Electrolysis as an efficient key step in the homogeneous polymer-supported synthesis of N-substituted pyrroles

Article abstract of DOI:10.1021/ol052096d

An efficient and general route to the soluble polymer-assisted synthesis of a set of 14 different N-substituted pyrroles using dendritic polyglycerol as a high-loading support is presented. The transformation of furan to the key intermediate 2,5-dialkoxyt

Full text of DOI:10.1021/ol052096d

ORGANIC
LETTERS
2006
Vol. 8, No. 3
403-406
Electrolysis as an Efficient Key Step in
the Homogeneous Polymer-Supported
Synthesis of N-Substituted Pyrroles
Sukanya Nad,†,‡ Sebastian Roller,† Rainer Haag,*,†,§ and Rolf Breinbauer*,†,‡
Organische Chemie, UniVersita¨t Dortmund, Otto-Hahn-Str. 6, D-44227 Dortmund,
Germany, Institut fu¨r Chemie und Biochemie, Freie UniVersita¨t Berlin, Takustr. 3,
14195 Berlin, Germany, and Max-Planck-Institut fu¨r molekulare Physiologie,
Otto-Hahn-Str. 11, D-44227 Dortmund, Germany
rainer.haag@chemie.fu-berlin.de; rolf-peter.breinbauer@mpi-dortmund.mpg.de
Received September 1, 2005 (Revised Manuscript Received December 20, 2005 )
ABSTRACT
An efficient and general route to the soluble polymer-assisted synthesis of a set of 14 different N-substituted pyrroles using dendritic polyglycerol
as a high-loading support is presented. The transformation of furan to the key intermediate 2,5-dialkoxytetrahydrofuran was performed by
electrochemical oxidation followed by catalytic hydrogenation with Pt/C in high yield. Both reactions required heterogeneous reagents which
can be conveniently used with polyglycerol as a soluble support.
Polymer-supported synthesis has become a valuable tool for
the synthesis of libraries of compounds with potential interest
for applications in life sciences, catalysis, and material
sciences. Solid-phase organic synthesis (SPOS) using in-
soluble solid supports such as polystyrene resins takes
advantage of the simple removal of excess or consumed
reagents by a simple filtration workup operation.1 On the
other hand slow reaction kinetics and the intrinsic difficulty
to monitor reaction progress are factors which limit the use
of SPOS in certain applications. Due to the heterogeneous
nature of the solid support in which more than 99% of the
substrate molecules are located in the interior of a bead, no
direct contact of these molecules with heterogeneous reagents
is possible, which imposes a severe limitation for the use of
such useful synthetic operations, such as catalytic hydrogena-
tion or electroorganic synthesis.2 Recently, we reported the
successful electrochemical oxidation of furans on solid phase,
in which a redox catalyst serves as an electron shuttle
between electrode and support.3 Having a method for the
solid-phase synthesis of 2,5-dialkoxydihydrofurans in hand,
we aimed at the synthesis of the pharmacologically interest-
† Universita¨t Dortmund.
‡ Max-Planck-Institut fu¨r molekulare Physiologie.
§ Freie Universita¨t Berlin.
(1) Reviews: (a) Fru¨chtel, J. S.; Jung, G. Angew. Chem. 1996, 108, 19-
46; Angew. Chem., Int. Ed. 1996, 35, 17-42. (b) Hermkens, P. H. H.;
Ottenheijm, H. C. J.; Rees, D. Tetrahedron 1996, 52, 4527-4554. (c)
Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D. C. Tetrahedron 1997,
53, 5643-5678. (d) Booth, S.; Hermkens, P. H. H.; Ottenheijm, H. C. J.;
Rees, D. C. Tetrahedron 1999, 54, 15385-15443. (e) Zaragoza Do¨rwald,
F. Organic Synthesis on Solid Phase, 2nd ed.; Wiley-VCH: Weinheim,
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10.1021/ol052096d CCC: $33.50
© 2006 American Chemical Society
Published on Web 01/06/2006

ing class of N-substituted pyrroles4 by condensation of
primary amines with 2,5-dialkoxytetrahydrofurans, which
would require the hydrogenation of the olefinic double bond
of a solid-phase bound substrate. Here, we faced a method-
ological problem which we could not solve even by the
attempted use of diimide reduction as a homogeneous
reduction method for the corresponding substrate molecule.5
Obviously, the use of an insoluble polymer support repre-
sented a dead end street for the planned synthetic strategy,
and we turned to soluble polymers, such as polyglycerol 1,
as an alternative support.2
Scheme 1. Synthesis of N-Substituted Pyrroles Using 1 as a
Soluble Support
Soluble polymeric supports enable the use of homogeneous
reaction conditions and standard analytical techniques for
reaction monitoring.6,7 Recently, we introduced hyper-
branched polyglycerol (1) as an inexpensive support to
parallel library synthesis, offering the advantages of high
loading capacity and facile monitoring of the reaction
progress (Figure 1).8
side product via dialysis, the loading of ester 2 was calculated
to be 6.5 mmol/g (see the Supporting Information). For the
oxidation of the furan substrate, it was planned to use the
electrochemical method of Clauson-Kaas.9 Due to the
modification with a hydrophobic residue at its tentacle
termini, the polyglycerol ester 2 was not soluble in MeOH
anymore, and for the subsequent electrolysis an electrolyte
of 0.2 M NH4Br in 1,4-dioxane/MeOH (1:1) was chosen
instead, for which 1,4-dioxane served as a cosolvent.
Electrolysis was performed in an undivided beaker type cell
using carbon electrodes and a current density of 0.015 A/cm2.
After consumption of 3 F/mol, NMR analysis revealed that
2 had been converted smoothly and quantitatively into 3-(2,5-
dihydro-2,5-dimethoxyfuran-2-yl)propanoic acid polyglycerol
ester (3). Gratifyingly, due to the clean conversion and the
polar properties of the electrolyte, a simple extractive workup
allowed the isolation of 3 without requiring further purifica-
tion by dialysis. The crucial hydrogenation step,10 which had
Figure 1. Hyperbranched polyglycerol (1): the depicted polymer
structure represents only one possible isomer and a small part of
the polyglycerol (Mn ) 8000 g/mol) scaffold.
2-Furanpropanoic acid was attached to polyglycerol (1)
using a DCC-mediated esterification protocol which we had
developed recently (Scheme 1).8c After removal of the urea
(4) Examples: (a) Yu, S.; Saenz, J.; Srirangam, J. K. J. Org. Chem.
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Dickerson, T. J.; Reed, N. N.; Janda, K. D. Chem. ReV. 2002, 102, 3325-
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A.; Haag. R. Angew. Chem. 2002, 114, 4136-4173; Angew. Chem., Int.
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(8) (a) Haag, R.; Sunder, A.; Hebel, A.; Roller, S. J. Comb. Chem. 2002,
112-119. (b) Hebel, A.; Haag, R. J. Org. Chem. 2002, 67, 9452-9455.
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404
Org. Lett., Vol. 8, No. 3, 2006

previously failed using insoluble polymer resins, turned out
to be facile when using polyglycerol as a homogeneous
support. Whereas Pd/C as a hydrogenation catalyst delivered
unsatisfying results in various solvents, hydrogenation with
Pt/C in MeOH enabled the clean conversion of 3 into 2,5-
dimethoxytetrahydrofuran derivative 4. Due to the hetero-
geneous nature of the reagents, a simple filtration through a
bed of Celite gave product 4 in pure form.
Scheme 2. Diversification via Pd-Catalyzed Cross-Coupling
Reactions
Having established a robust and scalable synthetic route
to key intermediate 4, we investigated the formation of
pyrrole derivatives 6a-e by in situ hydrolytic release of the
latent carbonyl moieties and concomitant Paal-Knorr-type
condensation with amines 5a-e.11 Using model reactions
in solution, we identified Jefford’s conditions with R-NH2/
AcOH/NaOAc (1/1/1) in MeOH at 80 °C as useful for our
purposes.12 Unfortunately, when applying these reaction
conditions for the condensation of polygycerol-supported
substrate 4 and aniline (5a) as a model substrate, we observed
not only the desired product 6a but also significant amounts
of the corresponding methyl ester product which resulted
from a transesterification side reaction. Slight modification
of the reaction conditions by using R-NH2/NaOAc (2/1) in
AcOH/1,4-dioxane (2/1) as the solvent system cleanly led
to the pyrrole condensation product 6a, which was subjected
to purification via dialysis.8a Product 7a was cleaved off the
polymer via saponification in the presence of LiOH in 1,4-
dioxane/H2O (10/1) and was isolated after purification by
column chromatography in respectable 55% overall yield
(starting from 2). The reaction sequence proved to be general
for any type of primary amines or anilines 5a-e delivering
N-substituted pyrrole propionic acids 7a-e in 50-65%
overall yield (Scheme 1).
overall yields 60-65% (Scheme 2, Figure 2). These modi-
fication reactions considerably contribute to the overall
diversity of the prepared compound set and highlight the
flexibility of our synthetic approach, which exploits the ready
accessibility of a variety of primary amines as building
blocks.
While condensation of the key intermediate 4 with a
variety of amines has already allowed the flexible synthesis
of a diverse array of N-substituted pyrroles, the diversity of
the compound set could be increased when appropriately
substituted intermediates were subjected to further modifica-
tion. Exemplifying this strategy, we performed a series of
Pd-catalyzed cross-coupling reactions with N-(4-iodophenyl)-
2-pyrrolpropanoic acid polyglycerol ester 6d (Scheme 2).8b,13
Suzuki reaction with Pd(PPh3)4 as a catalyst and K2CO3 as
base produced N-biphenyl derivatives 8a-c in good overall
yield. Similarily, Sonogashira reaction with [Pd(PPh3)2Cl2]
and Heck reaction using Jeffery’s conditions14 delivered the
corresponding coupling products 9a-d and 10 in good
(10) Nedenskov, P.; Elming, N.; Nielsen, J. T.; Clauson-Kaas, N. Acta
Chem. Scand. 1955, 9, 17-22.
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3061. (d) Fang, V.; Leysen, D.; Ottenheijm, H. C. J. Synth. Commun. 1995,
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1996, 61, 1180-1183.
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(13) For previous reports of Pd-cross coupling reactions using soluble
polymers as supports, see: (a) Hovestad, N. J.; Ford, A.; Jastrzebski, J. T.
B. H.; van Koten, G. J. Org. Chem. 2000, 65, 6338-6344. (b) De, D.;
Krogstad, D. J. Org. Lett. 2000, 2, 879-882. (c) Grether, U.; Waldmann,
H. Chem. Eur. J. 2001, 7, 959-971. (d) Le Notre, J.; Firet, J. J.; Sliedregt,
L. A. J. M.; van Steen, B. J.; van Koten, G.; Klein Gebbink, R. J. M. Org.
Lett. 2005, 7, 363-366.
Figure 2. Reaction products of diversification through Pd-catalyzed
cross-coupling reactions. Contains an impurity.
a
Org. Lett., Vol. 8, No. 3, 2006
405

In conclusion, we have demonstrated that hyperbranched
polyglycerol 1 is an excellent soluble support for the
synthesis of a diverse array of compounds using multistep
synthesis. In particular, polyglycerol offers the advantage of
(i) facile monitoring of reaction progress, which (ii) signifi-
cantly accelerates the optimization process of reaction
conditions, and (iii) due to its homogeneous nature allows
the use of heterogeneous reagents. This allowed us to use a
combination of reagents (electrolysis and catalytic hydro-
genation) which could not be used in the presence of an
insoluble polystyrene resin as support.
Acknowledgment. This work was supported by the
Deutsche Forschungsgemeinschaft (Grant No. Br2324/1-1
and Ha2549/5), the Fonds der Chemischen Industrie (Liebig-
fellowship for R.B. and Dozentenfellowship for R.H.), the
Max-Planck-Society (predoctoral fellowship for S.N.), the
State North Rhine Westfalia, and the University of Dort-
mund.
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Jeffery, T. Tetrahedron 1996, 52, 10113-10130.
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