Traceless solid phase synthesis of 2-substituted pyrimidines using an 'off-the-shelf' chlorogermane-functionalised resin

Article abstract of DOI:10.1039/b303064d

The parallel solid phase synthesis of an 18-member library of 2-substituted pyrimidines is described using a chlorogermane-functionalised resin. The success of the key Pinner-type condensations between a resin-bound enaminone and an array of amidine hydrochlorides highlights the stability of arylgermane linkers (cf. arylsilanes) towards strongly basic/nucleophilic conditions.

Full text of DOI:10.1039/b303064d

View Article Online / Journal Homepage / Table of Contents for this issue
Traceless solid phase synthesis of 2-substituted pyrimidines using
an ‘off-the-shelf’ chlorogermane-functionalised resin†
Alan C. Spivey,*a,b Ratnasothy Srikaran,a Christopher M. Diapera and David J. Turnera
a Department of Chemistry, University of Sheffield, Brook Hill, Sheffield, Yorkshire,
UK S3 7HF
b Department of Chemistry, Imperial College London, South Kensington campus, London,
UK SW7 2AZ. E-mail: a.c.spivey@imperial.ac.uk; Fax: ϩ44 (0)20 75945833;
Tel: ϩ44 (0)20 75945841
Received 20th March 2003, Accepted 16th April 2003
First published as an Advance Article on the web 25th April 2003
The parallel solid phase synthesis of an 18-member library
of 2-substituted pyrimidines is described using a chloro-
germane-functionalised resin. The success of the key
Pinner-type condensations between a resin-bound enam-
inone and an array of amidine hydrochlorides highlights
the stability of arylgermane linkers (cf. arylsilanes) towards
strongly basic/nucleophilic conditions.
conditions required for mono-chlorodemethylation [SnCl4–
MeNO2 (1 : 1) at 50 ЊC].§ Reasoning that this failure was likely
due to complexation of the SnCl4 with the Lewis basic PEG
side chains of ArgoGelTM, we investigated this transformation
on hydroxyethylpolystyrene (HEPSTM, 2)‡ and on Quadra-
gelTM-OH‡ (3). For these resins we coupled the phenol 4
via chlorodehydration of the resins with SOCl2 in DMF–CCl4
then Williamson etherification with Cs2CO3–n-Bu4NI in DMF.
Compared to the Mitsunobu protocol, this was more econom-
ical and gave improved loading levels. Mono-chlorodemethyl-
ation proceeded smoothly on both of these resins as judged by
IR and microanalysis, giving chlorogermane-functionalised
resins 5 and 6 respectively (Scheme 1).
In the last few years, solid phase synthesis (SPS) and parallel
techniques have been employed extensively to accelerate the
preparation of new chemical entities (NCEs) for property
screening.1 Prominent applications include the synthesis of
libraries of functionalised heterocycles in drug discovery2 and
crop protection programs,3 and of conjugated polyheterocycles
as new electronic materials.4 Linker selection plays a vital role in
the design of such libraries5 and ‘traceless’ linkers are often
preferred since they leave no ‘belly-button’ functional group on
the released library members.6
We have previously described a germanium-based traceless
linker for the SPS of substituted pyrazoles7 and oligo-
thiophenes8 and highlighted aspects of the reactivity of
arylgermanes that may make them superior to arylsilanes for
such applications. For example, as a consequence of the greater
β-effect of Ge cf. Si, arylgermanes undergo more facile SEAr
cleavage than arylsilanes.9 This allows for cleavage with con-
comitant functionalisation using a wide range of electrophiles
[e.g. Eϩ = Iϩ (ICl), Brϩ (Br2), Clϩ (NCS)]10 and for traceless
cleavage using mild acid (e.g. TFA). This is particularly signifi-
cant for π-deficient heterocycles for which arylsilane-based
linkers are unsuitable due to the harsh conditions (e.g. HF)
required for traceless cleavage.11 Moreover, arylgermanes are
stable towards strongly basic/nucleophilic conditions whereas
arylsilanes are not.8,12
Here we highlight the utility of an arylgermane linker for the
traceless synthesis of a library of 2-substituted-4-phenyl-
pyrimidines by condensation of an immobilised acetophenone-
derived enaminone with a series of amidines under strongly
basic/nucleophilic conditions. The synthesis employs a readily
prepared chlorogermane-functionalised resin which is stable
and can be stored for ‘off-the-shelf’ use. This strategy obviates
the need to pre-assemble a linker–scaffold conjugate prior to
immobilisation as required previously.7,10
Scheme
1
Preparation of chlorogermane-functionalised resins.
Reagents and conditions: i, 4 (3 equiv.), TMAD (4.2 equiv.), PBu3
(5 equiv.), PhH, rt, 16 h; ii, SnCl4 (5 equiv.), MeNO2, 50 ЊC, 20 h; iii, a)
SOCl2 (1.5 equiv.), DMF–CCl4 (1 : 10), rt, 16 h then b) 4 (2 equiv.),
Cs2CO3 (2.2 equiv.), nBu4NI (10 mol%), MeCN, 90 ЊC, 20 h.
We opted to employ QuadragelTM-based resin 6 for our
library synthesis because of its favourable swelling properties in
alcohol solvents (vide infra) and superior NMR characteristics.
Batches of chlorogermane-functionalised QuadragelTM 6 can
be stored in the dark under nitrogen for more than 3 months
without detectable decomposition.
Pyrimidines are common components of drug substances
and a number of methods for their preparation by SPS have
been reported.14 Most of these are Pinner-type syntheses [NCN
ϩ C3] in which either the ‘1,1-diamine’ (NCN) or the ‘1,3-
dicarbonyl’ (C3) components are resin-bound. We envisaged
employing a new variant of the latter strategy involving con-
densation of a p-acetophenone-derived enaminone, anchored
Our initial attempts to prepare
a
chlorogermane-
functionalised resin involved the attachment of trimethyl-
germylethylphenol 47 to ArgoGelTM-OH‡ (1) via Mitsunobu-
type coupling using TMAD–PBu3 in toluene13 followed by
‘on-resin’ mono-chlorodemethylation. However, the Argo-
GelTM proved to be incompatible with the strongly Lewis acidic
† Electronic supplementary information (ESI) available: experimental
procedures and key data for all the reactions described. See http://
www.rsc.org/suppdata/ob/b3/b303064d/
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 6 3 8 – 1 6 4 0
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
1638

View Article Online
Table 1 GC-MS data for library. Reagents and conditions: see Scheme 3
Compound
R
MW
Crude GC-MS purity (%)
Isolated yielda (%)
13
14
184
198
96
89
70
65
15
16
196
232
37
98
20
80
17
282
68
45
18
19
246
250
32
79
15
60
20
266
95
75
21
22
23
276
315
262
96
82
58
85
70
40
24
25
296
318
69
87
45
50
26
27
238
233
74
75
60
65
28
253
27
10
a After PLC purification.
to the resin via germanium, with a series of amidines.¶ In
solution, enaminones have been reported to condense with
thiourea,15 amidines,16 and guanidines17 to give 2-mercapto-,
2-alkyl/aryl-, and 2-aminoalkyl/arylpyrimidines, respectively,
in moderate to good yields.
Before proceeding with the SPS we examined the conden-
sation of acetamidine and benzamidine hydrochlorides with
trimethylgermyl enaminone 7|| in solution to give pyrimidines 9
and 10. Optimal conditions for both involved using excess
NaOMe in EtOH at reflux (Scheme 2).16 Interestingly, trimethyl-
silyl (TMS) enaminone 8 affords an intractable mixture of
products under these conditions comprising few signals in the
Scheme 2 Condensation of enaminone 7 with amidines. Reagents and
conditions: i, RC(᎐NH)NH2ؒHCl (3 equiv.), NaOMe (3.7 equiv.),
᎐
EtOH, 85 ЊC, 12 h.
1
crude H-NMR attributable to either the pyrimidine or TMS
groups. This contrasting behaviour probably reflects differences
in pπ–dπ conjugation between Ge/Si and the aryl ring18 and the
greater stability of arylgermanes cf. arylsilanes towards nucleo-
phile-induced ipso-demetalation. It certainly underscores the
advantages of arylgermane immobilisation for SPS under
strongly basic/nucleophilic conditions.
We were now in a position to proceed with SPS using the
chlorogermane-functionalised QuadragelTM resin. Immobilis-
ation of the required dioxolane-protected 4-lithioacetophenone,
deprotection with PPTS, and condensation with Bredereck’s
reagent gave resin-bound enaminone 11. The suitability of
resin 11 for library synthesis was verified by a trial conden-
sation with acetamidine hydrochloride followed by electrophilic
ipso-degermylative cleavage using TFA. This gave 2-methyl-
pyrimidine 12 in > 98% crude purity (GC-MS; 85% isolated
yield).
All the resin functionalisation steps were conveniently moni-
tored by IR because the position of the linker’s sharp v(Ge-Me)
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 6 3 8 – 1 6 4 0
1639

View Article Online
amidines, and to Dr Stephen Yeates, Avecia Ltd., for providing
the QuadragelTM resin.
Notes and references
‡ ArgoGelTM-OH (Argonaught Technologies) is a DVB crosslinked
PS-based resin with bifurcated, hydroxyl-terminated PEG grafts con-
taining ∼60 oxyethyl repeat units. HEPS (Rapp Polymere) is a DVB
crosslinked PS resin containing no PEG. QuadragelTM (Avecia Ltd.) is a
DVB crosslinked PS-based resin with hydroxyl-terminated PEG grafts
containing 4 oxyethyl repeat units.
§ Using a soluble model system we investigated a large number of
alternative conditions for mono-demethylation but failed to establish
less harsh conditions for this type of transformation.
¶ We have previously used enaminone-functionalised ArgoGelTM
for pyrazole synthesis by condensation with a series of hydrazines.
See ref 7.
|| Enaminones 7 and 8 were prepared by treating Me3GeBr/Me3SiCl
with dioxolane-protected 4-lithioacetophenone, deprotection with
PPTS, and condensation with Bredereck’s reagent.7
Scheme 3 Library synthesis. Reagents and conditions: i, p-BrC6H4C-
(OCH2CH2O)Me (2 equiv.), BuLi (2 equiv.), THF, Ϫ78 ЊC, 3 h then rt,
8 h; ii, PPTS, THF–H2O (∼10 : 1), 70 ЊC, 15 h; iii, Bredereck’s reagent
1 M. Leibl, J. Comb. Chem., 1999, 1, 3.
(10 equiv.), THF, 70 ЊC, 16 h; iv, RC(᎐NH)NH2ؒHCl (excess), NaOMe
2 R. A. Haughton, Annu. Rev. Pharmacol. Toxicol., 2000, 40, 273.
3 E. Ward and P. Bernasconi, Nat. Biotechnol., 1999, 17, 618.
4 C. A. Briehn and P. Bäuerle, Chem. Commun., 2002, 1015.
5 A. C. Comely and S. E. Gibson, Angew. Chem., Int. Ed., 2001, 40,
1012.
᎐
(excess), EtOH, 85 ЊC, 12 h; v, TFA, rt, 12 h.
absorption at ca. 600 cmϪ1 is very sensitive to the electronic
characteristics of the attached aryl group (Scheme 3).
An array of 16 alkyl, aryl and heteroaryl substituted amidine
hydrochlorides was then employed for the parallel SPS of a
library of 2-substituted-4-phenylpyrimidines on a ∼0.02 mmol
scale. The resulting pyrimidines were released from the resin in
a traceless fashion using TFA and the crude washings analysed
directly by GC-MS (see Table 1). All the amidines formed the
expected products although crude purities ranged from 27–
98%. Generally, alkyl derived substituted pyrimidines were
obtained in very high purity, otherwise there was no obvious
correlation between the crude purity and the nature of the
substituent.
To conclude, we have developed an efficient ‘off-the-shelf’
chlorogermane-functionalised QuadragelTM resin for SPS and
demonstrated its utility for the traceless synthesis of a library of
2-substituted-4-phenylpyrimidines. The success of the strategy
highlights the stability of the arylgermane linkage towards the
strongly basic/nucleophilic conditions employed for the key
condensation step.
6 P. Blaney, R. Grigg and V. Sridharan, Chem. Rev., 2002, 102,
2607.
7 A. C. Spivey, C. M. Diaper, H. Adams and A. Rudge, J. Org. Chem.,
2000, 65, 5253.
8 A. C. Spivey, D. J. Turner, M. L. Turner and S. Yeates, Org. Lett.,
2002, 4, 1899.
9 C. Eaborn, J. Organomet. Chem., 1975, 100, 43.
10 A. C. Spivey, C. M. Diaper and A. Rudge, Chem. Commun., 1999,
835.
11 M. J. Plunkett and J. A. Ellman, J. Org. Chem., 1997, 62, 2885.
12 R. W. Bott, C. Eaborn and T. W. Swaddle, J. Chem. Soc., 1963,
2342.
13 S. Itô and T. Tsunoda, Pure Appl. Chem., 1999, 71, 1053.
14 For a review see: P. M. S. Chauhan, S. K. Srivastava and K. Sanjay,
Comb. Chem. High Throughput Screening, 2001, 4, 35.
15 W. Klose and K. Schwarz, J. Heterocycl. Chem., 1982, 19, 1165.
16 (a) L. Mosti, G. Menozzi and P. Schenone, J. Heterocycl. Chem.,
1983, 20, 649; (b) A. Tanaka, Y. Motoyama and H. Takasugi,
Chem. Pharm. Bull., 1994, 42, 1828.
17 R. Paul, W. A. Hallett, J. W. Hanifin, M. F. Reich, B. D. Johnson,
R. H. Lenhard, J. P. Dusza, S. S. Kerwar, Y. Lin, W. C. Pickett,
C. M. Seifert, L. W. Torley, M. E. Tarrant and S. Wrenn, J. Med.
Chem., 1993, 36, 2716.
Grateful acknowledgement is made to Pfizer Ltd. and
the University of Sheffield for financial support of this work, to
Dr Jan Scicinski, GlaxoSmithKline, for providing most of the
18 J.-C. Marie, J. Marrot and R. Nabet, Bull. Chim. Soc. Fr., 1981, 429
and references therein.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 6 3 8 – 1 6 4 0
1640