Efficient cleavage- ross-coupling strategy for solid-phase synthesis - A modular building system for combinatorial chemistry

Full text of DOI:10.1002/(SICI)1521-3773(19990419)38:8<1071::AID-ANIE1071>3.0.CO;2-9

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exclusively of a single, delocalized, bishomoaromatic species
in the gas phase, remain as yet an intriguing myth.
synthesis because they proceed under mild conditions with the
formation of C ± C bonds.[3, 4] Recently, we have shown that
triazenes are suitable for the linkage of anilines to solid
supports and that they may be cleaved to form hydro-
carbons.[4] An advantage of this linker type is its accessibility
from a pool of aminoarenes. The cleavage of this traceless
linker proceeds via arene diazonium ions. We report herein on
the possibilities of a cleavage ± cross-coupling strategy starting
from these diazonium ions.
Received: October 26, 1998 [Z12566IE]
German version: Angew. Chem. 1999, 111, 1136 ± 1139
Keywords: Cope rearrangements ´ homoaromaticity ´ sol-
vent effects ´ transition states ´ valence isomerization
The Heck reaction[5] of arene diazonium salts bearing little
or no functionalization or triazenes, cleaved by acids, with
simple olefins proceeds in general under mild thermal
conditions to give the expected products in moderate to good
yields.[5, 6] Preliminary experiments with triazenes in methanol
as the solvent showed that the reduction products are formed
in various amounts together with aryl ether by-products
through reaction with the solvent.
The reactions on solid supports were conducted with the
known amine resin 2[4] (Scheme 1). Benzyl alcohol 3 bound
through the triazene system initially served as a test system.
The one-pot cleavage ± cross-coupling reaction was conducted
with cyclopentene (4a), a moderately reactive alkene for the
Heck reaction. The resin was cleaved with two equivalents of
trifluoracetic acid (TFA) in MeOH at 08C to give the
diazonium ion. In situ coupling with the alkene in the
[1] H. Quast, M. Seefelder, Angew. Chem. 1999, 111, 1132 ± 1136; Angew.
Chem. Int. Ed. 1999, 38, 1064 ± 1067.
[2] H. Quast, M. Heubes, T. Dietz, A. Witzel, M. Boenke, W. R. Roth,
Eur. J. Org. Chem. 1999, 484 ± 498.
[3] E. L. Eliel, S. H. Wilen, L. N. Mander, Stereochemistry of Organic
Compounds, 1st ed., Wiley, New York, 1994, pp. 32 ± 47.
[4] C. Reichardt, Solvents and Solvent Effects in Organic Chemistry,
2nd ed., VCH, Weinheim, 1990, pp. 392 ± 405.
[5] a) M. J. Kamlet, P. W. Carr, R. W. Taft, M. H. Abraham, J. Am. Chem.
Soc. 1981, 103, 6062 ± 6066; b) M. H. Abraham, M. J. Kamlet, R. W.
Taft, J. Chem. Soc. Perkin Trans. 2 1982, 923 ± 928; c) M. H. Abraham,
P. L. Grellier, J.-L. M. Abboud, R. M. Doherty, R. W. Taft, Can. J.
Chem. 1988, 66, 2673 ± 2686.
[6] This shows that the solvent cage has the same volume for A, A', and A*.
[7] a) For the p* parameter, see C. Laurence, P. Nicolet, M. T. Dalati, J.
Phys. Chem. 1994, 98, 5807 ± 5816; b) for the a and b parameters, see Y.
Marcus, Chem. Soc. Rev. 1993, 22, 409 ± 416.
[8] a) T. Mitsuhashi, J. Am. Chem. Soc. 1986, 108, 2400 ± 2405; b) T.
Mitsuhashi, G. Yamamoto, Bull. Chem. Soc. Jpn. 1990, 63, 643 ± 645.
ArN2+, THF
0
piperazine, DMF
48 h, 60 o
C
25 oC
N
Cl
NH
78%
95%
(Merrifield resin)
Efficient Cleavage ± Cross-Coupling Strategy
for Solid-Phase SynthesisÐA Modular
Building System for Combinatorial
Chemistry**
1
2
regeneration
N
4a
N
TFA, Pd(OAc)2,
MeOH, 2–12 h
N
Stefan Bräse* and Maarten Schroen
N
HO
Dedicated to Professor Armin de Meijere
on the occasion of his 60th birthday
HO
3a
5a
Solid-phase reactions play an important role in parallel
synthesis and combinatorial chemistry, particularly in the area
of medicinal chemistry, where its potential has emerged due to
the possibility of automation.[1] Research has focused on the
synthesis of small, nonpeptidic molecules, because they are
applicable systemically and their properties can be modified
so that they can cross the blood ± brain barrier more easily.[2]
Cross-coupling reactions serve as efficient methods for their
O
PPh2 N
HO
7
6a
Scheme 1. Synthesis and cleavage ± cross-coupling reactions on the tri-
azene resin 3a.
[*] Dr. S. Bräse, M. Schroen
Institut für Organische Chemie der Technischen Hochschule
Professor-Pirlet-Strasse 1, D-52074 Aachen (Germany)
Fax: (‡49)241-8888127
presence of catalytic amounts (5 mol%) of palladium(ii)
acetate furnished 2-cyclopent-2-eneylbenzyl alcohol (5a) in
over 92% purity (HPLC, GC, and NMR) and up to 95%
yields after 12 h at 408C in MeOH, filtration to remove the
resin, and removal of the solvent with a rotary evaporator.
The regioisomeric, achiral cyclopentene derivative 6a was
isolated as a by-product in 5% yield. An examination of the
use of various phosphane types as ligands gave the following
result: addition of triphenylphosphane lowered the purity
E-mail: braese@oc.rwth-aachen.de
[**] This work was supported by the Fonds der Chemischen Industrie
(Liebig stipendium to S. B.). We thank Prof. Dr. Dieter Enders for his
generous support and the companies Bayer AG, BASF AG, Degussa
AG, Hoechst AG, NovaBioChem-CalBioChem, and Grünenthal
GmbH for donations of chemicals. Dr. Nils Griebenow (Bayer AG,
Leverkusen) as well as Johannes Köbberling (RWTH Aachen) are
acknowledged for their helpful suggestions during this work.
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(80%, HPLC) and led to a change of the ratio of the isomers
(5a:6a ˆ 3:1). 2,3-O-Isopropylidene-2,3-dihydroxy-1,4-bis(di-
phenylphosphinyl)butane (DIOP) as ligand reversed this
ratio and gave the cyclopentene derivative 6a in 63% yield.
The oxazoline 7[5, 7] furnished the chiral product 5a, but with
low asymmetric induction (75% yield, <10% ee). The HPLC
analysis of the crude product showed the presence of the
corresponding phosphane oxides: presumably under the
reaction conditions the ligand is oxidized, for example
through the diazonium salt, resulting in a partial dissociation
that suggests that the ligand type is not suitable for
asymmetric induction. By using palladium on charcoal, the
coupling is achieved in lower purity (87%); however, the
method is advantageous in regard to the ease of removal of
the palladium catalyst, that is the filtrate is nearly colorless. A
remarkable feature of this new concept is that a multiple
phase change (solid ± liquid ± solid ± liquid) is observed.[8]
Cleavage with functionalization from the resin has been
used only seldomly,[9] since the coupling reagent or partner are
in general difficult to separate; however, this is possible in the
present case due to the volatility of the alkenes used. This case
is the first example of a solid support linker being used to
generate a reactive species for Heck reactions.
terminal position. However, an unexpected mixture of
double-bond regio- and diastereomeric products 10d, e
(1E:2E:2Z ꢀ 50:45:5) were isolated. Cyclic alkenes (cyclo-
pentene to cyclooctene, 4a ± e) also reacted smoothly (in
general >92% purity for 5a ± d). In addition, the palladium
catalyst on charcoal was still active for hydrogenation
reactions (1 bar H2, 258C, 2 h) and allows the formal coupling
of alkyl units in high yields and purities. Thus, the phenyl-
alanine derivative 12 was furnished by Heck coupling of the
resin 3 (X ˆ p-I) with acetamido acrylate, cleavage Heck
reaction with cyclopentene (4a), and subsequent hydrogena-
tion of the double bond.
Allyl alcohols such as but-1-en-3-ol were found to react
smoothly and gave the ketones 8. Enol ethers were however
not suitable for this reaction and yielded mixtures of products
by acid hydrolysis.
The reaction with 1,3-cyclohexadiene gave neither the
expected dienes nor the possible cyclization product;[5] only
the corresponding phenyl derivative 13 was detected (45%
yield, 92% purity). Seemingly, under the acidic conditions
various oxidative insertion/reductive elimination processes or
transfer hydrogenation can occur. These novel reaction
sequences offer the possibility of a formal biaryl coupling
and thus provide a potential alternative to Stille and Suzuki
couplings.[3a] A comparable experiment with phenyl boronic
acid for a Suzuki coupling yielded the expected product,
however, separation of excess of the coupling component is
more laborious.
The reaction under an atmosphere of carbon monoxide
(1 bar) in the absence of an alkene furnished the correspond-
ing benzoate 9 in 87% yield (92% purity). Basic amine
functionalities such as pyridine derivatives did not interfere
with the coupling procedure providing that the reaction was
conducted with an appropriate excess of trifluoroacetic acid.
Alkynes may also be used as the coupling component: tert-
butylacetylene furnished the expected product 11 in 85%
purity. The alkyne di- and trimerized under the reaction
conditions, thus, separation by chromatography or solid-phase
extraction was required to ensure sufficient purity. Alkyne
coupling reactions with diazonium salts have not been
reported to date.
After these successful reactions a series of activated alkenes
(styrene, tert-butyl acrylate, 2-vinylpyridine) were employed
in coupling reactions and yielded the desired trans-configured
products 10a ± c in excellent purities and yields (>92%
HPLC, GC) (Scheme 2). Even nonactivated alkenes such as
1-hexene or 1-octene were found to react smoothly at the
In this context, a novel unsymmetric biaryl synthesis on
solid support has been developed. The observation that Heck
reactions with unreactive alkenes led to dimerization of the
halogen component has allowed the development of a syn-
thesis of symmetrical biaryl units.[5, 10] The reaction of the
polymer-bound iodoarene 3 (X ˆ p-I) with iodobenzene in
presence of a palladium catalyst under Heck conditions
(Pd(OAc)2, PPh3, NEt3, DMF, 24 h, 808C) furnished a biaryl
resin 3 (X ˆ p-Ph), which could be subsequently used in a
second, cleavage ± cross-coupling reaction with acrylate to
give the functionalized arene 14 in good yield and purity.
The examples above have been chosen based on the boiling
point of the alkene to be coupled in order to ensure the
removal of the excess upon evaporation. With a boiling point
lower than or in the range of dimethyl sulfoxide, one of the
standard solvents for the high-throughput screening, coupling
with components such as 1-decene or crotonic acid can be
achieved. Up to this molecule size the cleavage products can
Scheme 2. Cleavage ± cross-coupling reactions on the triazene resin 3: a) 3,
alkene, alkyne, or diene, Pd(OAc)2 or Pd/C, 2 equiv TFA, MeOH, 2 h,
408C; b) H2 (1 bar), 2 h, 258C; c) 3 (X ˆ 2,6-Cl2), CO (1 bar), Pd(OAc)2,
ˆ
2 equiv TFA, MeOH, 2 h, 408C; d) (p-I), CH2 C(NHAc)CO2Me,
Pd(OAc)2, PPh3, NEt3, DMF, 24 h, 808C; e) (p-I), PhI, Pd(OAc)2, PPh3,
NEt3, DMF, 24 h, 808C; 10a: R ˆ Ph; 10b: R ˆ CO2tBu; 10c: R ˆ
2-pyridyl; 10d: R ˆ butyl; 10e: R ˆ hexyl.
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diazonium salts and triazenes, see: H. Zollinger, Diazo Chemistry,
VCH, Weinheim, 1994, pp. 385 ± 404; h) alkyne couplings: M. M.
Haley S. C. Brand, J. J. Pak, Angew. Chem. 1997, 109, 863 ± 866;
Angew. Chem. Int. Ed. Engl. 1997, 36, 835 ± 866; i) parallel, identical
experiments both in solution and on solid phase showed, that the
yields and purities are exceedingly higher using resin chemistry.
[7] O. Loiseleur, M. Hayashi, N. Schmees, A. Pfaltz, Synthesis 1997, 1338 ±
1345, and references therein.
be obtained without purification. For preparative purposes
involving chromatographic purification higher boiling com-
ponents are also accessible.[11]
This cleavage ± cross-coupling reaction is in all cases salt-
free, that is the exposed resin 2 functions as a ªscavenger-
resinº for the trifluoroacetic acid. The filtered, slightly
yellowish resin is, after washing, active for coupling steps
with diazonium salts and can therefore be recycled.
[8] X. H. Ouyang, R. W. Armstrong, M. M. Murphy, J. Org. Chem. 1998,
63, 1027 ± 1032.
In conclusion, this salt-free cleavage ± cross-coupling strat-
egy allows the clean synthesis of a series of (cyclo)alkenyl-,
alkynyl-, (cyclo)alkyl-, and aryl-substituted (hetero)arene
derivatives and is especially suitable for automated synthesis.
This building system comprising virtually any aminoarene or
nitroarene after their reduction as well as alkenes or alkynes
allows synthesis of highly lipophilic molecules and tolerates
most functional groups.[4, 12, 13] Multicomponent Heck reac-
tions (domino Heck Diels ± Alder reaction, Heck ± Stille
reaction etc.)[14] should be possible in this context and might
lead to a higher diversification.
[9] a) S. C. Schurer, S. Blechert, Synlett 1998, 166 ± 167, and references
therein; b) J. C. Nelson, J. K. Young, J. S. Moore, J. Org. Chem. 1996,
61, 8160 ± 8168; c) for
a functionalizing cleavage: S. Bräse, J.
Köbberling, D. Enders, R. Lazny, M. Wang, S. Brandtner, Tetrahedron
Lett. 1999, 40, 2105 ± 2108.
[10] See also: A. de Meijere, S. Bräse in Transition Metal Catalysed
Reactions (Eds.: S. Murahashi, S. G. Davies), Blackwell Sciences, 1999,
pp. 99 ± 131.
[11] Geminal substituted alkenes like camphene are suitable as substrates.
Methyl 1-cyclohexenecarboxylate as novel component for Heck
reactions furnished as a trisubstituted alkene the expected product
in low yields and purities (65%).
[12] For the synthesis of highly functionalized triazenes in the total
synthesis of vancomycin: a) K. C. Nicolaou, C. N. C. Boddy, S.
Natarajan, T.-Y. Yue, H. Li, S. Bräse, J. M. Ramanjulu, J. Am. Chem.
Soc. 1997, 119, 3421 ± 3422; b) K. C. Nicolaou, M. Takayanagi, N. F.
Jain, S. Natarajan, A. E. Koumbis, T. Bando, J. M. Ramanjulu, Angew.
Chem. 1998, 110, 2881 ± 2883; Angew. Chem. 1998, 37, 2717, and
references therein.
[13] All new, nonpolymeric compounds were completely characterized
(1H NMR, 13C NMR, IR, MS, elemental analysis, or HRMS),
literature known compounds were compared with their spectroscop-
ical data.
Received: November 12, 1998 [Z12651IE]
German version: Angew. Chem. 1999, 111, 1139 ± 1142
Keywords: cross-coupling ´ Heck reactions ´ solid-phase
synthesis ´ triazenes
[1] a) E. M. Gordon, R. W. Barrett, W. J. Dower, S. P. Fodor, M. A.
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Lansky, C. Zechel, Angew. Chem. 1996, 108, 2437 ± 2487; Angew.
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f) Combinatorial Peptide and Nonpeptide Libraries (Ed.: G. Jung),
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references therein.
[14] a) S. Bräse, A. de Meijere, Angew. Chem. 1995, 107, 2741 ± 2743;
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[2] a) J. A. Ellman, Chimia 1996, 50, 260 ± 261; b) M. J. Kurth, Chimia
1996, 50, 261 ± 266; c) C. Blackburn; F. Albericio, S. A. Kates, Drugs
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1997, 1, 79 ± 85; e) A. M. M. Mjalli, B. E. Toyonaga in High Through-
put Screening: The Discovery of Bioactive Substances (Ed.: J. P.
Devlin), Marcel Dekker, New York, 1997, pp. 209 ± 222; f) D. J.
Gravert, K. D. Janda, Curr. Opin. Chem. Biol. 1997, 1, 107 ± 113.
[3] Recent examples: a) B. A. Lorsbach, J. T. Bagdanoff, R. B. Miller,
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W. A. König, W. Stenzel, T. Schotten, Synlett 1998, 295 ± 297; c) S. K.
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An Oxidation-Labile Traceless Linker for
Solid-Phase Synthesis**
Frank Stieber, Uwe Grether, and Herbert Waldmann*
The combinatorial synthesis of small-molecule libraries on
polymeric supports is a powerful method for the discovery
and development of new molecules with a predetermined
profile of properties.[1] Vital to all solid-phase methodologies
is the design and utilization of suitable anchor groups (linkers)
that allow facile attachment, functionalization, and release of
the molecules of interest. Typically, linkage to the polymeric
support is achieved through functionality already present in
the target molecule. However, after cleavage from the support
[*] Prof. Dr. H. Waldmann, Dipl.-Chem. F. Stieber,
Dipl.-Chem. U. Grether
Institut für Organische Chemie der Universität
Richard-Willstätter-Allee 2, D-76128 Karlsruhe (Germany)
Fax: (‡49)721-608-4825
[6] a) S. Sengupta, S. Bhattacharya, J. Chem. Soc. Perkin Trans. 1 1993,
1934 ± 1943; b) S. Sengupta, S. Bhattacharya, Tetrahedron Lett. 1995,
36, 4475 ± 4478; c) S. Bhattacharya, S. Majee; R. Mukherjee, S.
Sengupta, Synth. Commun. 1995, 25, 651 ± 657; d) M. Beller, K.
Kühlein, Synlett 1995, 441 ± 442; e) S. Sengupta, S. Bhattacharya,
Synth. Commun. 1996, 26, 231 ± 236; f) G. Mehta, S. Sengupta,
Tetrahedron Lett. 1996, 37, 8625 ± 8626; g) for the chemistry of
E-mail: waldmann@ochhades.chemie.uni-karlsruhe.de
[**] This research was supported by the Bundesministerium für Bildung
und Forschung, the BASF AG, and the Fonds der Chemischen
Â
Industrie (Kekule-Stipendium for F. Stieber).
Angew. Chem. Int. Ed. 1999, 38, No. 8
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1433-7851/99/3808-1073 $ 17.50+.50/0
1073