A new germanium based linker for solid phase synthesis of aromatic compounds

Article abstract of DOI:10.1039/a900915i

An efficient three-step synthesis of germyl linker precursor 4 is described which enables a simple two step immobilisation of lithiated aromatics to Argogel(TM) polymer; cleavage from the polymer support via ipso-degermylation with TFA, ICI, Br₂ and NCS provides protio-, iodo-, bromo- and chloroaryls, respectively.

Full text of DOI:10.1039/a900915i

A new germanium based linker for solid phase synthesis of aromatic
compounds
Alan C. Spivey,*a Christopher M. Diapera and Andrew J. Rudgeb
a University of Sheffield, Brook Hill, Sheffield, Yorkshire, UK S3 7HF. E-mail: a.c.spivey@sheffield.ac.uk
b Pfizer Central Research, Sandwich, Kent, UK CT13 9NJ
Received (in Liverpool, UK) 2nd February 1999, Accepted 22nd March 1999
An efficient three-step synthesis of germyl linker precursor 4
i
GeCl2•O
O
GeCl4
is described which enables a simple two step immobilisation
of lithiated aromatics to Argogel™ polymer; cleavage from
the polymer support via ipso-degermylation with TFA, ICl,
Br2 and NCS provides protio-, iodo-, bromo- and chloro-
aryls, respectively.
1
Scheme 1 Reagents and conditions: i, TMDS, 1,4-dioxane, 3 h, 100 °C.
homobenzylic C–Cl bond of 4-(2-chloroethyl)phenol 2.† Sim-
ply heating the two components in a Carius tube with a
minimum amount of dioxane furnished trichlorogermane 3 in
91% yield. Exhaustive methylation by refluxing with an excess
of MeMgBr then furnished trimethylgermane linker precursor
4‡ in 82% yield11 (Scheme 2).
The development of new linkers for the immobilisation of
organic compounds on functionalised polymer supports is an
area of current interest.1 The immobilisation of aromatics has
commanded particular importance as compounds of this type
are pervasive constituents of pharmaceuticals. Protecting-group
linker strategies are suitable for this purpose provided that the
functional group unmasked on cleavage is required in the target
molecules. If not, then a traceless linker (e.g. arylsilane based)
can be employed.2 Arylsilane cleavage is generally achieved via
acidolytic or basic fluoridolytic ipso-protodesilylation,3 or by
electrophilic ipso-halodesilylation using Br2 or ICl to release
aryl bromides and iodides respectively.4 The ability to employ
a range of electrophiles for cleavage is desirable for library
preparation as diversity is introduced on release into solution.
We were interested in devising a new aryl linker susceptible
to cleavage by an increased range of electrophiles and to this
end the work of Vasella5 on trimethylgermane protection of
alkynes drew our attention. Vasella has noted that relative to the
corresponding alkynylsilanes, alkynylgermanes are more read-
ily cleaved by electrophiles (due to the more powerful b-effect
of germanium)6 and additionally display enhanced stability
towards bases and nucleophiles. These properties combined
with the low toxicity of aryl- and alkylgermane compounds
suggested to us that an arylgermane-based linker might provide
a useful addition to the current repertoire of traceless linkers.
During the course of our studies Ellman,7 in response to the
low reactivity of an electron deficient arylsilane bound
benzodiazepine library towards acidolytic cleavage, reported
the first arylgermane linker. Ellman demonstrated that his
arylgermane linker was more readily cleaved by electrophiles
(TFA, Br2) than the corresponding arylsilane linker and that his
linker was compatible with a range of transformations asso-
ciated with the introduction and manipulation of a diverse array
of functional groups. In the light of this pioneering ‘proof of
concept’ our efforts focussed on the development of a more
economic arylgermane linker as Ellman’s linker synthesis relied
on Me2GeCl2 for introduction of the germanium. This com-
pound is expensive and is difficult to prepare from GeCl4 (the
cheapest commercial source of germanium).
Cl
GeR3
i
HO
HO
ii
2
3 R = Cl
4 R = Me
Scheme 2 Reagents and conditions: i, GeCl2.C4H8O2 1, 1,4-dioxane, 16 h,
140 °C (91%); ii, MeMgBr, Et2O, toluene, 16 h, 110 °C (82%).
We envisaged that immobilisation of an aromatic compound
onto a hydroxy functionalised polymer support could be
achieved in a simple two step procedure using trimethylger-
mane linker precursor 4. This would involve selective mono-
halodemethylation and in situ arylation with the appropriate aryl
organometallic species (? I, Scheme 3) followed by Mitsunobu
coupling of the resulting phenolic dimethylarylgermane to the
polymer support (? II, Scheme 3).
GeMe2Ar
ii
GeMe2Ar
i
4
HO
O
I
II
Scheme 3 Two step immobilisation strategy: i, mono-halodemethylation
and in situ arylation with aryl organometallic; ii, Mitsunobu coupling to
resin.
To exemplify this protocol we report here the immobilisation
of two aromatic systems: 4-(4A-methoxy)biphenyl and 4-aceto-
phenone. The former was chosen as this biphenyl would provide
a stringent test system on which to assess electrophilic cleavage
by virtue of having an electron rich aryl group susceptible itself
to competitive electrophilic aromatic substitution. The latter
was chosen as acetophenone provides a versatile functional
handle for library construction.
Butyltrimethylgermane (Me3BuGe) has been shown to
undergo selective mono-chlorodemethylation to give chlor-
obutyldimethylgermane (Me2BuGeCl) upon treatment with
SnCl4.12 We were able to replicate this exquisite chemo-
selectivity with our linker precursor 4. Thus treatment with
SnCl4 in MeNO2 gave chlorodimethylgermane 5 quantitatively
(Scheme 4).
One interesting facet of germanium chemistry is the co-
ordination and insertion reactions associated with dihalogermy-
lenes.8 We opted to exploit this chemistry in the preparation of
our arylgermane linker. Thus, known dichlorogermylene–
1,4-dioxane complex, GeCl2.C4H8O2 1, was synthesised in one
step from GeCl4 by reduction with tetramethyldisiloxane
(TMDS) in refluxing dioxane (Scheme 1). This reaction
routinely provides 70–90% isolated yields of this stable
crystalline complex on a preparative scale.9
Arylation of 5 was accomplished by refluxing overnight in
toluene–THF with the appropriate aryllithium reagent.13 The
4-litho-4Amethoxybiphenyl and dioxolane protected 4-lithio-
acetophenone, used to prepare arylgermanes 6a and 6b
Various dichlorogermylene complexes have been reported to
undergo thermally induced insertion into C–Cl bonds.10 We
found that the dioxane complex 1 inserts cleanly into the
Chem. Commun., 1999, 835–836
835

GeMe2R
i
4
HO
5 R = Cl
ii
OMe
iii
6a R =
6b R =
Ac
Scheme 4 Reagents and conditions: i, SnCl4, MeNO2, 16 h, 50 °C (100%);
ii, 4-bromo-4A-methoxybiphenyl, BuLi, hexane, THF, toluene, 16 h, 110 °C
[6a (82%)]; iii, (a) 2-(4-bromophenyl)-2-methyl-1,3-dioxolane, BuLi, THF,
toluene, 16 h, 110 °C, (b) PPTS, acetone, H2O, 48 h, 67 °C [6b (84% from
5)].
respectively, were made from the corresponding bromides by
standard lithium–halogen exchange at 278 °C. Dioxolane
deprotection was accomplished using PPTS in acetone–H2O
(Scheme 4).
Fig. 1 HPLC traces of biaryls cleaved from Argogel™. [Column: Hichrom
spherisorb-S5W (25 3 0.8 cm), eluting with 80:20 hexane–CHCl3, 1.0 ml
min21]. Reagents and conditions: (a) TFA room temp., 16 h (? 9); (b) ICl,
CH2Cl2, room temp., 30 min (? 10); (c) NCS, THF, 67 °C, 14 h (? 12);
(d) Br2, CH2Cl2, room temp., 2 h (? 11).
Tsunoda’s modified Mitsunobu redox system of N,N,NA,NA-
tetramethylazodicarboxamide (TMAD)–PBu3 was found to
effect efficient coupling of arylgermanes 6a and 6b to
ethoxyethanol to give model systems 7a and 7b respectively.14
Ethoxyethanol was selected as a solution phase ‘surrogate’ for
PEG based Argogel™.§ Use of a solution phase model for
development of appropriate Mitsunobu coupling conditions was
vindicated when these optimised conditions were employed
without modification for the efficient loading of arylgermanes
6a and 6b to Argogel™. Thus following successive washing of
the polymer with DMF, EtOH, THF, Et2O and CH2Cl2 the aryl
functionalised polymers 8a and 8b were obtained with loading
levels of 0.47 and 0.43 mmol g21¶ respectively (Scheme 5).
electrophilic ipso-degermylation affords either protio-, iodo-,
bromo- or chloroaryls, depending on the electrophile em-
ployed.
We are currently preparing a library of aryl containing
compounds using functionalised polymer 8b and extending the
range of electrophiles able to effect cleavage of the aryl–
germanium bond.
Grateful acknowledgement is made to Pfizer for financial
support of this work.
GeMe2R
O
O
i
7a,b
6a,b
Notes and references
† 4-(2-Chloroethyl)phenol is readily prepared in 90% yield from commer-
cially available 4-(2-hydroxyethyl)phenol by heating in concentrated HCl
(ref. 15).
ArgogelTM
ii
GeMe2R
O
nO
‡ Now commercially available from AFChemPharm Ltd., Unit B31-14,
Manor Development Centre, 40 Alison Crescent, Sheffield, UK S2 1AS.
§ Commercial Argogel™ (nominal loading level 0.49 mmol g21) was
selected as the polymer support due to its non-benzylic hydroxy functional-
isation and favourable characteristics for high resolution MAS 1H NMR.
¶ As determined by mass balance (of introduction and subsequent cleavage).
Polymers 8a and 8b were also characterised by solid state MAS
1H NMR.
8a,b
OMe
a R =
b R =
Ac
Scheme 5 Reagents and conditions: i, EtOCH2CH2OH, TMAD, PBu3, PhH,
room temp. 16 h [7a (98%), 7b (87%)]; ii, Argogel™, TMAD, PBu3, PhH,
room temp., 16 h (8a, 8b, see text).
1 B. B. Backes and J. A. Ellman, Curr. Opin. Chem. Biol., 1997, 1, 86.
2 Y. Hu, J. A. Porco, J. W. Labadie, O. W. Gooding and B. M. Trost,
J. Org. Chem., 1998, 63, 4518 and references therein.
3 C. J. Eaborn, J. Organomet. Chem., 1975, 100, 43.
4 Y. Han, S. D. Walker and R. N. Young, Tetrahedron Lett., 1996, 37,
2703.
5 A. Vasella and C. Cai, Helv. Chim. Acta, 1996, 79, 255.
6 C. Dallaire and M. A. Brook, Organometallics, 1990, 9, 2873.
7 M. J. Plunkett and J. A. Ellman, J. Org. Chem., 1997, 62, 2885.
8 J. Satge, M. Massol and P. Riviere, J. Organomet. Chem., 1973, 56,
1.
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45, 94.
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(Engl. Transl.), 1970, 196, 85.
11 M. Lesbre, P. Mazerolles and J. Satge, The Organic Compounds of
Germanium, ed. D. Seyferth, Wiley, 1973.
12 E. J. Bulten and W. Drenth, J. Organomet. Chem., 1973, 61, 179.
13 C. Eaborn and K. C. Pande, J. Chem. Soc., 1960, 3200.
14 T. Tsunoda, J. Otsuka, Y. Yamamiya and S. Ito, Chem. Lett., 1994,
539.
Electrophilic cleavage conditions were optimised initially
using solution phase biarylgermane model system 7a. It was
pleasing to find that treatment with TFA, ICl and Br2 at room
temperature led to quantitative cleavage of the aryl–germanium
bond, yielding the protio-, iodo- and bromobiaryl products 9, 10
and 11 respectively. Furthermore, chlorobiaryl 12 could also be
obtained cleanly using NCS (or Dichloramine-T) in refluxing
THF. There were no traces of products resulting from
competitive electrophilic substitution in the anisole ring.
Minimal optimisation was required to translate this success to
cleavage from Argogel™. Thus when employing functionalised
resin 8a, monitoring release of the biaryl products into solution
by analytical HPLC of the crude washings revealed all these
protocols to proceed cleanly and quantitatively (Fig. 1). The
identity of the released biaryls 9, 10, 11 and 12 were confirmed
in each case by co-injection with authentic samples.
To conclude, we have developed an efficient three step
synthesis of germyl linker precursor 4 (from inexpensive
GeCl4) and demonstrated that this compound can be employed
in a simple two step immobilisation of lithiated aromatics to
Argogel™ polymer. Clean release from the polymer by
15 F. Ehrlich and P. Pistchimuka, Chem. Ber., 1912, 45, 2428.
Communication 9/00915I
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Chem. Commun., 1999, 835–836