The first stable diazonium ion on solid support - Investigations on stability and usage as linker and scavenger in solid-phase organic synthesis

Full text of DOI:10.1002/1521-3773(20001016)39:20<3681::AID-ANIE3681>3.0.CO;2-B

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The First Stable Diazonium Ion on Solid
SupportÐInvestigations on Stability and Usage
as Linker and Scavenger in Solid-Phase Organic
Synthesis**
StefanDahmenand StefanBräse*
Scheme 1. Synthesis of the T2* linker 3: a) 1. TMSCl inMeOH; 2. LiAlH 4,
THF, 08C !reflux, 2 h; b) sodium hydride inDMF, 40 8C, 4 h; c) tBuONO,
BF3 ´ OEt2 inTHF, 0 8C.
Diazonium ions represent one of the most versatile func-
tional groups in organic chemistry.[1, 2] The most important
reactions of aromatic diazonium ions are the Sandmeyer,
Schiemann, Meerwein, Pschorr, and Gomberg-Bachmann
reactions, but also the Heck reaction[3] and the formation of
triazenes[4] and azo compounds[5] represent important proc-
esses. Diazonium ions are also of interest in theoretical
chemistry. In more recent theoretical works they are consid-
ered as electron donor/acceptor complexes between a phenyl
cation and a dinitrogen molecule.[6, 7]
The property that limits the application of diazonium ions
most is their lability. Aromatic diazonium ions undergo
fragmentation to nitrogen and reactive phenyl intermediates.
Ionic and radical pathways, initiated by single-electron trans-
fer reactions, are known. Also our linker for secondary amines
(T2)[8] was only synthesized as an intermediate and had to be
stored and handled below 08C to avoid decomposition. Thus,
one of our aims was to develop a stable diazonium ion on solid
support, to combine the broad chemical usage of diazo
chemisty with the simple handling of solid-phase organic
chemistry.
The stability of diazonium ions can be increased by
[12]
complexationwith crownethers;
complexes with
[21]crown-7 show the highest thermal stability. Therefore
the polymer-bound diazonium ion 3 was treated with
[18]crown-6 as well as [21]crown-7 and the resulting resins
(3 ´ [18]c-6 and 3 ´ [21]c-7, respectively) were examined by IR
spectroscopy (Figure 1). The complexationby [18]crown-6
ꢀ
shifts the N N stretching vibration clearly to higher frequen-
cies (shifts of 20 ± 29 cmÀ1 are mentioned in literature[12]),
whereas for complexes from [21]crown-7 only small shifts are
observed (about ‡5 cmÀ1 compared to the uncomplexed
diazonium ion).
Most important for the stability of aromatic diazonium ions
is, besides the choice of the counterion,[9] the substitution
patternof the arene. Furthermore, the chosenarene had to be
highly tolerant towards as many chemical reactions as
possible. In the already mentioned theoretical studies of
Glaser,[10] and from experimental data[11] it was shownthat p-
chloro-substituted diazonium ions are very stable. For that
reason we chose 2-chloro-5-aminobenzyl alcohol (2) as
starting material for the formation of a stable diazonium ion
onsolid support (Scheme 1).
The aminobenzyl alcohol 2 was synthesized in two steps
from commercially available 2-chloro-5-aminobenzoic acid
(1). Esterificationwith trimethylchlorosilaen inmethaonl
gave the methyl ester, which was reduced with lithium
aluminum hydride (LiAlH4) in THF to the corresponding
benzyl alcohol 2. Coupling to Merrifield resin and subsequent
diazotation led to the polymer-bound diazonium ion 3.
Figure 1. Part of the IR spectra of polymer-bound diazonium ions; the
ꢀ
n(N N) bands of the uncomplexed diazonium ion (a), as well as that of
partly [18]crown-6 complexed (b), and that in the [21]crown-7 complex (c)
are displayed.
The stability of these resins (3´ [18]c-6, 3´ [21]c-7) was investi-
gated by differential scanning calorimetry (DSC) measure-
ments (Figure 2). The corresponding diazonium ions show a
high thermal stability. The rate of decompositionis olny
significant at temperatures higher than 908C. Analysis of the
DSC data gave a reactionenthalpy of DRH ˆ À120 kJmolÀ1
for the fragmentation reaction, which is independent of
complexation. Kinetic analysis based on DSC measurements
at different heating rates gave an activation energy for the
thermal decompositionof 3 of Ea ˆ 114 kJmolÀ1. The decom-
positionrates are consistent with a first-order reaction, which
[*] Dr. S. Bräse, Dipl.-Chem. S. Dahmen
Institut für Organische Chemie der Technischen Hochschule Aachen
Professor-Pirlet-Strasse 1, 52074 Aachen(Germany)
Fax : (‡49)241-8888 127
E-mail: Braese@oc.RWTH-Aachen.de
[**] Nitrogen-Based Linkers, Part 8. This work was supported by the
Fonds der Chemischen Industrie (Liebig-Stipend to S.B.) and the
Deutsche Forschungsgemeinschaft (BR1750-1). We thank Prof. Dr. D.
Enders for the generous support of our work. The companies BASF
AG, Bayer AG, Degussa-Hüls AG, and Calbiochem-Novabiochem
AG are acknowledged for donations of chemicals and Grünenthal
GmbH for financial support. For DSC measurements we also thank
Prof. Dr. Franz-Josef Wortmann and Dr. Numan Özgün at the
Deutsches Wollforschungsinstitut (DWI) at the RWTH Aachen.
Part 7: M. Lormann, S. Dahmen, S. Bräse, Tetrahedron Lett. 2000,
41, 3813 ± 3816.
[13]
was expected by comparisonwith the literature.
To gain insights into the shelf life of resin 3 during normal
laboratory use, decompositionstudies were carried out at
608C, and the conversion was examined by elemental analysis
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Scheme 2. Attachment of amines to the T2* linker. a) Amine 4 (2 ±
5 equiv) inTHF, 30 min, 0 8C.
Figure 2. DSC measurements on the polymer-bound diazonium ions 3,
3 ´ [18]c-6, and 3 ´ [21]c-7; measurements were performed with 8 ± 12 mg
Owing to the constantly increasing application of combi-
natorial chemistry in liquid phase, the use of scavenger resins
has become more and more important.[16, 17] Inmany cases the
application of scavenger resins avoids complicated workup
procedures to remove by-products or excess reagents and
makes an efficient high-throughput synthesis possible. The
temperature stability of the T2* linker should enable its
application as a scavenger for the removal of amines, anilines,
and phenols under formation of triazenes or azo compounds.
The ionic nature of diazonium ions requires the addition of
bases to remove tetrafluoroboronic acid from the reaction
equilibrium, which is generated by reaction with nucleophiles.
Tertiary amines are not suitable, because they may cause a
spontaneous decomposition of diazonium ions. On the other
À1
resinand heating rates of 10.0Kmin
.
(C,H,N).[14] The experimentally determined half-life of resin 3
was elevenhours at 60 8C, which leads to a calculated half-life
of 130 days at room temperature (208C) or 10 years for
storage at 08C. Thus resin 3 is, to the best of our knowledge,
the first, storable polymer-bound diazonium ion.
This so-called T2* linker represents an improvement of the
T2 linker and can be used to immobilize and modify
secondary amines on solid support.[8] Inadditionit is possible
to couple primary amines 4 with the diazonium resin 3 to give
the corresponding polymer-bound triazenes, which can be
used in further transformations (Scheme 2). In this case the
use of a polymer-bound system enables
the cleansytnhesis of 1,3-disubstituted
triazenes 5, while suppressing the forma-
tion of pentazenes, which is a competing
reactioninthe aanlogous liquid-phase
synthesis.[1]
The synthesized 1,3-disubstituted tri-
azenes 5 have successfully beenapplied in
various reactions. Alkylation with alkyl
bromides or acylationof the triazeens
5a ± d with carboxylic acid chlorides, iso-
cyanates, and isothiocyanates were suc-
cessfully carried out under mild condi-
tions, and gave rise to the trisubstituted
triazenes 6 inquatnitative yields. The
reactionis regioselective at the N3-nitro-
genatom of the triazeen group. The
alkylationof the polymer-bound thiourea
6e was performed, without affecting the
triazene group. Cleavage of the products
was conducted by using a solution of
Scheme 3. The T2* resin as a linker in the synthesis of amine derivatives. a) Carboxylic acid chloride
(1.5 ± 2 equiv), pyridine, DMF, room temperature, 2 h; b) sodium hydride, DMF, electrophile (2 ±
5 equiv), room temperature, 2 h; c) isocyanate (1.5 ± 2 equiv), DMF, room temperature, 2 h; d) MeI,
THF, room temperature, 30 min. Cleavage was conducted with 5% TFA in dichloromethane, room
temperature, 5 min. The overall yield for attachment, modification, and cleavage of the amines was
between 20 and 100%, generally greater than 80%, where the yields refer to the theoretically
possible loading of the resin given by the starting material. Attachment of the linker and diazotation
are considered as quantitative reactions, which was also confirmed by elemental analysis. After
trifluoroacetic acid (TFA; 5%) indi-
chloromethane. In Scheme 3 some of the
possible functionalizations of the T2*
linker are summarized. With the possibil-
ity of attachment and subsequent acyla-
tion of primary amines, this linker repre-
sents a new BAL concept (backbone
amide linker).[15]
1
cleavage all products were obtained in >95% purity, as determined by integration of the H NMR
signals and by HPLC analysis.
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available from Calbiochem-Novabiochem. All new compounds were fully
characterized or compared to known substances.
hand addition of insoluble bases (e.g. K2CO3 or KOH) or
polymer-bound tertiary amines appears appropriate as these
reagents undergo no side reactions with diazonium ions and
are easily separated from the reactionmixture by filtration.
Scheme 4 shows that primary and secondary amines can be
removed quantitatively from solution. Anilines and phenols
are removed in high yields, as long as they are not too electron
poor and therefore are not sufficiently nucleophilic. Never-
theless nearly all phenols could be removed by using the T2*
resinupondeprotonationof the phenol, but this procedure
requires strong bases like KOH or NaH, and therefore makes
aqueous workup necessary. However phenols, which react
only with very electrophilic diazonium ions (e.g. 2,6-di-tert-
butylphenol) could not be removed.
In summary, immobilized diazonium ions can have a high
stability, which enables their application as linkers and
scavengers in solid-phase organic chemistry. They could, for
example, be used as backbone amide linkers in peptide
chemistry, or for the immobilizationof carbonnucleophiles
such as malonic acid esters or silylenol ethers. Furthermore
they are easy to handle, both in terms of stability and toxicity
of the compounds. Thus triazenes, which are formed upon
reaction with amines and which are considered as carcinogens,
can be easily and safely handled.
The DSC measurements were carried out on a Perkin Elmer DSC 7 with a
polymer-bound diazonium ion with a loading of 1.0 mmolgÀ1. The DSC
analysis of the used chloromethylpolystyrene starting material resulted in
an endothermic melting enthalpy of 2.6 Jper gram resin at the melting
point of 1188C. The melting point lies in the region of the exothermal
decomposition of the diazonium ions, but the melting enthalpy is about 50
times smaller. As the tolerance of the method is about 10%, the melting
enthalpy was not taken into account for the examination of the reaction
enthalpy.
Typical procedure for the attachment of amines to the T2* resin: Resin 3
(5.0 g, 5.5 mmol, loading 1.1 mmolgÀ1) was suspended in THF (50 mL) and
cooled to 08C. Benzylamine (3.0 mL, 5 equiv, 27.5 mmol) was added slowly
under careful stirring. After 1 h, the resin was filtered, washed alternately
with THF and MeOH, and dried in high vacuum.
Typical procedure to remove nucleophiles with the T2* resinadn
diethylaminomethylpolystyrene: Resin
3 (100 mg, 0.11 mmol, loading
1.1 mmolgÀ1
)
and diethylaminomethylpolystyrene (50 mg, 0.116 mmol,
loading 2.33 mmolgÀ1) were weighed into a reaction vessel. Then, 2 mL
of an equimolar solution of nucleophile (0.05 mmol) and benzyl alcohol
(0.05 mmol) as an internal reference in THF were added, the reaction
vessel was closed and agitated for 1 h using a shaker. The resin was filtered
off and the eluate was analyzed by gas chromatography.
Received: May 3, 2000 [Z15072]
[1] H. Zollinger, Diazo Chemistry, Vol. 1, VCH, Weinheim 1994.
[2] D. S. Wulfmanin The Chemistry of Diazonium and Diazo Groups,
Vol. 1 (Ed.: S. Patai), Wiley, New York 1978, pp. 247 ± 339.
[3] S. Bräse, A. de Meijere in Metal-catalyzed Cross-coupling Reactions
(Eds.: F. Diederich, P. J. Stang), Wiley-VCH, Weinheim, 1998, p. 112.
[4] A. Engel, Methoden Org. Chem. (Houben-Weyl) 4th ed. 1952 ± ,
Vol. E 16a/2, 1990, pp. 1182 ± 1226.
Experimental Section
All resins were characterized by IR spectroscopy, and loadings and
conversions were evaluated by elemental analysis (C,H,N). Typical
loadings of the used chloromethylpolystyrene were between 0.6 and
1.4 mmolgÀ1. Chloromethylpolystyrene (Merrifield resin) was obtained
from Calbiochem-Novabiochem or Polymer Laboratories. The T2* resinis
[5] The chemistry of the hydrazo, azo and azoxy groups, Vol. 1 ‡ 2 (Ed.: S.
Patai), Wiley, New York, 1975.
[6] R. Glaser, J. Horan, J. Org. Chem. 1995, 60, 7518 ± 7528.
[7] R. Glaser, J. Horan, H. Zollinger, Angew. Chem. 1997, 109,
2324 ± 2328; Angew. Chem. Int. Ed. Engl. 1997, 36, 2210 ±
2213.
[8] S. Bräse, J. Köbberling, D. Enders, M. Wang, R. Lazny, S.
Brandtner, Tetrahedron Lett. 1999, 40, 2105 ± 2108.
[9] C. Colas, M. Goeldner, Eur. J. Org. Chem. 1999, 1357 ± 1366.
[10] R. Glaser, C. J. Horan, M. Lewis, H. Zollinger, J. Org. Chem.
1999, 64, 902 ± 913.
[11] C. G. Swain, J. E. Sheats, K. G. Harbison, J. Am. Chem. Soc.
1975, 97, 783 ± 790.
[12] R. A. Bartsch in Crown ethersand analogs (Eds.: S. Patai, Z.
Rappoport), Wiley, Chichester, 1989, p. 505 ± 517. Although
a high excess of the crownether was used, the polymer-
bound diazonium salts could not be transformed into their
[18]crown-6 complexes quantitatively, because the complex-
ation constants are smaller than in the case of the
corresponding [21]crown-7 complexes. Therefore it is pos-
sible that [18]crown-6 was partly washed off the resin during
workup.
[13] M. L. Crossley, R. H. Kienle, C. H. Benbrook, J. Am. Chem.
Soc. 1940, 62, 1400 ± 1403. Usually anS N1-type mechanism is
considered, although there are indications for an SNAr-type
mechanism in the presence of nucleophiles.
[14] Experimentally examined loading of the resins correlate
well with the results from CHN combustionanalysis.
[15] K. J. Jensen, J. Alsina, M. F. Songster, J. Vagner, F. Albericio,
G. Barany, J. Am. Chem. Soc. 1998, 120, 5441 ± 5452.
[16] D. L. Flynn, R. V. Devraj, J. J. Parlow in Solid-Phase Organic
Synthesis (Ed.: K. Burgess), Wiley, New York, 2000,
pp. 149 ± 194.
Scheme 4. The T2* resin as a scavenger for amines, anilines, and phenols. The
percentage of removed nucleophile is given. Benzyl alcohol was used as an internal
standard. a) Resin 3 (2 equiv), base in THF, 1 h. Filtration of the resin and analysis of
the filtrate by gas chromatography. [a] Base: diethylaminomethylpolystyrene
(2 equiv, loading 2.33 mmolgÀ1). [b] Base: a basic ion-exchange resin (Merck Lewatit
MP 5080). [c] Base: finely powdered potassium hydroxide (4 ± 5 equiv).
[17] V. Austel in Combinatorial Chemistry (Ed.: G. Jung), Wiley-
VCH, Weinheim, 1999, pp. 77 ± 123.
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