Investigation of the origin and synthetic application of the pseudodilution effect for Pd-catalyzed macrocyclisations in concentrated solutions with immobilized catalysts

Article abstract of DOI:10.1039/c3ob41020j

Immobilized Pd-complexes allowed macrocyclisations via the Tsuji-Trost-reaction in concentrated solutions. Systematic studies suggest that the origin of this pseudodilution effect is neither film diffusion nor gel diffusion, but the reduction in conformational freedom of intermediates and intramolecular prenucleophile activation. In contrast a pseudodilution effect could not be observed for Sonogashira- and Suzuki-macrocyclisations.

Full text of DOI:10.1039/c3ob41020j

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
COMMUNICATION
Investigation of the origin and synthetic application of
the pseudodilution effect for Pd-catalyzed
macrocyclisations in concentrated solutions with
immobilized catalysts†
Cite this: Org. Biomol. Chem., 2013, 11, 4750
Received 16th May 2013,
Accepted 18th June 2013
DOI: 10.1039/c3ob41020j
www.rsc.org/obc
Elisabeth Brehma,b and Rolf Breinbauer*a,b,c
Immobilized Pd-complexes allowed macrocyclisations via the loadings, which favors intramolecular reactions through site
Tsuji–Trost-reaction in concentrated solutions. Systematic studies isolation.8 We report now a systematic investigation to study
suggest that the origin of this pseudodilution effect is neither film several parameters which might be involved in the performance
diffusion nor gel diffusion, but the reduction in conformational of immobilized catalysts. In particular we were interested in the
freedom of intermediates and intramolecular prenucleophile acti- following questions: (1) How general is this effect? Can it be
vation. In contrast a pseudodilution effect could not be observed extended to other metal-catalyzed reactions? (2) Is the substrate
for Sonogashira- and Suzuki-macrocyclisations.
transport to and across the catalyst-bead an influencing factor?9
(3) Do other resin properties (loading, flexibility, hydrophilicity/
hydrophobicity) of the polymer support play a role?10
The conformational restriction caused by the macrocyclic
nature of many natural products and several drug molecules is
believed to be of superior importance for their biological
activity.1 The synthesis of such macrocyclic structures is a
challenging task as any cyclisation reaction of a difunctional
substrate has to compete with concurring intermolecular oligo-
merization reactions.2 According to the high dilution principle
of Ziegler and Ruggli, concentrations of 10−3 M or less are
applied to favor intramolecular reactions.3 In 1982 Trost and
Warner reported a stunning observation: with a polymer-
bound metal complex macrocyclisations via Pd-catalyzed
allylation of vinylepoxides succeeded in good yields at
0.1–0.5 M concentrations, while using a homogeneous variant
of the catalyst at the same concentrations delivered only oligo-
merization products.4 Besides another report of Tsuji–Trost
allylation,5 the only other examples of a similar effect have
been documented for macrocyclisations via Stille-coupling6
and Cu-catalyzed Huisgen-cycloaddition.7 The dramatic
improvements in macrocyclisation products using an immobi-
lized catalyst have been interpreted as originating from a
pseudodilution effect. This effect is well documented in solid
phase synthesis for immobilized substrates at low substrate
One prerequisite for our studies was a reliable access for
well characterized polymer bound phosphine ligands. A limit-
ation of previous studies which have relied on polystyrene (PS)
phosphine is that this ligand is not only difficult to prepare
but due to its monodentacity it might lead to several different
catalytically active species. We identified the bis(phosphino-
methyl)amine moiety11 as a convenient and suitable ligand
unit for our purposes, as it can be easily made from readily
accessible H2N-functionalized resins in quantitative yield.12
The bidentate ligand should warrant more defined Pd-coordi-
nation, which through the chelating effect should also dimin-
ish leaching. We synthesized a series of polymer-supported
bis(phosphinomethyl)amine ligands 1a–1g, in which we
varied loading, cross linking, bead size and hydrophilicity of
the support (Scheme 1, Table 1). All polymer ligands were
characterized by 31P-NMR showing only a single signal for the
P(III)-species. The ligands were converted to the Pd-complexes
1a–g/Pd by stirring the resin with Pd[PPh3]4 followed by exten-
sive washing.
For a first series of experiments in the Tsuji–Trost-macro-
cyclisation we needed a suitable substrate which can be
aMax-Planck-Institute of Molecular Physiology, Otto-Hahn-Str. 11, D-44227
Dortmund, Germany
bFachbereich Chemie, Technische Universität Dortmund, Otto-Hahn-Str. 6, D-44227
Dortmund, Germany
cInstitute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9,
A-8010 Graz, Austria. E-mail: breinbauer@tugraz.at; Fax: +43 316 873 32402;
Tel: +43 316 873 32400
Scheme 1 Synthesis of immobilized phosphine ligands 1a–g and the conver-
sion to the corresponding Pd-complexes. (i) (1) Ph2PH, HCHO, MeOH, 60 °C, (2)
resin, toluene, 105 °C, 2d; (ii) Pd[PPh3]4.
†Electronic supplementary information (ESI)
available. See DOI:
10.1039/c3ob41020j
4750 | Org. Biomol. Chem., 2013, 11, 4750–4756
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Communication
Table 1 Properties of immobilized phosphine ligands 1a–1g
Entry
1
Typea
Size [mesh] DVB [%] Loadingb [mmol g−1
]
1
2
3
4
5
6
7
a
b
c
d
e
f
PS
PS
PS
PS
PS
200–400
100–200
70–90
70–100
∼120
1
1
1
1
1
1
0.77
0.59
0.79
0.72
0.29
0.68
0.90
Tentagel ∼20
PS
g
∼100
High
a For more details about the resins see ESI. b Loading with respect to
NH2-groups.
synthesized in a convergent manner and would give ready
access to differently sized analogs. Similar to the methodology
reported before, substrate 8 was prepared from vinylepoxide 5,
which resulted from a reaction of sulfur ylide 4 with aldehyde
3.13 After silyl deprotection, alcohol intermediate 5 was esteri-
fied with carboxylic acid 7 to furnish cyclisation substrate 8 in
21% overall yield for the 6 step synthesis in the longest linear
sequence. Adapting the conditions of Fürstner and Weintritt
established for their total synthesis of roseophilin,5 we
achieved the Tsuji–Trost-macrocyclisation (10% Pd[PPh3]4,
20% dppe, THF, reflux, 0.0015 M) of 8 to form 17-membered
lactone 9 in 64% yield (Scheme 2).
In order to evaluate the performance of polymer-supported
catalysts for the same macrocyclisation of 8, we used catalyst
1a/Pd as a standard, as it featured the most popular resin pro-
Scheme 2 Synthesis of cyclisation substrate 8. (i) NaH, TBDMSCl, 67%; (ii)
(COCl)2, DMSO, Et3N, DCM, −78 °C to rt, 88%; (iii) MeOH–H2O (9/1); (iv) 3,
DCM–10 M NaOH (1/1), −20 °C to rt, 1 h, 80%; (v) NH4F, MeOH, reflux, 8 h,
perties (PS, 1% DVB, 200–400 mesh) used in solid phase 65%; (vi) MeOH, H2SO4, 89%; (vii) (PhSO2)2CH2, NaH, DMF, 81%; (viii) LiOH,
THF–MeOH–H2O (3/3/1), quant.; (ix) EDC, DMAP, DCM, RT, 12 h, 68%; (x) 10%
organic synthesis. Using 10% 1a/Pd under reflux conditions in
THF, we varied the substrate concentration from 0.002 to
Pd[PPh3]4, 20% dppe, syringe pump, 0.0015 M, THF, reflux, 64%.
0.2 M (Fig. 1). To our delight, we could observe that immobi-
lized catalyst 1a/Pd produced macrocycle 9 even at the high
concentration of 0.2 M in good yields (45%), confirming the
previously reported effect of catalyst immobilization in Tsuji–
Trost-cyclizations. The best yields were observed at 0.04 M
(63%) (Fig. 1).
We used the concentration of 0.04 M for the next experi-
ment in which we varied the reaction temperature. While at RT
the yield decreased to 59% yield, at 50 °C it improved to 67%.
As these experiments had confirmed that the immobilization
effect was also valid for our substrate, we were considering the
hypothesis that diffusion through the laminar layer surround-
ing the bead (film diffusion) resp. diffusion inside the bead
(pore/gel diffusion) might be rate limiting. In such a scenario
a locally lower substrate concentration inside the bead would
be created, potentially equivalent to high dilution concen-
trations.9,14 In order to validate this hypothesis, we performed
two sets of experiments. To test for potential film diffusion at
first, we varied the stirring rate of the magnetic stirrer, which
Fig. 1 Influence of the substrate concentration on the product yield for the
should influence the thickness of the laminar film layer
around the beads. No influence of film diffusion could be
macrocyclisation of substrate 8 with immobilized catalyst 1a/Pd.
detected, as the yields for a reaction at 0.022 M remained
produced from polymer-supported phosphine resins 1a–g
featuring different bead sizes and degrees of cross linking
(Table 2).
almost indistinguishable at the highest stirring rate (52%)
from the one where no stirring was applied (51%) and values
in between. Secondly, we screened our set of Pd-catalysts
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 4750–4756 | 4751

View Article Online
Communication
Organic & Biomolecular Chemistry
factors: (a) a pseudodilution effect, which results from the
intermittent immobilization of the substrate as a Pd–allyl
complex within a polymeric bead, thereby restricting the con-
formational reach of its reactive ends, and (b) the special case
of the internal base activation mechanism via intramolecular
deprotonation of the prenucleophile by the alkoxide resulting
from vinylepoxide opening by the Pd-catalyst, which positions
the nucleophile in close proximity to the electrophilic Pd–allyl
complex (Fig. 3).4
Table 2 Macrocyclisation yields for substrate 8 with immobilized Pd-catalysts
1a–g/Pd
We next set out to explore if the catalyst-immobilization
effect can be extended to other Pd-catalyzed transformations.
In particular, we were interested in the Sonogashira- and
Suzuki-macrocyclisations. Despite its frequent application in
synthesis these macrocyclisation reactions have not been per-
formed with immobilized Pd catalysts yet. For the Sonoga-
shira-macrocyclisation16 a set of eleven different substrates
was synthesized, which would result in 14- to 25-membered
rings. The synthetic strategy is based on the modular assembly
of terminal alkyne building blocks with various iodoarenes. As
Entry
Catalyst
Size [mesh]
9 Yield [%]
1
2
3
4
6
7
8
1a/Pd
1b/Pd
1c/Pd
1d/Pd
1e/Pd
1f/Pd
1g/Pd
200–400
100–200
70–90
70–100
∼120
∼20
∼100
67
67
59
62
70
51
44
When comparing the similarly structured catalysts 1a/Pd, an example the synthesis of 19 is described in Scheme 3 (for
1b/Pd, 1c/Pd, 1d/Pd, which differ primarily in their bead size,
consistently good yields (59–67%) could be observed. Catalyst
all other substrates see ESI†) (Table 3, Fig. 2).
12-Hydroxy undecanoic acid (16) was silyl-protected allow-
1e/Pd, which is in bead size similar to catalyst 1b/Pd but has ing the esterification with 5-hexyn-1-ol to produce ester 18.
only half its loading, performs equally well (70%). As the larger
beads (1c and 1d) exhibited similar or slightly diminished
Fluoride-mediated deprotection of the TBDMS-group quanti-
tatively furnished the free alcohol which underwent carbodi-
yields, the hypothesis that pore/gel diffusion might have any imide-mediated esterification with 2-iodo benzoic acid to
(or even a positive) effect on macrocycle yields is not sup-
produce macrocyclisation substrate 19 in 34% yield for the
ported. For comparison, the homogeneous catalyst Pd[PPh3P]4
entire four step synthetic sequence. The homogeneous catalyst
gave under otherwise identical conditions only 29% yield of 9. Pd[PPh3]4 and the standard polymer supported catalyst 1a/Pd
A resin which significantly performed differently, in this case
worse than others, was catalyst 1g made from a highly cross-
linked resin, which does not swell in solvents. Interestingly,
Tentagel-derived catalyst 1f which is most distinct from all
other resins in terms of bead size, ligand flexibility, loading
and hydrophilicity performed quite well with test substrate 8.
From these two series of experiments we conclude that we
have no evidence that limitation of substrate transport to and
across the beads has an influence on macrocyclisation yields
for the Pd-catalyzed Tsuji–Trost-macrocyclisation of our test
substrate. To explore other substrates we limited our investi-
gations to three catalysts: our standard catalyst 1a/Pd, its close
analog 1b/Pd, and Tentagel-derived catalyst 1f/Pd, and com-
pared them with the homogeneous catalyst Pd[PPh3]4.
were compared at 0.04 M substrate concentration for the
When comparing catalyst performance, it can be seen that
1a/Pd and 1b/Pd gave consistently good yields also for other
substrates, whereas the Tentagel-based catalyst 1f/Pd gave
results similar to the homogeneous catalyst with the previously
investigated standard substrate 8 as an exception. The almost
congruent behaviour between homogeneous and Tentagel-
immobilized catalysts matches well the perception that Tenta-
gel-resin through its long and flexible spacer units emulates
solution-phase behaviour, which has been used advanta-
geously for several applications.15 Together these data led us
to conclude that the observed effect, that catalyst immobiliz-
ation on cross-linked polystyrene resins leads to improved
Scheme 3 Synthesis of Sonogashira-cyclisation substrate 19. (i) TBMSCl, imid-
azole, 50%; (ii) EDC, DMAP, 83%; (iii) NH4F, quant.; (iv) 2-iodobenzoic acid, EDC,
DMAP, 83%; (v) 20% Pd[PPh3]4, 20% CuI, 0.04 M, 1,4-dioxane–piperidine (2/1),
yields for Tsuji–Trost-cyclisations, can be explained by two 60 °C, 15 h, 22%.
4752 | Org. Biomol. Chem., 2013, 11, 4750–4756
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Communication
Table 3 Tsuji–Trost-macrocyclisation yields with immobilized Pd-catalysts 1a,b,
f/Pd
Entry Catalyst
17-Ring 9 19-Ring 13 21-Ring 11 22-Ring 15
1
2
3
4
1a/Pd
1b/Pd
1g/Pd
67%
67%
51%
33%a
48%
28%
31%
46%
47%
35%
34%
53%
26%
19%
29%
Pd[PPh3]4 29%
Conditions: 10% 1/Pd, 50 °C, 0.04 M, THF, 15 h.a At 80% conversion.
Fig. 4 Sonogashira-macrocyclisation products. The bond formed in the cyclisa-
tion step is indicated in bold.
Table 4 Comparison between homogeneous catalyst and immobilized catalyst
for the Sonogashira-macrocyclisation
Entry Product Ring size Yield with Pd[PPh3]4 Yield with 1a/Pd
1
2
3
4
5
6
7
8
20
21
22
23
24
25
26
27
28
29
30
23
25
17
22
19
24
19
24
14
19
21
22%
—
40%
29%
0%
9%
6%
40%
0%
35%
14%
22%
25%
50%
27%
0%
13%
12%
38%
0%
Fig. 2 Tsuji–Trost-macrocyclisation products. The bond formed in the cyclisa-
tion step is indicated in bold.
9
10
11
33%
14%
Conditions: 20% catalyst, 20% CuI, 0.04 M, 1,4-dioxane/piperidine
(2/1), 60 °C, 15 h.
we cannot observe a catalyst immobilization effect for the
Sonogashira-macrocyclisation of the investigated substrates.
Apparently, the pseudodilution effect stemming from the tran-
sient immobilization of a reaction intermediate as it would
occur during oxidative addition of the substrate is not
sufficient to produce an improved cyclisation yield for the
Sonogashira reaction.
The Suzuki-reaction has achieved considerable attention for
macrocyclisations.17 However, to the best of our knowledge no
efforts have been made to explore the use of immobilized cata-
lysts in the context of this transformation. For substrate syn-
thesis we had to adapt our modular synthetic strategy, as a
direct transformation of our alkyne substrates for Sonogashira-
macrocyclisations via hydroboration failed because of sub-
strate decomposition. Our preferred synthetic route is illus-
trated for substrate 34 in Scheme 4 (for all other Suzuki
substrates, see ESI†).
Alkynol 31 was converted via hydroboration by catechol-
borane followed by in situ hydrolysis and transesterification to
vinyl pinacol boron ester 32. This intermediate underwent
carbodiimide-mediated esterification with carboxylic acid 33
to furnish cyclisation substrate 34 in 33% yield for the five-step
reaction sequence. All in all, we had six substrates in hand
which upon Suzuki-reaction would form 17- to 24-membered
rings (Fig. 5, Table 5).
Fig. 3 Mechanistic proposal for intramolecular cyclization at the active site
within a catalyst bead.
transformation of 19 to cyclisation product 20. Both catalysts
produced the 23-membered ring in 22% yield. In order to gain
a more representative view of the Sonogashira-macrocyclisa-
tion, more substrates were investigated to produce the macro-
cycles depicted in Fig. 4 (Table 4).
The experimental results allow two important conclusions:
(1) due to the conformational constraints imposed by the large
number of sp2- and sp-hybridized carbon atoms in our sub-
strates the yield depends strongly on the particular substrate
ranging from 0% for highly constrained rings 24 and 28
(entries 5 and 9) up to 50% (entry 3) for product 22, which is
less constrained. (2) The yields from the reactions with the
immobilized catalyst and the homogeneous reaction are very
similar with only slight variations. We interpret these data that
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 4750–4756 | 4753

View Article Online
Communication
Organic & Biomolecular Chemistry
formed compounds. Importantly, we also observed again a
largely coherent efficiency between heterogeneous and homo-
geneous catalysts, showing better yields with the homo-
geneous catalyst for substrates 35 (entry 1) and 38 (entry 4),
which led us to conclude that no substrate immobilization
effect can be observed for the Suzuki-macrocyclisation of our
tested substrates.
In conclusion, we have achieved the macrocyclisation of
suitable substrates via Tsuji–Trost-macrocyclisation, and for
the first time the Sonogashira-macrocyclisation and Suzuki-
macrocyclisation using polymer-bound Pd-complexes.18 Our
study has revealed that the catalyst-immobilization effect is
not of general applicability to Pd-catalyzed macrocyclisations.
For a set of eleven Sonogashira- and six Suzuki-macrocyclisa-
tion substrates we could not observe any evidence for such an
effect. However, we could consistently see such an effect for
Pd-catalyzed Tsuji–Trost-allylation of vinylepoxides. In contrast
to previous intermolecular alkylation reactions catalyzed by
solid-supported phase transfer catalysts,9 we could show that
for the intramolecular Tsuji–Trost-allylation, substrate trans-
port to and across the resin beads does not play a major role.
Instead we believe that the combination of restricted freedom
of the intermittently immobilized substrate and the idiosyn-
cratic intramolecular activation mechanism through the for-
mation of an alcoholate base and subsequent deprotonation of
the prenucleophile plays an important role in this reaction.
The flexibility of Tentagel resins does obscure the immobili-
zation effect. It remains to be seen that other macrocyclisation
reactions can be designed in which the effect of catalyst immo-
bilization will allow macrocyclisations even in concentrated
solutions,19 as has now been well exemplified for the intra-
molecular Tsuji–Trost-allylation with vinylepoxide substrates.
Scheme 4 Synthesis of Suzuki-macrocyclisation substrate 34. (i) TBDMSCl,
Et3N, DMAP, DCM, overnight, quant.; (ii) catecholborane, 75 °C, 6 h; (iii) H2O,
1 h, then CH2O, 1 h, then pinacol, overnight; (iv) NH4F, MeOH, 6 h, 49%
(3 steps); (v) DIC, DMAP, DCM, overnight, 68%; (vi) 10% Pd[PPh3]4, 0.04 M
DME–H2O–DMF (7/3/2), 2 eq. Cs2CO3, 80 °C, 15 h, 60%.
Notes and references
Fig. 5 Suzuki-macrocyclisation products. The bond formed in the cyclisation
step is indicated in bold.
1 Leading reviews: (a) E. M. Driggers, S. P. Hale, J. Lee and
N. K. Terrett, Nat. Rev. Drug Discovery, 2008, 7, 608–624;
(b) C. M. Madsen and M. H. Clausen, Eur. J. Org. Chem.,
2011, 3107–3115; (c) A. Isidro-Llobet, T. Murillo, P. Bello,
A. Cilibrizzi, J. T. Hodgkinson, W. R. J. D. Galloway,
A. Bender, M. Welch and D. R. Spring, Proc. Natl. Acad.
Sci. U. S. A., 2011, 108, 6793–6798; (d) C. J. White and
A. K. Yudin, Nat. Chem., 2011, 3, 509–524; and leading orig-
inal works: (e) Y.-k. Kim, M. A. Arai, T. Arai, J. O. Lamenzo,
E. F. Dean III, N. Patterson, P. A. Clemons and
S. L. Schreiber, J. Am. Chem. Soc., 2004, 126, 14740–14745;
(f) M. T. Burger and P. A. Bartlett, J. Am. Chem. Soc., 1997,
119, 12697–12698.
Table 5 Comparison between homogeneous catalyst and immobilized catalyst
for the Suzuki-macrocyclisation
Entry Product Ring size Yield with Pd[PPh3]4 Yield with 1a/Pd
1
2
3
4
5
6
35
36
37
38
39
40
17
22
19
24
19
26
60%
57%
0%
61%
22%
0%
41%
58%
0%
47%
30%
0%
Conditions: 10% Pd[PPh3]4, 0.04 M DME–H2O–DMF (7/3/2), 2 eq.
Cs2CO3, 80 °C, 15 h.
2 Reviews: (a) B. Dietrich, P. Viout and J.-M. Lehn, Macro-
cyclic Chemistry, VCH, Weinheim, 1992; (b) Q. Meng and
M. Hesse, Top. Curr. Chem., 1991, 161, 107–176; (c) C. J.
Roxburgh, Tetrahedron, 1995, 51, 9767–9822.
When performing the cyclisations with immobilized cata-
lyst 1a/Pd and homogeneous catalyst Pd[PPh3]4 at 0.04 M sub-
strate concentration, we again saw
dependence originating from the conformational strain of the
a
great substrate
3 Reviews: (a) P. Knops, N. Sendhoff, H.-B. Mekelburger and
F. Vögtle, Top. Curr. Chem., 1991, 161, 1–36; (b) K. Ziegler,
4754 | Org. Biomol. Chem., 2013, 11, 4750–4756
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Communication
Methoden der Organischen Chemie (Houben-Weyl), 4th edn,
1955, Vol. 4/II, pp. 729–822.
4 (a) B. M. Trost and R. W. Warner, J. Am. Chem. Soc., 1982,
104, 6112–6114; (b) B. M. Trost and R. W. Warner, J. Am.
Chem. Soc., 1983, 105, 5940–5942; (c) B. M. Trost, Angew.
Chem., Int. Ed., 1999, 28, 2817–2825.
H. Knözinger and J. Weitkamp, VCH, Weinheim, 1997,
pp. 1209–1252; (b) M. Baerns, H. Hofmann and A. Renken,
Chemische Reaktionstechnik, 2, Aufl. Thieme, Stuttgart,
1992; (c) F. Kapteijn and J. A. Moulijn, in Handbook of
Heterogeneous Catalysis, ed. G. Ertl, H. Knözinger and
J. Weitkamp, VCH, Weinheim, 1997, 1359–1376;
(d) R. J. Madon and M. Boudart, Ind. Eng. Chem. Fundam.,
1982, 21, 438–447.
5 A. Fürstner and H. Weintritt, J. Am. Chem. Soc., 1998, 120,
2817–2825.
6 J. K. Stille, H. Su, D. H. Hill, P. Schneider, M. Tanaka, 15 See for example: (a) K. Kuramochi, T. Haruyama,
D. L. Morrison and L. S. Hegedus, Organometallics, 1991,
10, 1993–2000.
7 A. R. Kelly, J. Wei, S. Kesavan, J.-C. Marie, N. Windmon,
D. W. Young and L. A. Marcaurelle, Org. Lett., 2009, 11,
2257–2260.
R. Takeuchi, T. Sunoki, M. Watanabe, M. Oshige,
S. Kobayashi, K. Sakaguchi and F. Sugawara, Bioconjugate
Chem., 2005, 16, 97–104; (b) B. Lehr, H.-J. Egelhaaf,
H. Fritz, W. Rapp, E. Bayer and D. Oelkrug, Macromolecules,
1996, 29, 7931–7936; (c) P. Wright, D. Lloyd, W. Rapp and
A. Andrus, Tetrahedron Lett., 1993, 34, 3373–3376.
8 (a) M. Fridkin, A. Patchornik and E. Katchalski, J. Am.
Chem. Soc., 1965, 87, 4646–4648; (b) S. Mazur and 16 For selected examples of Sonogashira-macrocyclisations,
P. Jayalekshmy, J. Am. Chem. Soc., 1979, 101, 677–683;
(c) J. Rebek Jr. and J. E. Trend, J. Am. Chem. Soc., 1979, 101,
737; (d) H. Franzyk, M. K. Christensen, R. M. Jorgensen,
M. Meldal, H. Cordes, S. Mouritsen and K. Bock, Bioorg.
Med. Chem., 1997, 5, 21–40; (e) C. Herb and M. E. Maier,
J. Org. Chem., 2003, 68, 8129–8135; (f) E. Gonthier and
R. Breinbauer, Mol. Diversity, 2005, 9, 51–62.
9 The influence of transport processes on intermolecular
reactions on beads has been demonstrated before, see:
(a) S. L. Regen and J. J. Besse, J. Am. Chem. Soc., 1979, 101,
4059–4063; (b) M. Tomoi and W. T. Ford, J. Am. Chem. Soc.,
1980, 102, 7140–7141; (c) M. Tomoi and W. T. Ford, J. Am.
Chem. Soc., 1981, 103, 3821–3828; (d) M. Tomoi and
W. T. Ford, J. Am. Chem. Soc., 1981, 103, 3828–3837;
see: (a) M. Schmittel and H. Ammon, Synlett, 1999, 750–
752; (b) A. C. Spivey, J. McKendrick, R. Srikaran and
B. A. Helm, J. Org. Chem., 2003, 68, 1843–1851;
(c) T. Harada, S.-I. Matsui, T. M. T. Tuyet, M. Hatsuda,
S. Ueda, A. Oku and M. Shiro, Tetrahedron: Asymmetry,
2003, 14, 3879–3884; (d) S. Odermatt, J. L. Alonso-Gomez,
P. Seiler, M. M. Cid and F. Diederich, Angew. Chem., Int.
Ed., 2005, 44, 5074–5078; (e) J. Krauss, D. Unterreitmeier,
C. Neudert and F. Bracher, Arch. Pharm., 2005, 338, 605–
608; (f) V. Balraju, D. S. Reddy, M. Periasamy and J. Iqbal,
J. Org. Chem., 2005, 70, 9626–9628; (g) J. Sakamoto and
D. A. Schlüter, Eur. J. Org. Chem., 2007, 2700–2712;
(h) G. Chen, L. Wang, D. W. Thompson and Y. Zhao, Org.
Lett., 2008, 10, 657–660.
(e) B. Kim, P. Kirszensztejn and S. L. Regen, J. Am. Chem. 17 For selected examples of Suzuki-macrocyclisations, see:
Soc., 1983, 105, 1567–1571.
(a) R. Ostaszewski, W. Verboom and D. N. Reinhoudt,
Synlett, 1992, 354–356; (b) W. Li and K. Burgess, Tetrahe-
dron Lett., 1999, 40, 6527–6530; (c) N. C. Kallan and
R. L. Halcomb, Org. Lett., 2000, 2, 2687–2690;
(d) V. Lobregat, G. Alcaraz, H. Bienayme and M. Vaultier,
Chem. Commun., 2001, 817–818; (e) J. D. White,
R. Hanselmann, R. W. Jackson, W. J. Porter, J. Ohba,
T. W. Tille and S. Wang, J. Org. Chem., 2001, 66, 5217–5231;
(f) M. Bauer and M. E. Maier, Org. Lett., 2002, 4, 2205–
2208; (g) J. T. Njardarson, K. Biswas and S. J. Danishefsky,
Chem. Commun., 2002, 2759–2761; (h) P. J. Mohr and
R. L. Halcomb, J. Am. Chem. Soc., 2003, 125, 1712–1713;
(i) G. A. Molander and F. Dehmel, J. Am. Chem. Soc., 2004,
126, 10313–10318; ( j) T. Esumi, M. Wada, E. Mizushima,
N. Sato, M. Kodama, Y. Asakawa and Y. Fukuyama, Tetrahe-
dron Lett., 2004, 45, 6941–6945; (k) B. Wu, Q. Liu and
G. A. Sulikowski, Angew. Chem., Int. Ed., 2004, 43, 6673–
6675; (l) D. Deng, B. Wang, A. J. Augatis and N. I. Totah,
Tetrahedron Lett., 2007, 48, 4605–4607; (m) J. M. W. Chan
and T. M. Swager, Tetrahedron Lett., 2008, 49, 4912–4914;
(n) M. Tortosa, N. A. Yakelis and W. R. Roush, J. Org.
Chem., 2008, 73, 9657–9667; (o) A. B. Smith, M. A. Foley,
S. Dong and A. Orbin, J. Org. Chem., 2009, 74, 5987–6001;
(p) Z. Wang, M. Bois-Choussy, Y. Jia and J. Zhu, Angew.
Chem., Int. Ed., 2010, 49, 2018–2022; (q) J. Dufour,
10 For studies on diffusion and reactivity phenomena on poly-
meric beads, see: (a) W. Li, X. Xiao and A. W. Czarnik,
J. Comb. Chem., 1999, 1, 127–129; (b) A. R. Vaino and
K. D. Janda, J. Comb. Chem., 2000, 2, 579–596;
(c) J. Rademann, M. Barth, R. Brock, H.-J. Egelhaaf and
G. Jung, Chem.–Eur. J., 2001, 7, 3884–3889; (d) T. Groth,
M. Grotli and M. Meldal, J. Comb. Chem., 2001, 3, 461–468;
(e) J. Kress, R. Zanaletti, A. Rose, J. G. Frey,
W. S. Brocklesby and M. Bradley, J. Comb. Chem., 2003, 5,
28–32.
11 (a) A. M. LaPointe, J. Comb. Chem., 1999, 1, 101–104;
(b) M. T. Reetz, G. Lohmer and R. Schwickardi, Angew.
Chem., Int. Ed. Engl., 1997, 36, 1526–1529; (c) M. T. Reetz
and S. R. Waldvogel, Angew. Chem., Int. Ed. Engl., 1997, 36,
865–867.
12 (a) Y. Uozumi and Y. Nakami, Org. Lett., 2002, 4, 2997–
3000; (b) E. Gonthier and R. Breinbauer, Synthesis, 2003,
1049–1051; (c) M. Westhus, E. Gonthier, D. Brohm and
R. Breinbauer, Tetrahedron Lett., 2004, 45, 3141–3142.
13 M. Rosenberger, C. Newkom and E. R. Aig, J. Am. Chem.
Soc., 1983, 105, 3656–3661.
14 For authoritative reviews about diffusion phenomena in
heterogeneous catalysis, see: (a) G. Emig and R. Dittmeyer,
in Handbook of Heterogeneous Catalysis, ed, G. Ertl,
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 4750–4756 | 4755

View Article Online
Communication
Organic & Biomolecular Chemistry
L. Neuville and J. Zhu, Chem.–Eur. J., 2010, 16, 10523–
10534; (r) W. Huang, M. Wang, C. Du, Y. Chen, R. Qin,
L. Su, C. Zhang, Z. Liu, C. Li and Z. Bo, Chem.–Eur. J., 2011,
17, 440–444; (s) A. Afonso, L. Feliu and M. Planas, Tetra-
hedron, 2011, 67, 2238–2245; (t) M. Dieckmann,
M. Kretschmer, P. Li, S. Rudolph, D. Herkommer and
D. Menche, Angew. Chem., Int. Ed., 2012, 51, 5667–5670;
Chem., 2002, 9, 2147; (b) N. End and K. U. Schöning, Top.
Curr. Chem., 2004, 242, 241; (c) Y. Uozumi, Top. Curr.
Chem., 2004, 242, 77–112; (d) M. Guino and K. K. Hii,
Chem. Soc. Rev., 2007, 36, 608–617; (e) L. Yin and
J. Liebscher, Chem. Rev., 2007, 107, 133–173; (f) A. Molnar,
Chem. Rev., 2011, 111, 2251–2320; (g) A. C. Albeniz and
N. Carrera, Eur. J. Inorg. Chem., 2011, 2347–2360.
(u) F.-M. Meyer, J. C. Collins, B. Borin, J. Bradow, S. Liras, 19 Recently, the ring closing metathesis with Ru-complexes
C. Limberakis, A. M. Mathiowetz, L. Philippe, D. Price,
K. Song and K. James, J. Org. Chem., 2012, 77, 3099–3114.
18 Reviews about the synthesis and application of polymer-
bound Pd complexes: (a) N. E. Leadbeater, Curr. Med.
immobilized in silica nanopores has been reported to
occur with improved yields for macrocyclisation products:
J. E. Jee, J. L. Cheong, J. Lim, C. Chen, S. H. Hong and
S. S. Lee, J. Org. Chem., 2013, 78, 3048–3056.
4756 | Org. Biomol. Chem., 2013, 11, 4750–4756
This journal is © The Royal Society of Chemistry 2013