Polymer-assisted solution-phase library synthesis of 4-alkoxy-2-hydroxy-3,5,6-trifluorobenzoic acids

Article abstract of DOI:10.1016/S0040-4039(00)02252-8

The efficient synthesis of a small library of 4-alkoxy-2-hydroxy-3,5,6-trifluorobenzoic acids is described via the fluoride mediated alkylation of 5,6,8-trifluoro-7-hydroxy-2-methyl-benzo[1,3]dioxin-4-one with a collection of structurally diverse bromoalkanes. The use of ion-exchange resins during the reaction sequence enabled the preparation of the majority of the products in 82-98% purity without the need for chromatography.

Full text of DOI:10.1016/S0040-4039(00)02252-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1363–1365
Polymer-assisted solution-phase library synthesis of
4-alkoxy-2-hydroxy-3,5,6-trifluorobenzoic acids
Ian R. Hardcastle,* Amelia Moreno Barber, Jonathan H. Marriott and Michael Jarman
CRC Centre for Cancer Therapeutics at the Institute of Cancer Research, Cotswold Road, Sutton, Surrey SM2 5NG, UK
Received 8 May 2000; revised 17 November 2000; accepted 5 December 2000
Abstract—The efficient synthesis of a small library of 4-alkoxy-2-hydroxy-3,5,6-trifluorobenzoic acids is described via the fluoride
mediated alkylation of 5,6,8-trifluoro-7-hydroxy-2-methyl-benzo[1,3]dioxin-4-one with a collection of structurally diverse bromo-
alkanes. The use of ion-exchange resins during the reaction sequence enabled the preparation of the majority of the products in
82–98% purity without the need for chromatography. © 2001 Elsevier Science Ltd. All rights reserved.
We have previously reported the synthesis of 4-farnesy-
loxy-2-hydroxy-3,5,6-trifluorobenzoic acid (1a) during a
search for novel inhibitors of the enzyme farnesyl trans-
ferase (FTase) an important target for cancer therapy.1
Similarly, we have reported the solid-phase synthesis of
a library of 1-alkoxy-3-hydroxy-4-nitro-2,5,6-trifluoro-
benzenes via Mitsunobu alkylation of the correspond-
ing phenol with a diverse collection of alcohols.2 We
required a rapid, efficient and general route to 4-
alkoxy-2-hydroxy-3,5,6-trifluorobenzoic acids (1) to pro-
vide a small library of compounds of sufficient purity
for biological evaluation against FTase.
of solid-phase bases such as conventional ion-exchange
resins4 and polymer supported organic bases,5 however,
has proved popular to promote alkylation. One advan-
tage of this approach is that the alkylation reaction
liberates the product from the resin, thus yielding pure
product. Polymer-supported scavenging reagents have
also been used extensively to provide clean, efficient
reaction sequences.6–8 In this paper we report the syn-
thesis and alkylation of 5,6,8-trifluoro-7-hydroxy-2-
methyl-benzo[1,3]dioxin-4-one (2) with a collection of
structurally diverse bromoalkanes, followed by depro-
tection and purification using polymer-supported scav-
enging reagents to provide a library of 4-alkoxy-
2-hydroxy-3,5,6-trifluorobenzoic acids (1).
The key intermediate protected o-hydroxybenzoic acid
2 was prepared from the pentafluorophenyl ester 6,
which was prepared by an improved route modified
from that previously published (Scheme 1).1 Pen-
Efficient methods for the alkylation of solid-phase-teth-
ered alcohols and phenols are rarely reported.3 The use
Scheme 1. Reagents and conditions: (a) PhCH2Br, Cs2CO3, DMF; (b) PhCH2OH, KOtBu, THF; (c) H2, Pd-C, MeOH-H2O; (d)
C6F5OCOCF3, pyridine, CH2Cl2; (e) i. CH3CHO, DABCO; ii. BioRad AG 50W X-4 H+, MeOH.
* Corresponding author. Current address: Department of Chemistry, Newcastle University, Newcastle upon Tyne NE1 7RU, UK.; e-mail:
i.r.hardcastle@ncl.ac.uk
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02252-8

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I. R. Hardcastle et al. / Tetrahedron Letters 42 (2001) 1363–1365
Figure 1. Structures of diverse alkyl bromides (7).
tafluorobenzoic acid was converted to the benzyl ester
3, which was subjected to a double nucleophilic aro-
matic substitution with potassium benzylalkoxide to
give the 2,4-substituted product (4) in 62% yield,
accompanied by the 2,4,6-trisubstituted product (ca.
12%). Hydrogenolysis smoothly deprotected 4 to give
the o-hydroxybenzoic acid derivative 5 in 91% yield.
Conversion of acid 5 to the activated pentafluorophenyl
ester 6 under standard conditions enabled conversion to
the 1,3-benzodioxinone 2 by treatment with DABCO in
neat acetaldehyde.9 The resulting DABCO salt precipi-
tated from the reaction mixture. The phenol 2 was
liberated by passing a methanolic solution of the salt
through a cation exchange column (BioRad AG 50W
X-4 H+ form), and was isolated in 45% yield, based on
6.
berlyst 15 acid resin in THF to protonate any unreacted
cesium phenoxide ion and (b) Amberlyst A-21 basic
resin to sequester the unreacted phenol 2, leaving a
mixture of the product 8 and remaining unreacted
bromoalkane (7c–v). Deprotection was effected with
aqueous sodium hydroxide (0.5 M) in dioxane (1:3) to
give the o-hydroxybenzoic acid sodium salts, which
were converted to the corresponding acids 1 by treat-
ment with acidic Dowex 50WX2-200 resin in ethanol/
water (1:1). The acids were sequestered from the crude
mixture with basic Amberlyst A-21 and purified by
repeated washing with THF, then released from the
resin by treatment with 20% aq. formic acid in THF.
The solvent was evaporated and the products analysed
1
by LCMS, and H and 19F NMR spectroscopy. The
crude yields, estimated purities and molecular masses
found are summarised in Table 1.
Alkylation of phenol 2 with geranyl bromide using
cesium carbonate as base gave the sodium salt of the
product 1b following deprotection in good yield (82%).
However, as anticipated, the electron-poor phenoxide
ion was unreactive towards simple alkyl bromides, thus
a more general method was sought. Initial attempts to
alkylate the phenoxide generated on solid-phase with
either weakly basic Amberlite® IRA-68, strongly basic
Amberlite® IRA-900,4 or the polystyrene supported
The results show that for 11 of the 20 alkyl bromides
(7c–m) chosen the desired product was formed with an
isolable yield. In three cases the product (1n–p) was
observed in the LCMS, but the concentration was
judged to be insufficient for further purification. The
failed reactions could be attributed to the presence of a
b-ketone in the alkyl bromide (7p,q,v), poor solubility
(7s,t,v), or reactivity towards the fluoride base (7u). In
six of the cases the product (1c,e,f,i–k) was formed in
>80% purity and 13–46% yield without the need for
further purification. In five cases (1d,g,h,l,m) prepara-
tive TLC purification was required to provide suffi-
ciently pure product, albeit in low yield. Products
(1c–m) were assayed for activity versus farnesyl trans-
ferase and geranylgeranyl transferase I according to
guanidine
base
1,5,7-triazabicyclo[4.4.0]dec-5-ene
(PTBD)5 met with failure.
The use of fluoride as a base for O-alkylation of
phenols, including acidic phenols, e.g. 2-nitrophenol,
has been reported.10–13 Alkylation of phenol (2) was
attempted with a selection of fluoride bases, i.e. CsF,
KF on alumina, Et4NF, n-Bu4NF on alumina. The
optimal conditions were found to be cesium fluoride (5
equiv.) as base, alkyl bromide (7) (3 equiv.), in DMF
with vigorous stirring at 60°C.
A selection of 20 diverse bromoalkanes (7c–v, Fig. 1)
was chosen from a list of commercially available chem-
icals using a 2D dissimilarity clustering program.14
Alkylation of 2 under the optimal conditions with the
majority of bromoalkanes (7c–v) proceeded smoothly
to give the products 8 (Scheme 2). The DMF and
volatile alkyl bromides were removed by evaporation.
Unreacted phenol 2 was removed from the filtered
reaction mixture by sequential treatment with (a) Am-
Scheme 2. Reagents and conditions: (a) i. RBr (7c–v), CsF,
DMF; ii. Amberlyst 15, THF; iii. Amberlyst A-21, THF; (b)
i. aq. NaOH (0.5 M), dioxane; ii. Dowex 50WX2-200, H2O,
EtOH; iii. Amberlyst A-21, THF; iv. 20% formic acid, H2O,
THF.

I. R. Hardcastle et al. / Tetrahedron Letters 42 (2001) 1363–1365
1365
Table 1.
Alkyl bromide (7)
Product (1)
Yield (%)
Purity (%)a
HPLC-ESMS datac calcd/found [M−H]−
c
d
e
c
d
e
31
25
36
46
18
14
13
24
34
2
10
Nd
Nd
Nd
0
82
275/275
330/330
311/311
375/375
267/267
451/451
426/426
297/297
345/345
331/331
297/297
433/433
385/385
370/370
–
94b (60)
87
f
f
97
g
h
i
j
k
l
m
n
o
p
q–v
g
h
i
j
k
l
m
n
o
p
q–v
85b (59)
100b (71)
96
95
98
93b (20)
86b (57)
14
52
49
0
a Analysis by LCMS (C18 reverse phase Supelco Discovery 50×4.6 mm column; gradient elution 90–10% 0.1% aq. formic acid/methanol, 1.0
ml/min for 10 min) by area integration.
b Following purification by preparative TLC.
c Obtained using a Finnigan LCQ ion trap mass spectrometer.
published procedures.15 None of the compounds dis-
played significant activity against the target enzymes.
1997.
2. Moreno Barber, A.; Hardcastle, I. R.; Rowlands, M. G.;
Nutley, B. P.; Marriott, J. H.; Jarman, M. Bioorg. Med.
Chem. Lett. 1999, 9, 623–626.
In conclusion, we have prepared a library of diverse
4-alkoxy-2-hydroxy-3,5,6-trifluorobenzoic acids (1c–m).
The utility of fluoride as a base in alkylation reactions
with poorly nucleophilic phenols has been demon-
strated. Solid-phase reagents have been used through-
out the synthetic route to provide the desired
compounds in a rapid, efficient manner. Biological
evaluation of the library has demonstrated the poor
activity of this group of compounds against the target
enzymes.
3. Furth, P. S.; Reitman, M. S.; Gentles, R.; Cook, A. F.
Tetrahedron Lett. 1997, 38, 6643–6646.
4. Parlow, J. J. Tetrahedron Lett. 1996, 37, 5257–5260.
5. Xu, W.; Mohan, R.; Morrissey, M. M. Tetrahedron Lett.
1997, 38, 7337–7340.
6. Habermann, J.; Ley, S. V.; Scicinski, J. J.; Scott, J. S.;
Smits, R.; Thomas, A. J. Chem. Soc., Perkin Trans. 1
1999, 2425–2427.
7. Habermann, J.; Ley, S. V.; Smits, R. J. Chem. Soc.,
Perkin Trans. 1 1999, 2421–2423.
8. Caldarelli, M.; Habermann, J.; Ley, S. V. J. Chem. Soc.,
Perkin Trans. 1 1999, 107–110.
Acknowledgements
9. Perlmutter, P.; Puniani, E. Tetrahedron Lett. 1996, 37,
3755–3756.
This work was supported by grants from the Cancer
Research Campaign (SP2330/0201) and CRC Technol-
ogy (A.M.B.). We thank Dr. B. Nutley and A. Hayes
for providing LCMS data and Dr. M. G. Rowlands for
enzyme assays.
10. Miller, J. M.; So, K. H.; Clark, J. H. Can. J. Chem. 1979,
57, 1887–1889.
11. Clark, J. H. Chem. Rev. 1980, 80, 429–452.
12. Ando, T.; Yamawaki, J.; Kawate, T.; Sumi, S.; Hana-
fusa, T. Bull. Chem. Soc. Jpn. 1982, 55, 2504–2507.
13. Sato, T.; Otera, J. Synlett 1995, 336–338.
14. ChemX; 1999; Oxford Molecular Ltd.
15. Hardcastle, I. R.; Rowlands, M. G.; Moreno Barber, A.;
Grimshaw, R. M.; Mohan, M.; Nutley, B. P.; Jarman, M.
Biochem. Pharmacol. 1999, 57, 801–809.
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