Solid-phase organic synthesis in the presence of compressed carbon dioxide

Article abstract of DOI:10.1002/anie.200801653

Under pressure: The mass-transfer limitation in solid-phase organic synthesis with pressurized gaseous reagents is overcome by using carbon dioxide in the homogeneous supercritical state (right) for hydroformylation or under expandedliquid conditions (lef

Full text of DOI:10.1002/anie.200801653

Communications
DOI: 10.1002/anie.200801653
Solid-Phase Synthesis
Solid-Phase Organic Synthesis in the Presence of Compressed Carbon
Dioxide**
Annika Stobrawe, Piotr Makarczyk, CØline Maillet, Jean-Luc Muller, and Walter Leitner*
Solid-phase organic synthesis (SPOS) has been established as
an important tool for preparative chemistry with a broad
range of applications in modern organic synthesis.[1] In very
few reaction steps,libraries of molecularly diverse com-
pounds can be synthesized by taking advantage of the
efficient removal of excess or unconsumed reagents by
extraction and filtration as simple workup operations. How-
ever,solid-supported reactions are often characterized by
slow reaction kinetics as a result of severe mass-transfer
limitations. In particular,this effect is observed for reactions
that occur under triphasic (g/l/s) conditions with gaseous
reagents under elevated pressure (Figure 1a). In most cases,
standard methods for agitation under elevated pressure can
not be applied owing to the mechanical instability of the solid
supports and/or the typically small scales of parallel syn-
thesis.[2]
Consequently,the use of SPOS has been limited for many
synthetically useful catalytic processes that involve medium
to high pressures of gaseous building blocks,such as hydro-
genation or carbonylation reactions. To overcome this
limitation,Marchetti and co-workers used a special reactor
setup,whereby the solid support was incorporated in a stirrer
device and thus agitated through the solution.[3] Breinbauer
and co-workers addressed the problem at a molecular level by
using soluble polymers as supports to remove one mass-
transfer barrier.[4] The reaction products were separated after
cleavage by dialysis over a period of 12–36 h.
We report herein an alternative approach,whereby the
use of compressed carbon dioxide either as a supercritical
fluid[5] or with expanded liquids (XPLs)[6] leads to an efficient
enhancement in the mass-transfer properties in catalytic
SPOS. The concept is readily applicable to small-scale and
parallel synthesis,as demonstrated for two types of carbonyl-
ation reaction.
Under conventional SPOS conditions (Figure 1a),mass
transfer and the availability of the gaseous reagents are very
low,whereas the catalyst concentration is high in the organic
solvent. In contrast,supercritical conditions (Figure 1c) result
in a maximized gas availability and mass transfer,but at the
same time in a decrease in catalyst concentration because of
the larger volume of the supercritical phase. The situation in
the expanded liquid (Figure 1b) is intermediate,with signifi-
cantly increased gas availability relative to the gas availability
under conventional conditions and a higher catalyst concen-
tration relative to supercritical conditions. The best operating
conditions are difficult to predict and depend on the reaction
system.
As a first benchmark reaction,the hydroformylation of
polymer-supported 1-hexen-5-ol (1) was investigated. Trityl
polystyrene resin was chosen as the support,as it enables the
use of straightforward coupling and cleavage conditions.[1,2]
[Rh(CO)2(acac)] (2),which is known to exhibit high solubility
and activity in hydroformylation reactions in conventional
solvents and in scCO2,[7] was used as an unmodified Rh
catalyst for the carbonylation reaction. To prevent the
formation of aldol condensation products under these con-
ditions,the aldehyde 3 was reduced to the corresponding diol
4 with NaBH4 prior to cleavage.[2a] The product 4 was cleaved
from the resin with trifluoroacetic acid (TFA) in CH2Cl2.
Representative results are summarized in Table 1.
Figure 1. Catalytic carbonylation of solid-supported substrates a)under
conventional conditions, b)in an expanded liquid, and c)in scCO
2
(g=gas phase, l=liquid phase, s=solid phase).
[*] Dr. A. Stobrawe, Dr. P. Makarczyk, Dr. C. Maillet, Dr. J.-L. Muller,
Prof. Dr. W. Leitner
Institut für Technische und Makromolekulare Chemie
RWTH Aachen University
Worringerweg 1, 52074 Aachen (Germany)
Fax: (+49)241-802-2177
E-mail: leitner@itmc.rwth-aachen.de
Prof. Dr. W. Leitner
First,the reaction was carried out using conventional
conditions with toluene as the solvent under synthesis gas
(40 bar) in a high-pressure view cell (10 mL stainless-steel
reactor). No significant conversion occurred without agitation
(Table 1,entry 1). The use of a magnetic stir bar was not
possible,since grinding of the substrate beads resulted,as
Max-Planck-Institut für Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 Mülheim a.d. Ruhr (Germany)
[**] Financial support from the Fonds der Chemischen Industrie and the
Max-Buchner-Foundation (A.S.)is gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200801653.
6674
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Table 1: Solid-supported hydroformylation in toluene and scCO2.[a]
Entry
1
[mg]
2
[mg]
Substrate/Rh
Toluene
[mL]
p(CO/H2)
[bar]
CO2
[g]
ptot
Agitation
Yield of
4 [%]
4a/4b
[bar][b]
1
2
3
4
250
250
250
10
10
9
10:1.5
10:1.5
10:1.4
10:0.4
5
5
40
40
30
40
–
–
8.0
8.5
45
45
200
250
no
yes
no
no
<1
>98
10
–
1.2:1
–
1.2:1
–
1000
10
1[c]
>98
[a] Reaction conditions: Vreactor =10 mL, T=608C, t=24 h. acac=acetylacetonate. [b] Total pressure at the reaction temperature. [c] A single phase
was observed (by visual inspection).
reported previously.[2] The use of a modified shaker to shake
the entire reactor setup resulted in quantitative conversion
after the standard reaction time of 24 h,a result that shows the
importance of mass transfer for the system (Table 1,entry 2).
Initial experiments with the non-agitated reactor and
supercritical CO2 (scCO2) as the only solvent were disap-
pointing,despite the fact that a homogeneous phase contain-
ing the dissolved catalyst was observed as expected (Table 1,
entry 3). It is most likely that the poor swelling properties of
[8]
the resin in scCO2 hinder the accessibility of the substrate
under these conditions. Indeed,the addition of small amounts
of organic cosolvents,such as 1-hexene,CH 2Cl2,or toluene,
resulted in excellent performance of the system and led to
quantitative conversion without the need for mechanical
agitation (Table 1,entry 4). No liquid phase was observed by
visual inspection,and the supercritical phase showed the
typical coloration of the rhodium catalyst.
To demonstrate the applicability of the method to parallel
synthesis,we carried out the hydroformylation of the
supported allylic alcohol 5,1-hexen-5-ol ( 1),and 1-decen-9-
ol (6). The solid-supported substrates were introduced into
the reactor by using a simple glass liner with three compart-
ments (Figure 2). Following the reaction under the standard
reaction conditions,the three materials were subjected
separately to cleavage and workup (Scheme 1). Quantitative
Scheme 1. Parallel SPOS: Hydroformylation in scCO2. Reaction con-
ditions: Vreactor =10 mL, p(CO/H2)=40 bar, T=608C, t=24 h, total
pressure (ptot)=230 bar.
yields and typical n/iso ratios were observed in all cases,
without any indication of cross-contamination between the
materials in the reactor.
The ready access to solid-supported hydroformylation
products makes more-complex diversification processes pos-
sible,as demonstrated for the Hantzsch synthesis of pyridines
from an allylic alcohol starting material. After the hydro-
formylation of 5 in scCO2 under the previously described
conditions,the solid-supported aldehydes 7a,b were sub-
jected directly and without further purification to multi-
component coupling with methyl acetoacetonate (11) and
methyl 3-aminocrotonate (12). Aromatization with ceric
ammonium nitrate and subsequent cleavage of the anchoring
group with TFA gave the two isomeric pyridines 14a,b in
99% yield and a 1.4:1 ratio (Scheme 2). The ratio of 14a to
14b corresponds well with the n/iso ratio of the products 7a,b
of the hydroformylation step. The branched product 13b
underwent cyclization under the workup conditions.
The cobalt-catalyzed Pauson–Khand reaction (PKR) was
investigated as a second benchmark reaction. This [2+2+1]
cycloaddition of alkynes with alkenes and carbon monoxide is
a versatile synthetic approach to cyclopentenones with
various substitution patterns.[9] The use of scCO2 as the
solvent for the PKR under homogeneous conditions with
Figure 2. Experimental setup to show the simple compartmentalization
for parallel hydroformylation reactions in scCO2.
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soluble substrate upon passing into the
supercritical phase,which occupies the
entire reactor volume.
The simple glass liner used for
parallel hydroformylation reactions can
not be used for parallel PKRs,as the
presence of a liquid phase is necessary
for optimum performance. However,
commercially available micro-x-kans[12]
proved efficient for the compartmental-
ization of the substrate beads under
XPL conditions. As a proof of principle,
parallel PKRs were carried out with
solid-supported 16 and 10-undecyn-1-ol
(19). The corresponding cyclopente-
nones 18a and 20 were obtained in
67% yield (Scheme 4).
In summary,we have shown that
compressed carbon dioxide can be used
to overcome the mass-transfer limita-
tion in solid-phase organic synthesis
Scheme 2. Solid-phase catalytic hydroformylation in scCO2 and Hantzsch synthesis.
DMA=dimethylacetamide, DMF=N,N-dimethylformamide, MS=molecular sieves.
[Co2(CO)8] (15) as the catalyst was described by Jeong and
Hwang.[10]
PKRs with solid-supported substrates under conventional
conditions have been reported,but reactions were found to be
sluggish,and stoichiometric amounts of the catalyst were
required.[11] We first studied the PKR of solid-supported 1-
pentyn-5-ol (16) using THF with a catalytic amount of catalyst
15 (0.1 equiv) and norbornene (17a; 10 equiv) under CO
(20 bar) at 1208C (Scheme 3). After 17 h,cleavage by TFA in
CH2Cl2 gave the polycyclic product 18a in 80% yield,even
without agitation during the reaction.
Figure 3. PKRs on a solid support. Reaction conditions: 15 (0.1 equiv),
17a (10 equiv), p(CO)=20 bar, T=1208C, t=17 h.
with pressurized gaseous reagents. Depending on the relative
importance of mass-transfer resistance and catalyst/substrate
concentration,the optimum conditions may be found in the
homogeneous supercritical state (Figure 1c,hydroformyla-
tion) or under conditions of expanded liquids (Figure 1b,
Pauson–Khand reaction). The reactions can be carried out in
Scheme 3. Pauson–Khand reaction on a solid support. Reaction con-
ditions: 15 (0.1 equiv), 17a/b (10 equiv), p(CO)=20 bar, T=1208C.
[a] ptot =120 bar.
The application of compressed carbon dioxide led to a
significant increase in yield to quantitative formation of 18a
(Scheme 3). A similar increase in yield was observed when
norbornadiene (17b) was used as the substrate. The highest
yields were observed under the conditions of an expanded
liquid (XPL) rather than under homogeneous supercritical
conditions (Figure 3). This behavior can be rationalized by
considering the effects illustrated in Figure 1. Initially,the
application of compressed CO2 enhances the mass-transfer
properties and leads to an increase in reaction rate in the
XPL. This positive effect is offset,however,by the sharp
decrease in the concentration of both the catalyst and the
Scheme 4. Parallel PKRs of the solid-supported alkynols 16 and 19
with 17a under XPL conditions.
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Chemie
standard high-pressure vessels,which are also required for
these reactions with pressurized gaseous reagents under
conventional conditions. As the use of compressed CO2
removes the need for mechanical agitation,simple and
commercially available receptacles can be utilized for the
compartmentalization of substrate-loaded beads. As a result,
parallelization is straightforward. Thus,the use of compressed
CO2 should lead to a significant expansion in the range of
catalytic reactions that can be applied to generate molecular
diversity through SPOS methodologies.
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Experimental Section
Safety warning: Experiments with compressed gases must be carried
out only with appropriate equipment and under rigorous safety
precautions.
Parallel hydroformylation in scCO2: Catalyst
2 (10 mg,
0.03 mmol) and toluene (1 mL) were placed in a high-pressure view
cell (V= 10 mL,see Figure 2) under an inert atmosphere. The solid-
supported olefins 1, 5,and 6 (250 mg each,1 mmolg À1 loading) were
placed inside the cell in a glass liner with three compartments. The cell
was pressurized with synthesis gas (40 bar) and CO2 (8.0 g) and
heated to 608C for 24 h (ptot = 230 bar). Reduction and cleavage were
carried out as described in the Supporting Information.[2]
[7] a) D. Koch,W. Leitner, J. Am. Chem. Soc. 1998, 120,13398 –
13404; b) S. Kainz,W. Leitner, Catal. Lett. 1998, 55,223 – 225.
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Serrano,G. Dominguez,J. Pꢀrez-Castells, Chem. Soc. Rev. 2004,
33,32 – 42.
Parallel Pauson–Khand reactions in an XPL: A high-pressure
view cell was loaded with 17a (230 mg,2.49 mmol), 15 (9.0 mg,
0.02 mmol),and THF (4 mL) under inert conditions. Two micro-x-
kans,one filled with 16 and the other with 19 (42 mg each,loading:
0.7 mmolgÀ1),were placed in the reactor. The reactor was pressurized
with CO (17 bar) and CO2 (2.4 g),and the mixture was heated at
1208C for 72 h. Workup and cleavage were carried out as described in
the Supporting Information.
[10] N. Jeong,S. H. Hwang, Angew. Chem. 2000, 112,650 – 652;
Angew. Chem. Int. Ed. 2000, 39,636 – 638.
Received: April 8,2008
[11] a) G. L. Bolton,J. C. Hodges,J. R. Rubin, Tetrahedron 1997, 53,
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Published online: July 21,2008
Keywords: carbon dioxide · hydroformylation · Pauson–
.
[12] www.nexusbio.com.
Khand reaction · solid-phase synthesis · supercritical fluids
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