33:1
32:1
30:1
32:1
32:1
26:1
25:1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
Benzene
Toluene
Ethyl acetate
THF
Ether
Hexane
10
16
22
22
22
22
22
22
22
22
22
22
22
22
22
22
96
>99d
>99
>99
>99
>99
>99
97
10
11
12
13
14
15
16
17
18
600
400
1000
1000
1000
1000
1000
1000
1000
>99
>99
>99
>99
93
87
89
Similar results were obtained for the hydroformylation of
4-isobutylstyrene, 4-vinylanisole, and 2-vinyl-6-methoxynaph-
thalene. The presence of the isobutyl group at the 4-position of
the phenyl ring slightly decreased the selectivity (Table 3,
Supporting Information). However, the high preference for the
branched aldehydes was observed when the methoxyl group is
at the 4-position of the phenyl ring or the 6-position of the
naphthyl ring (Tables 4 and 5, Supporting Information).
Compared to other olefins, reactivity was modestly reduced for
a 2 mmol of styrene, 10 mL of solvent, 1:1 ratio of CO:H2, 25 mg of
catalyst. b Determined by 1H NMR and GC. c Determined by 1H NMR.
d 99% isolated yield.
sole, 2-vinyl-6-methoxynaphthalene, vinyl benzoate, vinyl ac-
etate, and dimethyl vinylphosphonate. In a typical reaction, a
mixture of 2 mmol of the olefin in 10 mL of dichloromethane
with 25 mg of the catalyst was treated with a mixture of 500
psi of carbon monoxide and 500 psi of hydrogen gas at room
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J. AM. CHEM. SOC. VOL. 125, NO. 43, 2003 13129

A R T I C L E S
Lu and Alper
CD3SOCD3) δ 27.76, 41.79, 80.41, 101.98, 102.18, 135.65, 149.07,
168.07, 169.24. MS (EI), m/z: 265 [M+].
the hydroformylation of vinyl benzoate and vinyl acetate. For
example, with vinyl benzoate, catalyst G1 exhibited >99%
conversion up to the fifth cycle, but the conversion to product
decreased to 93% for the sixth cycle. Employing G2 as the
catalyst, >99% conversion was obtained up to the sixth cycle,
whereas 98% conversion resulted for the seventh cycle (Table
6, Supporting Information). When vinyl acetate was examined
as a substrate, the ratios of branched-to-linear aldehydes varied
from 20:1 to 23:1 (Table 7, Supporting Information). To our
surprise, high activity and selectivity resulted from the hydro-
formylation of dimethyl vinylphosphonate; both G1 and G2
exhibited >99% conversions with about 43:1 ratios of branched-
to-linear aldehydes up to the seventh cycle (Table 8, Supporting
Information).
Coupling Reaction of N-r,E-di-Fmoc-L-Lysine with Compound
1. To a solution of N-R,ꢀ-di-Fmoc-L-lysine (6.4977 g, 11 mmol), 3,5-
diamino-N-benzamide glycine tert-butyl ester (1) (1.3266 g, 5 mmol)
and N,N-diisopropylethylamine (1.4218 g, 1.92 mL, 11 mmol) in dry
N,N-dimethylformamide (30 mL) was added to 2-(1H-benzotriazole-
1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) (4.1723
g, 11 mmol) in an ice-water bath. The reaction mixture was stirred
for 2 h at 0 °C and an additional 18 h at room temperature. The solvent
was removed under reduced pressure, and the oily residue was dissolved
in dichloromethane (100 mL), which was washed with 10% aqueous
citric acid solution (2 × 80 mL), saturated sodium chloride solution (2
× 80 mL), 10% aqueous sodium hydrogencarbonate solution (2 × 80
mL), and saturated sodium chloride solution (2 × 80 mL). The organic
layer was dried over anhydrous sodium sulfate and concentrated in
vacuo. The resulting oil was purified by silica gel chromatography with
a mixture of hexane and ethyl acetate as the eluant to give a white
solid as compound 2 (5.8541 g, 83%). 1H NMR (300 MHz, CD3SOCD3)
δ 1.22-1.70 (m, 21H), 2.97-3.00 (m, 4H), 3.85 (d, 2H), 4.12-4.34
(m, 14H), 7.27-7.87 (m, 38H), 8.15 (s, 1H), 8.76 (t, 1H), 10.22 (s,
2H); 13C NMR (300 MHz, CD3SOCD3) δ 23.84, 28.58, 30.10, 32.24,
42.82, 47.55, 56.30, 66.03, 66.50, 81.42, 110.63, 120.90, 122.24, 125.98,
126.17, 127.89, 128.14, 128.44, 128.48, 129.77, 138.27, 140.18, 141.57,
143.41, 144.62, 144.75, 156.96, 167.69, 169.78, 172.27. MS (ESI),
m/z: 1410 [MH+].
Deprotection of Compound 2. Trifluoroacetic acid (15 mL) was
added dropwise to a solution of compound 2 (4.2319 g, 3 mmol) in
dichloromethane (15 mL) at 0 °C, and the resulting mixture was stirred
for 3 h at room temperature. The solution was concentrated by rotary
evaporation and washed with diethyl ether (3 × 10 mL, followed by
reconcentration) to give a white solid as product 3 (3.8604 g, 95%).
1H NMR (300 MHz, CD3SOCD3) δ 1.21-1.71 (m, 12H), 2.96-2.99
(m, 4H), 3.88 (d, 2H), 4.11-4.29 (m, 14H), 7.27-7.87 (m, 38H), 8.14
(s, 1H), 8.74 (t, 1H), 10.21 (s, 2H); 13C NMR (300 MHz, CD3SOCD3)
δ 23.84, 29.96, 32.23, 42.12, 47.54, 56.29, 66.02, 66.49, 111.22, 120.96,
125.98, 126.17, 127.89, 128.44, 128.49, 136.22, 140.07, 141.57, 144.62,
144.72, 144.76, 156.96, 167.57, 172.10, 172.27. MS (ESI), m/z: 1354
[MH+].
General Procedure for the Solid-Phase Synthesis. Rink amide
MBHA resin (400 mg, 0.54 mmol/g) was swollen with dimethylfor-
mamide (15 mL, 30 min, 3×) and treated with a solution of 20%
piperidine in dimethylformamide (10 mL, 30 min, 3×) to remove the
Fmoc protecting group. After washing with dimethylformamide (3 ×
15 mL) and dichloromethane (5 × 15 mL), a solution of compound 3
(1.1703 g, 0.864 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethy-
luronium hexafluorophosphate (0.3277 g, 0.864 mmol), and N,N-
diisopropylethylamine (0.2234 g, 1.728 mmol) in dimethylformamide
(10 mL) was added, and the mixture was reacted for 16 h. The resin
was washed with dimethylformamide (3 × 15 mL) and dichloromethane
(5 × 15 mL) and subsequently treated with 20% piperidine in
dimethylformamide (15 mL, 30 min, 3×). After washing with dim-
ethylformamide (3 × 15 mL) and dichloromethane (5 × 15 mL), a
light yellow resin was obtained as the first-generation dendrimer.
The second-generation dendrimer was prepared in a similar manner
by repeating the required steps.
General Procedure for the Phosphonation Reaction. The mixture
of paraformaldehyde (0.2253 g, 7.5 mmol) and diphenylphosphine (1.74
mL, 10 mmol) in degassed toluene (15 mL) was heated at 110 °C for
2 h under argon and then cooled to room temperature. The resin (0.5
mmol with respect to NH2) from the solid-phase synthesis was added
to the above solution. The reaction was stirred at 70 °C for 2 h and at
room temperature overnight. After filtration under a stream of argon,
the product was washed with methanol (5 × 15 mL) and dried in vacuo.
General Procedure for the Complexation Reaction. The resin (0.4
mmol with respect to PPh2) was added to a solution of chloro(dicar-
Summary
In conclusion, dendrimer rhodium complexes having both
interior and exterior functional groups are found to be very
efficient catalysts for the hydroformylation of a variety of
olefins, affording exceptionally high selectivity for the branched
aldehydes with excellent yields even up to the tenth cycle.
Moreover, the reactions occur under remarkably mild conditions
(room temperature) and are simple in execution and workup.
These results indicate a dramatic improvement over previously
described rhodium-complexed dendrimers for the hydroformy-
lation reactions.10h,i,11 This may be attributed to cooperative
catalytic behavior of the multiple coordination sites on the
interior and exterior functional groups of rhodium-complexed
dendrimers. Our studies also demonstrate that it is possible to
achieve high reactivity in the heterogeneous catalytic systems.
Of particular note are 2-(4-isobutylphenyl)propanal and 2-(6-
methoxy-2-naphthyl)propanal as important intermediates for the
synthesis of ibuprofen and naproxen.
Experimental Section
Materials. 4-Isobutylstyrene14 and 2-vinyl-6-methoxynaphthalene15
were prepared according to literature procedures. Other chemicals were
purchased from commercial sources. All solvents were dried and
distilled prior to use.
Coupling Reaction of 3,5-Diaminobenzoic Acid with Glycine tert-
Butyl Ester Hydrochloride. Glycine tert-butyl ester hydrochloride
(3.5204 g, 21 mmol), 1-hydroxybenzotriazole monohydrate (2.8377 g,
21 mmol), 3,5-diaminobenzoic acid (3.0430 g, 20 mmol), and N,N-
diisopropylethylamine (2.7143 g, 3.66 mL, 21 mmol) were dissolved
in dry N,N-dimethylformamide (40 mL), and the solution was stirred
and cooled in an ice-water bath while dicyclohexylcarbodiimide
(4.3329 g, 21 mmol) was added. Stirring was continued for 2 h at 0 °C
and an additional 12 h at room temperature. The 1,3-dicyclohexylurea
which separated was removed by filtration and washed with N,N-
dimethylformamide (3 × 5 mL), and the solvent was evaporated under
reduced pressure. The oily residue was dissolved in dichloromethane
(100 mL), which was washed with 10% aqueous sodium hydrogen-
carbonate solution (3 × 80 mL) and saturated sodium chloride solution
(3 × 80 mL). The organic layer was dried over anhydrous sodium
sulfate and evaporated in vacuo. The resulting oil was purified by silica
gel chromatography with a mixture of hexane and ethyl acetate as the
eluant to give a pale-yellow solid as compound 1 (4.5527 g, 86%). 1H
NMR (200 MHz, CD3SOCD3) δ 1.40 (s, 9H), 3.76 (d, 2H), 4.89 (ws,
4H), 5.94 (s, 1H), 6.22 (s, 2H), 8.27 (t, 1H); 13C NMR (200 MHz,
(14) Parrinello, G.; Stille, J. K. J. Am. Chem. Soc. 1987, 109, 7122-7127.
(15) Wahler, D.; Badalassi, F.; Crotti, P.; Reymond, J.-L. Chem.sEur. J. 2002,
8, 3211-3228.
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13130 J. AM. CHEM. SOC. VOL. 125, NO. 43, 2003

Recyclable Rhodium-Complexed Dendrimers on Resin
A R T I C L E S
bonyl)rhodium(I) dimer (0.0389 g, 0.1 mmol) in freshly distilled
dichloromethane (20 mL). The mixture was stirred for 3 h at room
temperature under argon. After filtration under a stream of argon, the
product was washed with dichloromethane (5 × 15 mL) and dried in
vacuo.
General Procedure for the Hydroformylation Reaction. A glass
liner containing the substrate (2 mmol), catalyst (25 mg), and
dichloromethane (10 mL) was placed in a 45 mL autoclave equipped
with a magnetic stirring bar. The autoclave was flushed 3 times with
carbon monoxide and pressurized to the desired level. The hydrogen
line was then attached to the autoclave and purged before pressurizing
the autoclave up to the desired level. The autoclave was placed in an
oil bath preset to the desired temperature on a stirring hot plate. After
the appropriate reaction time (see Table 1), the autoclave was removed
from the oil bath and cooled to room temperature prior to the release
of the excess carbon monoxide and hydrogen. The resulting solution
was filtered to remove the catalyst, and the solvent was evaporated in
vacuo. The product aldehydes were analyzed by 1H NMR and gas
chromatography and identified by comparison with literature data. The
recovered catalyst was washed with dichloromethane and reused in
subsequent cycles.
Acknowledgment. We are grateful to the Natural Sciences
and Engineering Research Council of Canada for support of
this research.
Supporting Information Available: Tables 2-8. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.
JA0303384
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