A novel phase-switching protecting group for multi-step parallel solution phase synthesis

Article abstract of DOI:10.1039/b400110a

A new phase-tag 1 which facilitates the parallel solution phase synthesis of carboxylic acids, esters, and carboxamides is reported. The new phase tag assists compound purification by enabling the selective resin capture of reaction products in either a reversible pH dependent manner (solid-phase extraction), or irreversibly in a Diels-Alder reaction.

Full text of DOI:10.1039/b400110a

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A novel phase-switching protecting group for multi-step parallel
solution phase synthesis
Xin Li,a Chris Abell,b Miles S. Congreve,†a Brian H. Warringtona and Mark Ladlow*a
a GlaxoSmithKline Cambridge Technology Centre, University Chemical Laboratory,
Lensfield Road, Cambridge, UK CB2 1EW. E-mail: Mark.2.Ladlow@gsk.com;
Fax: ϩ44 (0)1223 331532; Tel: ϩ44 (0)1223 336349
b University of Cambridge, University Chemical Laboratory, Lensfield Road, Cambridge,
UK CB2 1EW
Received 7th January 2004, Accepted 28th January 2004
First published as an Advance Article on the web 25th February 2004
A new phase-tag 1 which facilitates the parallel solution phase synthesis of carboxylic acids, esters, and carboxamides
is reported. The new phase tag assists compound purification by enabling the selective resin capture of reaction
products in either a reversible pH dependent manner (solid-phase extraction), or irreversibly in a Diels–Alder
reaction.
Herein, we report the preparation and use of a new
bifunctional anthracenyl-tagged protecting group 1 that aids
the solution phase synthesis and purification of carboxylic
acids, esters and carboxamides (Fig. 1).
Introduction
The high-throughput screening of synthetic compound
libraries has emerged as a key strategy for the identification
of starting points in new medicinal chemistry programs.1 This
has created an increased demand for large numbers of new
compounds. Towards this end, solid-phase synthesis has
enjoyed much success in allowing the high-throughput
synthesis of a wide-range of compound types.2 However, this
approach often suffers from long development times, together
with the inability to adequately monitor chemistries and
separate by-products prior to cleavage from the resin. This
has prompted a re-evaluation of solution phase strategies,
whereby reactions are easily monitored using well-established
techniques.3 Moreover, the introduction of an increasingly wide
variety of polymer-supported reagents and scavenger resins has
greatly facilitated reaction work-up and often allows for the
isolation of the desired products in high purity without the
need for subsequent column chromatography.4
Both of these strategies confine the substrate to either
the solid or solution phase respectively, and relegate other
reactants to the alternative phase. An attractive complementary
approach, which combines the inherent advantages of both
solid- and solution phase methodologies, uses the concept of
‘phase-switching’. Here, the substrate is moved between the
solid and solution phases as required to assist both synthesis
and compound isolation. In practice, this may be achieved by
solid-phase extraction (SPE) or resin ‘capture and release’
protocols, whereby the substrate is temporarily ‘immobilised’
via an activated linkage to a functionalised support.5 This
linkage is subsequently cleaved by introducing a co-reactant
which derivatises and concomitantly releases the modified
substrate back into solution.
Alternatively, where suitable ‘affinity’ groups are not present,
phase-switching during synthesis may be performed by tempor-
arily ‘tagging’ the substrate with a removable soluble ‘phase-
switching’ tag. Several methods including the introduction of
anthracenyl,6 polyaromatic,7 crown ether affinity,8 ionisable,9
precipitation-enabling,10 Cu-ion chelating,11 and fluorous
phase-tags12 have been described to allow substrate, or reagent,
sequestration from solution.
Fig. 1 Tagged protecting groups for resin ‘capture and release’ phase-
switching applications.
The new ‘phase-switching’ protecting group benefits from
several key features. Firstly, the presence of a UV chromo-
phoric anthracenyl moiety both enables convenient substrate
visualisation by UV detection (ε254 = 36000) and facilitates
quantitative reaction monitoring by UV detection at 386 nm
(ε386 = 9000), a region of the UV spectrum that is typically free
from competing absorptions.13 Secondly, in contrast to our
recently reported anthracenyl tagging group 2,14 which under-
goes an effectively irreversible15 ‘phase-switch’ in a Diels–Alder
reaction with polystyrene-supported maleimide, the new
tagging group 1 may alternatively be reversibly attached to a
solid support in an orthogonal manner. This latter process is
achieved by the incorporation of a tertiary amino functionality
which enables pH dependent reversible solid phase extraction
by salt formation with an acidic solid support. This affords
a particularly versatile bifunctional phase-tag. In addition,
† Current address: Astex Technology Ltd, 436 Cambridge Science Park,
Milton Road, Cambridge, UK CB4 0QA.
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 4
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Scheme 1 Reagents and conditions: i. benzyl bromide, K2CO3, DMF, 90 ЊC, 91%; ii. a) dimethylformamide dimethyl acetal, DMF, reflux; b) 10%
aqueous HCl, diethyl ether, reflux, 82%; iii. TFA, 93%; iv. 1,3-propanediol, Amberlyst H-15, CH2Cl2, reflux, 92%; v. iodoacetic acid ethyl ester, DMF,
PS-BEMP, 98%; vi. methylamine, Amberlyst H-15, THF, 98%; vii. a) NaBH4, I2, THF, reflux; b) diethylamine, THF, 55 ЊC, 89%; viii. 3-anthracen-9-
yl-propionyl chloride, PS-DIPEA, CH2Cl2, 93%; ix. NaBH4, Cu(acac)2, CH2Cl2/MeOH/iPrOH, reflux, 89%; x. LiAlH4, THF, 90%.
the incorporation of Fukuyama’s anilino safety-catch
methodology16 to robustly attach the tagging group 1 to the
substrate ensures a high resistance to premature cleavage
during compound synthesis and renders the tagged adduct 3
compatible with a wide variety of chemistries.
Results and discussion
The bifunctional tagged protecting group 1 was prepared start-
ing from 3-methyl-4-nitrophenol 4 which was protected as the
benzyl ether 5 prior to treatment with N,N-dimethylformamide
dimethyl acetal and subsequent de-benzylation to afford the
phenyl acetaldehyde 7 (Scheme 1). This was converted to
the acetal 8 upon exposure to 1,3-propanediol followed by
O-alkylation with ethyl iodoacetate to provide the ester 9. The
ester was converted to the corresponding methyl carboxamide
17
10 and then reduced with NaBH4–I2 to afford the secondary
amine 11 in good yield. The anthracenyl group was then
introduced to give the carboxamide 12. Reduction of the
nitro group proceeded smoothly in the presence of NaBH4–
18
Cu(acac)2 affording the aniline 13 and, finally, exposure of
13 to lithium aluminium hydride in THF gave gram quantities
of the desired tertiary amine phase-tag 1 in 40% overall yield
from 4.
To illustrate the use of 1 in assisting parallel multi-step
solution phase synthesis, we targeted the preparation of a
representative selection of carboxylic acid derivatives display-
ing the well-known biaryl pharmacophoric motif.19 Routinely,
purification of intermediates was performed by a standard
protocol which involved resin capture onto an acidic Isolute
SCX-220 cartridge, followed by a wash step to remove con-
taminants, and then release of the desired substrate by elution
with 2 M methanolic ammonia solution. Importantly, the use
of the acidic SCX-2 support was not observed to give rise to
Fig. 2 Schematic application of bifunctional phase-tags to mediate
both reversible and irreversible phase-switching during solution phase
any by-products associated with premature loss of the acetal
protecting group. However, clearly when both a reagent and the
desired product contain basic functionality, then purification is
not possible simply by SPE with an acidic support. In these
instances, an alternative work-up and purification procedure
was invoked whereby the anthracenyl phase-tag participates in
a Diels–Alder reaction with a polymer-supported maleimide
resin to immobilise the desired tagged substrate and facilitate
its separation from all soluble reagents and impurities (Fig. 2).
The phase tag 1 was first introduced as the anilide of a
representative carboxylic acid. For example, 4-bromobenzoic
acid was derivatised with 1 in the presence of diisopropyl-
synthesis and compound manipulation.
carbodiimide (DIC) and 1-hydroxybenzotriazole (HOBt) to
afford the corresponding carboxamide 3a (Scheme 2) which was
readily purified by the standard SCX ‘capture and release’
protocol previously described, as shown in Fig. 3. Alternatively,
this amidation could also be performed by treating 1 with
4-bromobenzoyl chloride in the presence of polymer-supported
diisopropylamine to afford 3a in 92% yield and >99% purity
according to LC-MS. The nicotinamide 3b was prepared in a
similar way using the DIC/HOBt protocol. In this case, the
introduction of aminomethyl polystyrene resin was necessary
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Fig. 4 Boronic acid set for biaryl couplings.
good yields. Again, all products were isolated with excellent
purities (>91% by LC-MS), following purification by SPE using
SCX-2 cartridges. In a similar way, the nicotinamide 3b
was converted into the biaryl 15d which after SCX-2 SPE
purification was obtained in quantitative yield.
To demonstrate the compatibility of tagged substrates with
the use of polymer-supported reagents, the tagged aldehyde 15c
was subjected to reductive amination with N-methylbenzyl-
amine in the presence of polymer-supported triacetoxyboro-
hydride (PS-BH(OAc)3) to afford the tertiary amine 16.
Removal of excess N-methylbenzylamine was readily achieved
by the introduction of the scavenger resin PS-NCO, which does
not react with the tertiary amine in the tag. Subsequently,
purification by SCX-2 SPE gave the desired amine 16 in 88%
yield and 86% purity according to LC-MS analysis.
At this stage, we turned our attention to the removal of the
phase-tag by nucleophilic displacement. After some experi-
mentation, we found that treatment of the tagged anilide
intermediates 15a, 15b, 15d and 16 with 20% trifluoroacetic acid
in aqueous acetone at 58 ЊC for 6 h reliably led to transacetalis-
ation and cyclisation to form the corresponding N-acyl indoles
17a–d (Table 1). These reactions could be conveniently moni-
tored by HPLC at 386 nm and, following purification by SCX-2
SPE, the desired compounds were all obtained in high yields
(>85%) and purities (>85% by LC-MS). Two complementary
nucleophilic cleavage protocols were then envisaged depending
upon the presence or absence of basic functionality in the
desired product.
For target molecules lacking a basic group, the N-acyl indoles
were treated with an appropriate nucleophile and the cleaved
phase-tag 19 was subsequently captured by SCX-2 SPE, leaving
only the desired product in solution. Thus, 17a was treated with
excess methylamine at ambient temperature to afford the
methylamide 18a, and with methanol in the presence of
4-dimethylaminopyridine (DMAP) to afford the methyl ester
18b. Similarly, treatment of 17b with piperidine gave the
tert-carboxamide 18c. In all of these cases, purification of the
products was readily achieved using the standard SCX-2 SPE
protocol to remove the cleaved phase-tag 19.
Scheme 2 Reagents & conditions: i. a) 4-bromobenzoic acid, DIC,
HOBt, DMF, 84% or 4-bromobenzoyl chloride, PS-DIPEA, DCE,
92%; b) SCX-2 SPE; ii. a) 5-bromonicotinic acid, DIC, HOBt, DMF,
89%; b) PS-NH2; c) SCX-2 SPE, 89%; iii a) 14a–c, Pd(Ph3P)4, Cs2CO3,
DME, 80 ЊC; b) SCX-2 SPE; iv. a) N-methylbenzylamine, PS-
BH(OAc)3, CH2Cl2, rt, 4 h; b) PS-NCO; c) SCX-2 SPE, 88%.
Conversely, when the desired cleavage product contained
basic functionality, it was necessary to first invoke the ortho-
gonal Diels–Alder separation strategy. Thus, the tagged-amines
17c and 17d were heated at reflux with polystyrene-supported
maleimide21 in toluene to afford the immobilised Diels–Alder
adducts 20a and 20b respectively. Under these conditions, no
anthracenyl containing material was left in solution according
to HPLC analysis. The resin 20b was then treated with either
excess methylamine in tetrahydrofuran or aqueous caesium
hydroxide to afford the methylamide 21c and the carboxylic
acid 21d respectively. In principle, further purification of the
products could have been performed by SCX-2 SPE, but this
was not necessary since both compounds were obtained in good
yield and excellent purity.
In a similar way, treatment of the resin 20a with propylamine
in tetrahydrofuran gave the carboxamide 21a in high yield and
purity after simple evaporation, and treatment of 20a with
piperidine at 65 ЊC gave the tert-carboxamide 21b. In this latter
case, removal of traces of residual piperidine from the product
was performed by incubation with PS-NCO scavenger resin. All
the adducts 21a–d were obtained in good yields (62–82%) and
with high purities (>96% according to LC-MS and NMR). The
1H NMR spectrum of a representative analogue 21a is shown in
Fig. 5.
Fig.
3
Purification of tagged intermediate 3a by solid-phase
extraction with an acidic SCX-2 SPE cartridge.
to remove excess 5-bromonicotinic acid prior to ‘catch and
release’ purification with an SCX-2 SPE cartridge.
Next we investigated arylation of the tagged aryl bromide 3a
(Scheme 2). Under typical Suzuki coupling conditions (Pd-
(PPh3)4, Cs2CO3, DME, 80 ЊC), reaction with a series of
boronic acids 14a–c (Fig. 4) all proceeded rapidly in solution
within 0.5 h to afford the corresponding tagged biaryls 15a–c in
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Table 1 Summary of % yields and % HPLC purities for safety-catch activation and nucleophilic cleavage to afford analogues 18a–c and 21a–d
Reagents and conditions: i. a) (1 : 1 : 3) TFA : H2O : Me2CO, 58 ЊC, 6 h, b) SCX-2 SPE; ii. NuH, THF, rtϪ80 ЊC; iii. PS-maleimide, PhMe, 100 ЊC,
16 h; iv. NuH, THF, rtϪ80 ЊC
Starting material
Product
Ar1
Ar2
NuH
Yield (%)a
HPLC purity (%)b
15a
17a
—
96
98
15b
17b
—
100
97
16
17c
17d
—
—
100
86
>99
>99
15d
17c
17d
20a
20b
—
—
Quant.
Quant.
N/A
N/A
17a
17a
17b
18a
18b
18c
MeNH2
MeOH
96
76
75
>99
>99
97
Piperidine
20a
20a
20b
21a
21b
21c
n-PrNH2
Piperidine
MeNH2
82
79
79
98
96
98
20b
21d
H2O, CsOHؒH2O
62
>99
a Isolated yield. b Estimated from HPLC peak areas 220–290 nm.
time under standard conditions (tR) is taken as representative
of lipophilicity,22 it is notable that the biaryl derivatives
compounds 18a–c and 21a–d prepared displayed a wide
range of values (tR = 2.58–5.90 min23). The ability to prepare
such compounds in a single process is an attractive attribute
of this phase-tagging approach. Indeed, the incorporation of
compounds displaying diverse structural and physical char-
acteristics is a desirable objective in preparing compound
libraries for drug discovery applications. We believe that the
present study clearly illustrates the advantages inherent in the
use of bifunctional tagging strategies to facilitate the parallel
solution phase multi-step synthesis of compound arrays. The
additional effort required to introduce the phase-tag in the first
instance is offset by both simplified downstream work-up
procedures, and the ability to obtain reaction products in high
purity without the need for conventional chromatographic
purification.
Conclusions
In summary, we have described the preparation of the novel
bifunctional phase-tag 1, and demonstrated its use to facilitate
the convenient solution phase preparation of carboxylic acids,
esters and carboxamides in good yields and excellent purities,
without the need for conventional column chromatographic
purification. The incorporation of both anthracenyl and tert-
amino functionalities in the phase-tagging group allows for
either irreversible solid-phase capture of the tagged substrate in
a Diels–Alder reaction with PS-maleimide resin, or reversible
‘capture and release’ by an acidic solid-support, such as a
sulfonic acid derivatised silica. The judicious combination of
these orthogonal phase-switching processes allows for great
versatility in product purification and manipulation, and in
particular, is compatible with the incorporation of polar basic
functionalities in reaction products. Where RP-HPLC retention
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128.1 (2C), 127.8, 126.9, 126.9 (2C), 117.7, 111.9, 69.8, and
21.1; LC-MS (ESI): tR = 4.57 min (242.4 [M Ϫ H]Ϫ). HRMS
(ESI): m/z calcd (C14H13NO3Na) 266.0793, found 266.0790
[M ϩ Na]ϩ.
(5-Benzyloxy-2-nitrophenyl)-acetaldehyde (6)
To a solution of benzyl ether 5 (18.7 g, 77.0 mmol) in DMF
(100 ml), was added N,N-dimethylformamide dimethyl acetal
(20 ml, 150 mmol). The resulting mixture was heated at reflux
under nitrogen for 24 h and then concentrated in vacuo. The
residue was dissolved in diethyl ether (100 ml), treated with 10%
aq. HCl (25 ml), and the resulting mixture was heated at reflux
for 2 h. The separated organic layer was washed with saturated
brine, dried (Na2SO4), and concentrated in vacuo until a pre-
cipitate was formed (∼20 ml). After cooling at 4 ЊC for 2 h,
the precipitate was collected by filtration and washed with a
mixture of ethyl acetate and hexane (1 : 1) to give a solid which
was recrystallised from diethyl ether to afford 6 as an off-white
solid (17.2 g, 82%). HPLC: (254 nm): tR = 5.22 min (100%); IR:
νmax/cmϪ1 1724, 1579 and 1334; H NMR (400 MHz, CDCl3):
1
Fig. 5 400 MHz 1H NMR spectrum of 21a.
δ 4.08 (2H, s), 5.14 (2H, s), 6.84 (1H, d, J = 2.8), 6.98 (1H, dd,
J = 2.8 and 9.2), 7.38 (5H, m), 8.20 (1H, d, J = 9.2) and 9.83
(1H, s); 13C NMR (100 MHz, CDCl3): δ 196.1, 162.1, 141.2,
134.7, 130.9, 128.2 (2C), 127.9, 127.5, 126.9 (2C), 118.9, 113.3,
70.1, and 48.4; LC-MS (ESI): tR = 4.20 min (272.3 [M ϩ H]ϩ).
HRMS (ESI): m/z calcd (C15H13NO4Na) 294.0742, found
294.0739 [M ϩ Na]ϩ.
Experimental
All moisture-sensitive reactions were carried out under
a nitrogen atmosphere in oven-dried glassware. All solvents
and reagents were used as supplied unless otherwise stated.
Analytical thin layer chromatography (TLC) was carried
out on Polygram SIL G/UV254 plates. Analytical high
pressure liquid chromatography (HPLC) was performed using a
Hewlett Packard Series 1050 instrument. Column: Supelcosil
ABZϩPLUS 3.3 cm × 4.6 mm, 3 µm. Eluent A: water, 0.1%
TFA, B: acetonitrile 95%, water 5%, TFA 0.05%. Flow rate:
1 cm3 minϪ1. Detection: UV (diode array). Method: gradient
10–95% B in A over 7 min. Infrared spectra were collected on a
Perkin-Elmer Spectrum One ATR FT-IR instrument or by
DRIFTS using a BioRad FT-IR. Liquid chromatography-
mass spectra (LC-MS) were recorded on a Waters Alliance
HT/Micromass ZQ under electrospray positive and negative
ionisation conditions. Column: Supelcosil ABZϩPLUS 3.3 cm
× 4.6 mm, 3 µm. Eluent A: 10 mM solution of ammonium
acetate in water, 0.1% formic acid, B: acetonitrile 95%, water
5%, formic acid 0.05%. Flow rate: 1 mL minϪ1. Detection: UV
(diode array: 215, 230, 254 nm). Method: gradient 0–100% B in
A over 3.5 min. Accurate mass spectra were recorded on a VG
Autospec mass spectrometer in positive electrospray mode.
NMR spectra were recorded in the indicated solvent. Chemical
shifts (δ) are reported in parts per million (ppm) relative to
tetramethylsilane as an internal standard; the following
abbreviations are used for multiplicities: s = singlet; d = doublet;
t = triplet; m = multiplet; dd = doublet of doublets; br = broad;
(5-Hydroxy-2-nitrophenyl)-acetaldehyde (7)
Benzyl ether 6 (7.48 g, 27.6 mmol) was dissolved in trifluoro-
acetic acid (50 ml) and the resulting solution was stirred at
room temperature for 24 h. The reaction mixture was con-
centrated in vacuo, and the residue was purified by column
chromatography to give phenol 7 as white solid (4.67 g, 93%).
HPLC (254 nm): tR = 4.70 min (100%); IR: νmax/cmϪ1 3360,
1719, 1582 and 1324; 1H NMR (400 MHz, CDCl3): δ 4.08 (2H,
s), 6.24 (1H, br), 6.69 (1H, d, J = 2.4), 6.84 (1H, dd, J = 2.4 and
8.8), 8.15 (1H, d, J = 8.8), 9.84 (1H, s); 13C NMR (100 MHz,
CDCl3): δ 198.5, 162.4, 140.0, 132.5, 127.8, 119.7, 114.7, and
48.1; LC-MS (ESI): tR = 3.31 min (180.4 [M Ϫ H]Ϫ); HRMS
(ESI): m/z calcd (C8H7NO4Na) 204.0273, found 204.0265
[M ϩ Na]ϩ.
3-[1,3]Dioxan-2-ylmethyl-4-nitrophenol (8)
To a solution of acetaldehyde 7 (3.19 g, 17.6 mmol) in
anhydrous CH2Cl2 (100 ml) was added 1,3-propanediol (10 ml)
and Amberlyst H-15 resin (500 mg). The resulting suspension
was stirred at room temperature for 16 h then filtered and the
resin thoroughly washed with CH2Cl2 (3 × 15 ml). The com-
bined filtrates were washed with saturated brine, dried (Na2SO4)
and concentrated in vacuo to afford the acetal 8 as an oil (3.87 g,
92%). HPLC (254 nm): tR = 3.81 min (100%); IR: νmax/cmϪ1
3286, 1581 and 1332; 1H NMR (400 MHz, CDCl3): δ 1.33 (1H,
m), 2.08 (1H, m), 3.24 (2H, d, J = 5.2), 3.74 (2H, m), 4.07 (2H,
m), 4.84 (1H, t, J = 5.2), 6.02 (1H, s), 6.77 (1H, dd, J = 2.8 and
8.8), 6.80 (1H, d, J = 2.8), 7.98 (1H, d, J = 8.8); 13C NMR (100
MHz, CDCl3): δ 158.8, 142.0, 133.9, 127.1, 119.6, 113.8, 100.3,
66.3 (2C), 38.9, and 25.0; LC-MS (ESI): tR = 3.56 min (240.3
[M ϩ H]ϩ). HRMS (ESI): m/z calcd (C11H13NO5Na) 262.0691,
found 262.0678 [M ϩ Na]ϩ.
1
and coupling constant J-values are quoted in Hz. H NMR
spectra were recorded on a Bruker AM 400 spectrometer at
400 MHz. 13C NMR spectra were recorded on a Bruker AM
400 at 100 MHz with proton decoupling.
4-Benzyloxy-2-methyl-1-nitrobenzene (5)
To a solution of 3-methyl-4-nitro-phenol 4 (16.8 g, 110 mmol)
in anhydrous DMF (100 ml), was added anhydrous potassium
carbonate (15.0 g, 152 mmol) and benzyl bromide (12.0 ml, 100
mmol). The resulting suspension was stirred at 90 ЊC for 2 h
then concentrated in vacuo, and the residue diluted with 2 M aq.
NaOH (200 ml). The mixture was extracted with ethyl acetate
(3 × 150 ml) and the combined organic extracts were dried
(Na2SO4) and concentrated in vacuo to afford 5 as a yellow solid
(22.2 g, 91% yield). HPLC: (254 nm): tR = 6.03 min (100%); IR:
(3-[1,3]Dioxan-2-ylmethyl-4-nitrophenoxy)-acetic acid ethyl
ester (9)
To a solution of phenol 8 (3.00 g, 12.6 mmol) in DMF (100 ml),
was added anhydrous potassium carbonate (5.00 g, 36.2 mmol)
and ethyl iodoacetate (3.00 ml, 25.3 mmol). The resulting
suspension was stirred at 90 ЊC for 2 h, then concentrated
in vacuo, and the residue partitioned between 2 M aq. NaOH
1
νmax/cmϪ1 1578 and 1333; H NMR (400 MHz, CDCl3): δ 2.62
(3H, s), 5.12 (2H, s), 6.86 (2H, m), 7.38 (5H, m), 8.07 (1H, d, J =
9.6); 13C NMR (100 MHz, CDCl3): δ 161.5, 141.6, 136.5, 135.0,
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(50 ml) and diethyl ether (50 ml). The organic layer was
separated, washed with saturated brine, and dried (Na2SO4).
The solvent was evaporated in vacuo, and the residue was
purified by column chromatography eluting with a mixture of
ethyl acetate and hexane (1 : 4) to afford the ethyl ester 9 as light
yellow solid (4.00 g, 98%). HPLC (254 nm): tR = 4.68 min
(100%); IR: νmax/cmϪ1 1755, 1581 and 1339; 1H NMR
(400 MHz, CDCl3): δ 1.31 (4H, m), 2.05 (1H, m), 3.22 (2H, d,
J = 5.2), 3.70 (2H, m), 4.04 (2H, m), 4.27 (2H, q, J = 7.2), 4.67
(2H, s), 4.78 (1H, t, J = 5.2), 6.82 (1H, dd, J = 2.8 and 9.2), 6.88
(1H, d, J = 2.8), 7.98 (1H, d, J = 9.2); 13C NMR (100 MHz,
CDCl3): δ 167.2, 159.9, 142.9, 133.8, 126.5, 118.7, 112.6, 100.0,
66.2 (2C), 64.7, 61.0, 38.8, 25.0, and 13.5; LC-MS (ESI):
tR = 3.94 min (326.3 [M ϩ H]ϩ); HRMS (ESI): m/z calcd
(C15H19NO7Na) 348.1059, found 348.1046 [M ϩ Na]ϩ.
tion of 2 M oxalyl chloride in CH2Cl2 (10 ml) with ice–water
bath cooling. The resulting suspension was warmed to ambient
temperature, and heated at reflux for 2 h. The reaction mixture
was concentrated in vacuo to dryness and the residue was re-
dissolved in CH2Cl2 (50 ml). The resulting solution was treated
with triethylamine (5 ml), and then a solution of amine 11 (1.03
g, 3.48 mmol) in CH2Cl2 (5 ml) was added. The mixture was
stirred at room temperature for 2 h and then concentrated
in vacuo. The residue was diluted with saturated brine (50 ml)
and extracted with ethyl acetate (3 × 50 ml). The combined
organic extracts were dried (Na2SO4), concentrated in vacuo,
and the residue was purified by column chromatography eluting
with a mixture of ethyl acetate and hexane (2 : 1) to give the
carboxamide 12 (1.72 g, 93%). HPLC (254 nm): tR = 6.28 min
(100%); IR: νmax/cmϪ1 1640, 1579 and 1335; 1H NMR (400
MHz, DMSO, 140 ЊC): δ 1.27 (1H, m), 1.85 (1H, m), 2.79 (2H,
t, J = 7.8), 2.89 (3H, s), 3.13 (2H, d, J = 5.0), 3.63 (4H, m), 3.92
(4H, m), 4.15 (2H, t, J = 5.7), 4.71 (1H, t, J = 5.0), 6.89 (2H, m),
7.49 (4H, m), 7.84 (1H, d, J = 8.9), 8.03 (2H, d, J = 8.0), 8.29
(2H, d, J = 8.6), 8.41 (1H, s); 13C NMR (100 MHz, CDCl3): δ
172.0, 161.5, 143.7, 134.1, 133.9, 131.7 (2C), 129.6 (2C), 129.2
(2C), 126.8, 126.0, 125.9 (2C), 125.1 (2C), 124.4 (2C), 119.3,
113.6, 100.7, 66.8, 66.4 (2C), 40.2 (2C), 38.3, 34.1, 25.5 and
23.3; LC-MS (ESI): tR = 4.68 min (529.4 [M ϩ H]ϩ); HRMS
(ESI): m/z calcd (C31H32N2O6Na) 551.2158, found 551.2145
[M ϩ Na]ϩ.
2-(3-[1,3]Dioxan-2-ylmethyl-4-nitrophenoxy)-N-methyl-
acetamide (10)
The ethyl ester 9 (2.88 g, 8.86 mmol) was dissolved in a solution
of methylamine in THF (1 M × 75 ml) and the resulting solu-
tion was treated with Amberlyst H-15 resin (100 mg) at room
temperature for 24 h. The reaction mixture was filtered and
the resin was thoroughly washed with THF (3 × 20 ml). The
combined organic filtrates were concentrated in vacuo and
the residue was recrystallised from ethyl acetate to give the
carboxamide 10 as a yellow solid (2.70 g, 98%). HPLC (254
nm): tR = 3.47 min (100%); IR: νmax/cmϪ1 3332, 1669, 1581 and
N-[2-(4-Amino-3-[1,3]dioxan-2-ylmethyl-phenoxy)-ethyl]-3-
anthracen-9-yl-N-methyl-propionamide (13)
1
1338; H NMR (400 MHz, CDCl3): δ 1.32 (1H, m), 2.05 (1H,
m), 2.91 (3H, d, J = 4.8), 3.24 (2H, d, J = 5.0), 3.71 (2H, m), 4.05
(2H, m), 4.54 (2H, s), 4.80 (1H, t, J = 5.0), 6.49 (1H, brs), 6.85
(1H, dd, J = 2.8 and 9.2), 6.93 (1H, d, J = 2.8), 8.00 (1H, d,
J = 9.2); 13C NMR (100 MHz, CDCl3): δ 166.8, 159.1, 143.3,
134.0, 126.7, 119.0, 112.4, 99.9, 66.8, 66.3 (2C), 38.7, 25.2, and
25.0; LC-MS (ESI): tR = 3.31 min (311.3 [M ϩ H]ϩ); HRMS
(ESI): m/z calcd (C14H18N2O6Na) 333.1063, found 333.1077
[M ϩ Na]ϩ.
To a solution of the nitrobenzene 12 (1.45 g, 2.75 mmol) in a
mixture of CH2Cl2 and isopropanol (50 ml/5 ml) was added
copper acetylacetonate (0.72 g, 2.75 mmol) and NaBH4(0.32 g,
8.25 mmol) with ice–water bath cooling. The resulting mixture
was stirred at room temperature for 5 min, then methanol (5 ml)
was slowly added and the mixture was heated at reflux for
30 min. The reaction was quenched by slowly adding water
(∼5 ml). When gas evolution ceased, the mixture was filtered
through a Celite pad. The filtrate was concentrated in vacuo
and the residue was diluted with saturated brine (50 ml) and
extracted with ethyl acetate (3 × 50 ml). The combined, dried
(Na2SO4) organic extracts were concentrated in vacuo and the
crude product was loaded onto a pre-washed SCX-2 cartridge.
The cartridge was thoroughly washed with methanol, and then
with 2 M ammonia in methanol. The eluate was concentrated in
vacuo to give the amine 13 as yellow solid (1.21 g, 89%). HPLC
(254 nm): tR = 4.21 min (100%); IR: νmax/cmϪ1 3417, 3346 and
[2-(3-[1,3]Dioxan-2-ylmethyl-4-nitrophenoxy)-ethyl]-methyl-
amine (11)
To a suspension of amide 10 (1.50 g, 4.80 mmol) and NaBH4
(0.60 g, 15.9 mmol) in anhydrous THF (30 ml), was slowly
added (30 min) a solution of iodine (1.22 g, 4.80 mmol) in THF
(10 ml) with ice–water bath cooling. The resulting suspension
was heated at reflux for 4 h, then cooled to 0 ЊC and quenched
by carefully adding 10% aqueous HCl solution. When gas
evolution ceased, the mixture was neutralised using 2 M aq.
NaOH and extracted with diethyl ether (3 × 50 ml). The com-
bined organic extracts were washed with saturated brine, dried
(Na2SO4), and the solvent was evaporated in vacuo. The residue
was dissolved in anhydrous THF (50 ml), and the resulting
solution was treated with diethylamine (5 ml) at 55 ЊC for 2 h to
liberate the free amine. The reaction mixture was evaporated in
vacuo and the residue was purified by SCX-2 SPE to give the
1
1634; H NMR (400 MHz, DMSO, 120 ЊC): δ 1.29 (1H, m),
1.89 (1H, m), 2.65 (2H, d, J = 5.0), 2.78 (2H, t, J = 7.9), 2.89
(3H, s), 3.54 (2H, t, J = 5.5), 3.66 (2H, m), 3.94 (6H, m), 4.11
(2H, brs), 4.68 (1H, t, J = 5.0), 6.54 (3, m), 7.48 (4H, m), 8.02
(2H, d, J = 8.0), 8.28 (2H, d, J = 8.6), 8.42 (1H, s); 13C NMR
(100 MHz, CDCl3): δ 172.2, 151.0, 141.2, 134.4, 131.9 (2C),
129.9 (2C), 129.4 (2C), 126.2 (2C), 126.1, 125.3 (2C), 124.6
(2C), 123.1, 118.6, 116.9, 114.5, 102.2, 67.1, 66.6 (2C), 40.2
(2C), 37.9, 34.4, 25.8 and 23.7; LC-MS (ESI): tR = 4.04 min
(499.4 [M ϩ H]ϩ); HRMS (ESI): m/z calcd (C31H34N2O4Na)
521.2416, found 521.2403 [M ϩ Na]ϩ.
amine 11 as yellow solid (1.27 g, 89%). HPLC: (254 nm): tR
=
2.43 min (100%); IR: νmax/cmϪ1 1579 and 1336; H NMR (400
MHz, CDCl3): δ 1.30 (1H, m), 1.60 (1H, brs), 2.05 (1H, m), 2.50
(3H, s), 2.98 (2H, t, J = 5.2), 3.24 (2H, d, J = 5.2), 3.71 (2H, m),
4.06 (2H, m), 4.12 (2H, t, J = 5.2), 4.79 (1H, t, J = 5.2), 6.82 (1H,
dd, J = 2.8 and 9.2), 6.87 (1H, d, J = 2.8), 7.99 (1H, d, J = 9.2);
13C NMR (100 MHz, CDCl3): δ 161.3, 142.1, 133.8, 126.8,
118.6, 112.4, 100.1, 67.2, 66.3 (2C), 49.8, 39.0, 35.7, and 25.0;
LC-MS (ESI): tR = 2.65 min (297.3 [M ϩ H]ϩ); HRMS: (ESI):
m/z calcd (C14H21N2O5) 297.1450, found 297.1451 [M ϩ H]ϩ.
1
4-{2-[(3-Anthracen-9-yl-propyl)-methylamino]-ethoxy}-2-[1,3]-
dioxan-2-ylmethyl-phenylamine (1)
To a solution of the amide 13 (1.16 g, 2.33 mmol) in THF (50
ml), was added a solution of LiAlH4 in diethyl ether (1 M × 7.5
ml, 7.50 mmol) with ice–water bath cooling. The resulting
suspension was stirred at room temperature for 16 h, then the
reaction was quenched by carefully adding methanol (∼10 ml).
When gas evolution ceased, the mixture was washed with water
(100 ml) and the organic layer was separated. The aqueous layer
was extracted with diethyl ether (3 × 50 ml) and the combined
organic extracts were dried (Na2SO4). The solvent was evapor-
3-Anthracen-9-yl-N-[2-(3-[1,3]dioxan-2-ylmethyl-4-nitro-
phenoxy)-ethyl]-N-methyl-propionamide (12)
To a suspension of 3-anthracen-9-yl-propionic acid (1.18 g,
4.70 mmol) in anhydrous CH2Cl2 (100 ml), was added a solu-
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 9 8 9 – 9 9 8
994

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ated in vacuo and the residue was purified by column chromato-
graphy eluting with a mixture of methanol and CH2Cl2 (1 : 15)
to give the phase-tag 1 (1.02 g, 90%) as an oil. HPLC (254 nm):
(1H, d, J = 2.8), 6.89 (1H, dd, J = 2.8 and 8.8), 7.47 (4H, m),
7.87 (1H, d, J = 8.8), 7.99 (2H, d, J = 8.4), 8.32 (3H, m), 8.40
(1H, s), 8.81 (1H, s), 9.04 (1H, s), 9.44 (1H, s); 13C NMR (100
MHz, CDCl3): δ 161.0, 155.5, 152.5, 145.7, 137.2 (2C), 134.3,
131.5, 131.0 (2C), 129.0 (2C), 128.7, 128.5 (2C), 125.0, 124.8
(2C), 124.4, 124.2 (2C), 123.8 (2C), 120.3, 117.4, 112.6, 102.5,
66.5 (2C), 65.8, 57.4, 55.5, 42.2, 38.2, 28.3, 24.9, 24.8; LC-MS
(ESI): tR = 3.74 min (670.4 [M ϩ H]ϩ); HRMS (ESI): m/z calcd
(C37H39N3O4Br) 668.2124, found 668.2104 [M ϩ H]ϩ.
1
tR = 3.47 min (100%); IR: νmax/cmϪ1 3425, 3347 and 1623; H
NMR (400 MHz, CDCl3): δ 1.29 (1H, m), 2.03 (3H, m), 2.38
(3H, s), 2.69 (2H, t, J = 7.0), 2.81 (4H, m), 3.69 (4H, m), 4.07
(4H, m), 4.67 (1H, t, J = 5.2), 6.60 (1H, d, J = 8.4), 6.69 (2H, m),
7.47 (4H, m), 7.99 (2H, d, J = 8.2), 8.32 (3H, m); 13C NMR (100
MHz, CDCl3): δ 151.2, 139.2, 134.3, 131.0 (2C), 129.0 (2C),
128.5 (2C), 125.0, 124.8 (2C), 124.1 (2C), 123.9 (2C), 122.9,
117.5, 116.5, 113.3, 102.7, 66.2 (2C), 66.1, 57.5, 55.7, 42.2, 37.7,
28.2, 24.9 (2C); LC-MS (ESI): tR = 3.31 min (485.4 [M ϩ H]ϩ);
HRMS (ESI): m/z calcd (C31H37N2O3) 485.2804, found
485.2813 [M ϩ H]ϩ.
General Suzuki coupling procedure
A solution of the tagged bromide 3a or 3b (approx. 0.10 mmol)
in DME (1 ml) was added to a reaction tube containing a
suspension of Cs2CO3 (8 eq.), Pd(PPh3)4 (0.1 eq.) and a boronic
acid 14a–c (2 eq.) in DME (3 ml) and water (1 ml). The
resulting mixtures were stirred at 80 ЊC for 0.5 h, then diluted
with saturated brine and extracted with ethyl acetate (3 × 3 ml).
The combined organic extracts were loaded onto a pre-washed
SCX-2 cartridge and the cartridge was thoroughly washed with
methanol. Elution with 2 M ammonia in methanol gave the
biaryls 15a (84%), 15b (59%), 15c (100%) and 15d (98%).
N-(4-{2-[(3-Anthracen-9-yl-propyl)-methylamino]-ethoxy}-2-
[1,3]dioxan-2-ylmethyl-phenyl)-4-bromobenzamide (3a)
Method A: To a suspension of 4-bromobenzoyl chloride (439
mg, 2.00 mmol) and PS-DIPEA (2.00 g, 3.83 mmol gϪ1) in 1,2-
dichloroethane (DCE; 16 ml), was added a solution of the
phase-tag 1 (484 mg, 1.00 mmol) in DCE (4 ml). The resulting
mixture was stirred at room temperature for 30 min, then
filtered and the resin washed with CH2Cl2 (3 × 3 ml). The
combined organic extracts were evaporated, and the residue
was loaded onto an SCX-2 cartridge. The cartridge was
thoroughly washed with methanol, and finally with 2 M
ammonia solution in methanol to release the carboxamide 3a
which was isolated as a yellow solid (614 mg, 92%).
2Ј-Fluoro-biphenyl-4-carboxylic acid N-(4-{2-[(3-anthracen-9-yl-
propyl)-methylamino]-ethoxy}-2-[1,3]dioxan-2-ylmethyl-phenyl)-
amide (15a)
Mp 92–93 ЊC; HPLC (254 nm): tR = 5.44 min (98%); IR: νmax
/
cmϪ1 3345 and 1664; 1H NMR (400 MHz, CDCl3): δ 1.37 (1H,
m), 2.02 (2H, m), 2.12 (1H, m), 2.40 (3H, s), 2.70 (2H, t, J =7.2),
2.86 (2H, t, J = 5.8), 2.95 (2H, d, J = 4.8), 3.68 (2H, t, J = 8.0),
3.77 (2H, m), 4.13 (4H, m), 4.74 (1H, t, J = 4.8), 6.81 (1H, d, J =
2.8), 6.90 (1H, dd, J = 2.8 and 8.8), 7.19 (1H, m), 7.25 (1H, m),
7.37 (1H, m), 7.47 (5H, m), 7.67 (2H, d, J = 8.2), 7.93 (1H, d, J =
8.8), 8.01 (4H, m), 8.32 (3H, m), 9.50 (1H, s); 13C NMR (100
MHz, CDCl3): δ 164.2, 159.1 (1C, d, 1JC,F = 246.8), 155.1, 138.3,
134.3, 133.7, 131.0 (2C), 130.0, 129.7, 129.0 (3C), 128.7, 128.5
(4C), 127.4, 126.6 (2C), 125.0, 124.8 (2C), 124.6, 124.2 (2C),
123.9 (3C), 117.2, 115.6 (1C, d, 2JC,F = 22.3), 112.5, 102.6, 66.4
(2C), 65.8, 57.5, 55.6, 42.2, 38.1, 28.2 and 24.9 (2C); LC-MS
(ESI): tR = 4.07 min (683.4 [M ϩ H]ϩ); HRMS (ESI): m/z calcd
(C44H44N2O4F) 683.3285, found 683.3281 [M ϩ H]ϩ.
Method B: To a solution of 4-bromobenzoic acid (80 mg,
0.40 mmol) and HOBt (20 mg, 0.15 mmol) in DMF (2 ml), was
added DIC (100 µl, 0.64 mmol). After 15 min, a solution of the
phase-tag 1 (400 µl × 0.25 M, 0.10 mmol) in DMF (1 ml)
was added and the resulting mixture was stirred at room tem-
perature for 2 h before loading onto an SCX-2 SPE cartridge.
This was eluted as in method A to afford the carboxamide 3a as
yellow solid (56.1 mg, 84%). Mp: 89–90 ЊC; HPLC (254 nm):
1
tR = 5.29 min (94%); IR: νmax/cmϪ1 3344 and 1668; H NMR
(400 MHz, CDCl3): δ 1.37 (1H, m), 2.04 (3H, m), 2.39 (3H, s),
2.69 (2H, t, J = 7.2), 2.84 (2H, t, J = 5.8), 2.91 (2H, d, J = 4.8),
3.67 (2H, t, J = 8.0), 3.76 (2H, m), 4.11 (4H, m), 4.71 (1H, t, J =
4.8), 6.79 (1H, d, J = 2.8), 6.88 (1H, dd, J = 2.8 and 8.8), 7.47
(4H, m), 7.61 (2H, d, J = 8.8), 7.80 (2H, d, J = 8.4), 7.88 (1H, d,
J = 8.8), 7.99 (2H, d, J = 8.4), 8.32 (3H, m), 9.43 (1H, s); 13C
NMR (100 MHz, CDCl3): δ 163.6, 155.2, 134.3, 133.5, 131.1
(2C), 131.0 (2C), 129.5, 129.0 (2C), 128.7, 128.5 (2C), 128.1
(2C), 125.4, 125.0, 124.8 (2C), 124.5, 124.2 (2C), 123.8 (2C),
117.3, 112.5, 102.6, 66.4 (2C), 65.8, 57.5, 55.6, 42.2, 38.1, 28.2,
24.9 (2C); LC-MS (ESI): tR = 3.93 min (669.3 [M ϩ H]ϩ);
HRMS (ESI): m/z calcd (C38H40N2O4Br) 667.2171, found
667.2166 [M ϩ H]ϩ.
N-(4-{2-[(3-Anthracen-9-yl-propyl)-methylamino]-ethoxy}-2-
[1,3]dioxan-2-ylmethyl-phenyl)-4-thiophen-2-yl-benzamide (15b)
Mp 79–80 ЊC; HPLC (386 nm): tR = 5.55 min (91%); IR: νmax
/
cmϪ1 3345 and 1663; 1H NMR (400 MHz, CDCl3): δ 1.38
(1H, m), 2.02 (2H, m), 2.14 (1H, m), 2.40 (3H, s), 2.69 (2H, t,
J = 7.2), 2.85 (2H, t, J = 5.8), 2.93 (2H, d, J = 4.4), 3.67 (2H, t,
J = 7.8), 3.77 (2H, m), 4.13 (4H, m), 4.74 (1H, t, J = 4.4),
6.80 (1H, d, J = 2.8), 6.89 (1H, dd, J = 2.8 and 9.0), 7.11 (1H,
dd, J = 3.6 and 5.0), 7.34 (1H, dd, J = 0.8 and 5.0), 7.41 (1H, dd,
J = 0.8 and 3.6), 7.47 (4H, m), 7.71 (2H, d, J = 8.4), 7.98 (5H,
m), 8.33 (3H, m), 9.46 (1H, s); 13C NMR (100 MHz, CDCl3):
δ 164.0, 155.1, 142.6, 136.7, 134.2, 133.2, 131.0 (2C), 129.8,
129.0 (2C), 128.7, 128.5 (2C), 127.6, 127.2 (2C), 125.3, 125.1
(2C), 125.0, 124.8 (2C), 124.6, 124.2 (2C), 123.8 (2C), 123.5,
117.2, 112.5, 102.6, 66.4 (2C), 65.6, 57.4, 55.5, 42.1, 38.1, 28.1,
24.9 (2C); LC-MS (ESI): tR = 4.01 min (671.5 [M ϩ H]ϩ);
HRMS (ESI): m/z calcd (C42H43N2O4S) 671.2943, found
671.2951 [M ϩ H]ϩ.
N-(4-{2-[(3-Anthracen-9-yl-propyl)-methylamino]-ethoxy}-2-
[1,3]dioxan-2-ylmethyl-phenyl)-5-bromonicotinamide (3b)
To a solution of 5-bromonicotinyl acid (81 mg, 0.40 mmol) and
HOBt (20 mg, 0.15 mmol) in DMF (2 ml), was added DIC
(100 µl, 0.64 mmol). After 15 min, a solution of aniline 1 (400 µl
× 0.25 M 0.10 mmol) in DMF (1 ml) was added followed, after
2 h, by aminomethyl polystyrene resin (200 mg, 4.5 mmol gϪ1
,
0.90 mmol). The suspension was agitated for 16 h, then filtered
and the resin washed with CH2Cl2 (3 × 3 ml). The combined
organic filtrates were loaded onto a pre-washed SCX-2 cart-
ridge and the cartridge was thoroughly washed with methanol.
Elution with 2 M ammonia in methanol afforded the nicotin-
amide 3b which was isolated as a yellow solid (59 mg, 89%).
Mp 159–160 ЊC; HPLC (254 nm): tR = 4.79 min (>99%); IR:
4Ј-Formyl-biphenyl-4-carboxylic acid N-(4-{2-[(3-anthracen-9-
yl-propyl)-methylamino]-ethoxy}-2-[1,3]dioxan-2-ylmethyl-
phenyl)amide (15c)
Mp 60–61 ЊC; HPLC (386 nm): tR = 5.22 min (92%); IR: νmax
/
1
νmax/cmϪ1 3335 and 1675; H NMR (400 MHz, CDCl3): δ 1.39
cmϪ1 3339, 1700 and 1670. 1H NMR (400 MHz, CDCl3): δ 1.39
(1H, m), 2.02 (2H, m), 2.13 (1H, m), 2.40 (3H, s), 2.70 (2H, t,
J = 7.0), 2.86 (2H, t, J = 5.8), 2.94 (2H, d, J = 4.8), 3.67 (2H, t,
J = 8.0), 3.78 (2H, m), 4.14 (4H, m), 4.74 (1H, t, J = 4.8), 6.80
(1H, m), 2.02 (2H, m), 2.16 (1H, m), 2.39 (3H, s), 2.69 (2H, t,
J = 7.0), 2.84 (2H, t, J = 5.8), 2.92 (2H, d, J = 4.8), 3.67 (2H, t,
J = 8.0), 3.77 (2H, m), 4.14 (4H, m), 4.74 (1H, t, J = 4.8), 6.80
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 9 8 9 – 9 9 8
995

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(1H, d, J = 2.8), 6.90 (1H, dd, J = 2.8 and 9.0), 7.47 (4H, m),
7.74 (2H, d, J = 8.4), 7.80 (2H, d, J = 8.0), 7.93 (1H, d, J = 9.2),
7.99 (4H, m), 8.06 (2H, d, J = 8.0), 8.32 (3H, m), 9.50 (1H, s),
10.09 (1H, s); 13C NMR (100 MHz, CDCl3): δ 191.1, 185.4,
164.0, 155.2, 145.4, 142.0, 135.0, 134.4, 134.3, 131.0 (2C), 129.7
(2C), 129.0 (2C), 128.7, 128.5 (2C), 127.23 (2C), 127.18 (2C),
126.9 (2C), 125.0, 124.8 (2C), 124.6, 124.2 (2C), 123.9 (2C),
117.3, 112.5, 102.6, 66.6 (2C), 65.8, 57.5, 55.6, 42.2, 38.1, 28.2,
24.9 (2C); LC-MS (ESI): tR = 3.96 min (693.5 [M ϩ H]ϩ);
HRMS (ESI): m/z calcd (C45H45N2O5) 693.3328, found
693.3348 [M ϩ H]ϩ.
treated with a mixture of TFA, acetone and water (1 : 3 : 1, ∼40
µmol mlϪ1) at 58 ЊC for 6 h. The reaction mixtures were evap-
orated in vacuo and the residues loaded onto pre-washed SCX-2
cartridges. The cartridges were thoroughly washed with ethyl
acetate, and then eluted with a mixture of triethylamine and
ethyl acetate (1 : 1) to afford the indoles 17a (70 mg, 96%), 17b
(50 mg, 100%), 17c (92 mg, 100%), and 17d (114 mg, 86%)
respectively.
(5-{2-[(3-Anthracen-9-yl-propyl)-methylamino]-ethoxy}-indol-1-
yl)-(2Ј-fluorobiphenyl-4-yl)-methanone (17a)
HPLC (220–290 nm): tR = 5.88 min (98%); IR: νmax/cmϪ1 1678;
1H NMR (400 MHz, CDCl3): δ 2.04 (2H, m), 2.42 (3H, s), 2.72
(2H, t, J = 7.0), 2.90 (2H, t, J = 5.9), 3.68 (2H, t, J = 8.0), 4.19
(2H, d, J = 5.9), 6.54 (1H, d, J = 3.8), 7.02 (1H, dd, J = 2.8 and
9.0), 7.09 (1H, d, J = 2.8), 7.23 (2H, m), 7.32 (1H d, J = 3.8),
7.38 (1H, m), 7.47 (5H, m), 7.70 (2H, d, J = 8.0), 7.80 (2H, d,
J = 8.0), 7.99 (2H, d, J = 8.0), 8.33 (4H, m); 13C NMR (100
MHz, CDCl3): δ 167.4, 159.1 (1C, d, 1JC,F = 246.9), 155.4, 138.7,
134.3, 133.0, 131.1, 131.0 (2C), 130.1, 130.0, 129.3 (1C, d, 4JC,F
= 8.0), 129.0 (2C), 128.7 (2C), 128.5 (4C), 127.6 (2C), 127.1 (1C,
N-(4-{2-[(3-Anthracen-9-yl-propyl)-methylamino]-ethoxy}-2-
[1,3]dioxan-2-ylmethyl-phenyl)-5-(2-fluorophenyl)-nicotinamide
(15d)
Mp 104–105 ЊC; HPLC (254 nm): tR = 4.89 min (>99%); IR:
1
νmax/cmϪ1 3336 and 1672; H NMR (400 MHz, CDCl3): δ 1.33
(1H, m), 2.05 (3H, m), 2.40 (3H, s), 2.69 (2H, t, J = 7.0), 2.85
(2H, t, J = 5.8), 2.94 (2H, d, J = 4.8), 3.67 (2H, t, J = 8.0), 3.75
(2H, m), 4.12 (4H, m), 4.73 (1H, t, J = 4.8), 6.81 (1H, d, J = 2.8),
6.90 (1H, dd, J = 2.8 and 9.0), 7.25 (2H, m), 7.46 (6H, m), 7.90
(1H, d, J = 8.8), 7.99 (2H, d, J = 8.2), 8.32 (3H, m), 8.43 (1H, s),
8.93 (1H, s), 9.14 (1H, s), 9.62 (1H, s); 13C NMR (100 MHz,
CDCl3): δ 162.4, 159.2 (1C, d, 1JC,F = 247.6), 155.4, 151.3, 146.6,
134.7, 134.3, 131.0, 130.98 (2C), 129.99, 129.92, 129.86, 129.77,
129.2, 128.99 (2C), 128.88, 128.5 (2C), 124.98, 124.80 (2C),
124.6, 124.2 (3C), 123.9 (2C), 117.3, 115.7 (1C, d, 2JC,F = 22.0),
112.6, 102.6, 66.5 (2C), 65.8, 57.5, 55.6, 42.2, 38.1, 28.3, 24.9
and 24.7; LC-MS (ESI): tR = 3.88 min (684.5 [M ϩ H]ϩ);
HRMS (ESI): m/z calcd (C43H43N3O4F) 684.3237, found
684.3223 [M ϩ H]ϩ.
2
d, JC,F = 13.1), 125.0, 124.8 (2C), 124.2 (2C), 123.9, 123.8,
116.6, 115.7 (1C, d, 2JC,F = 22.4), 113.4, 108.0, 104.0, 66.1, 57.5,
55.6, 42.3, 28.2 and 24.9; LC-MS (ESI): tR = 4.28 min (607.5
[M ϩ H]ϩ); HRMS (ESI): m/z calcd (C41H36N2O2F) 607.2761,
found 607.2763 [M ϩ H]ϩ.
(5-{2-[(3-Anthracen-9-yl-propyl)-methylamino]-ethoxy}-indol-1-
yl)-(4-thiophen-2-yl-phenyl)-methanone (17b)
HPLC (220–290 nm): tR = 5.87 min (97%); IR: νmax/cmϪ1 1677;
1H NMR (400 MHz, CDCl3): δ 2.03 (2H, m), 2.42 (3H, s), 2.72
(2H, t, J = 7.0), 2.89 (2H, t, J = 5.9), 3.68 (2H, t, J = 8.0), 4.18
(2H, d, J = 5.9), 6.53 (1H, d, J = 3.6), 7.01 (1H, dd, J = 2.6 and
8.8), 7.08 (1H, d, J = 2.8), 7.13 (1H, dd, J = 3.6 and 5.0), 7.30
(1H, d, J = 3.6), 7.38 (1H, dd, J = 0.8 and 5.0), 7.47 (5H, m),
7.74 (4H, s), 7.99 (2H, d, J = 8.0), 8.29 (1H, d, J = 8.8), 8.33 (3H,
m); 13C NMR (100 MHz, CDCl3): δ 167.2, 155.3, 142.1, 137.1,
134.2, 132.4, 131.1, 131.0 (2C), 130.1, 129.4 (2C), 129.0 (2C),
128.5 (2C), 127.7, 127.5, 125.7, 125.0 (3C), 124.8 (2C), 124.2
(2C), 123.8 (3C), 116.5, 113.4, 107.9, 104.0, 66.1, 57.5, 55.6,
42.3, 28.2 and 24.9; LC-MS (ESI): tR = 4.32 min (595.5 [M ϩ
H]ϩ); HRMS (ESI): m/z calcd (C39H35N2O2S) 595.2419, found
595.2418 [M ϩ H]ϩ.
4Ј-[(Benzyl-methylamino)-methyl]-biphenyl-4-carboxylic acid
N-(4-{2-[(3-anthracen-9-yl-propyl)-methylamino]-ethoxy}-2-
[1,3]dioxan-2-ylmethyl-phenyl)amide (16)
To a solution of aldehyde 15c (83.5 mg, 0.12 mmol) in
anhydrous CH2Cl2 (5 ml), was added N-benzylmethylamine
(47 µl, 0.36 mmol). The mixture was stirred at room temper-
ature for 1 h when PS-BH(OAc)3 (300 mg, 2.1 mmol gϪ1, 0.63
mmol) was added. The resulting suspension was shaken at
room temperature for 3 h, then filtered and the resin washed
with CH2Cl2 (3 × 3 ml). The combined filtrates were treated
with PS-isocyanate resin (500 mg, 1.6 mmol gϪ1, 0.80 mmol) for
16 h, then filtered and the resin washed with CH2Cl2 (3 × 3 ml).
The combined filtrates were loaded onto a pre-washed SCX-2
cartridge. The cartridge was thoroughly washed with methanol
and then the amine 16 was eluted with 2 M ammonia in
methanol (84 mg, 88%). HPLC (386 nm): tR = 4.35 min (86%);
(5-{2-[3-Anthracen-9-yl-propyl)-methylamino]-ethoxy}-indol-1-
yl)-{4Ј-[(benzyl-methylamino)-methyl]-biphenyl-4-yl}-meth-
anone (17c)
HPLC (220–290 nm): tR = 4.65 min (>99%); IR: νmax/cmϪ1 1679;
1H NMR (400 MHz, CDCl3): δ 2.06 (2H, m), 2.23 (3H, s), 2.44
(3H, s), 2.75 (2H, t, J = 7.0), 2.93 (2H, t, J = 5.9), 3.56 (2H, s),
3.59 (2H, s), 3.69 (2H, t, J = 8.0), 4.20 (2H, t, J = 5.9), 6.54 (1H,
d, J = 3.6), 7.00 (1H, dd, J = 2.6 and 9.0), 7.08 (1H, d, J = 2.6),
7.26 (1H, m), 7.36 (5H, m), 7.47 (6H, m), 7.60 (2H, d, J = 8.0),
7.72 (2H, d, J = 8.4), 7.79 (1H, d, J = 8.4), 7.99 (2H, d, J = 8.0),
8.32 (4H, m); 13C NMR (100 MHz, CDCl3): δ 167.6, 155.2,
143.9, 138.9, 138.4, 137.8, 134.0, 132.3, 131.1, 131.0 (2C), 130.2,
129.2 (2C), 128.9 (4C), 128.5 (2C), 128.3 (2C), 127.6 (3C), 126.5
(2C), 126.4 (3C), 125.1, 124.9 (2C), 124.2 (2C), 123.8 (2C),
116.5, 113.3, 107.9, 103.9, 65.8, 61.2, 60.7, 57.4, 55.4, 42.1, 41.7,
27.9 and 24.9; LC-MS (ESI): tR = 3.94 min (722.6 [M ϩ H]ϩ and
362.2 [M ϩ 2H]2ϩ); HRMS (ESI): m/z calcd (C50H48N3O2)
722.3746, found 722.3747 [M ϩ H]ϩ.
1
IR: νmax/cmϪ1 3336 and 1666; H NMR (400 MHz, CDCl3):
δ 1.37 (1H, m), 2.03 (2H, m), 2.13 (1H, m), 2.23 (3H, s), 2.40
(3H, s), 2.70 (2H, t, J = 7.0), 2.86 (2H, t, J = 5.8), 2.94 (2H, d,
J = 4.8), 3.56 (2H, s), 3.58 (2H, s), 3.68 (2H, t, J = 7.8), 3.78 (2H,
m), 4.14 (4H, m), 4.74 (1H, t, J = 4.8), 6.81 (1H, d, J = 2.8), 6.90
(1H, dd, J = 2.8 and 9.0), 7.25 (1H, m), 7.33 (2H, m), 7.38 (2H,
m), 7.47 (6H, m), 7.61 (2H, d, J = 8.4), 7.70 (2H, d, J = 8.4), 7.93
(1H, d, J = 9.2), 8.00 (4H, m), 8.32 (3H, m), 9.48 (1H, s); 13C
NMR (100 MHz, CDCl3): δ 164.4, 155.1, 143.4, 138.7, 138.6,
138.1, 134.3, 133.1, 131.0 (2C), 129.8, 129.0 (2C), 128.8 (2C),
128.7, 128.5 (2C), 128.3 (2C), 127.6 (2C), 127.0 (2C), 126.4
(4C), 126.3, 125.0, 124.8 (2C), 124.6, 124.2 (2C), 123.9 (2C),
117.2, 112.5, 102.6, 66.4 (2C), 65.7, 61.2, 60.8, 57.4, 55.6, 42.2,
41.7, 38.1, 28.2, 24.9 (2C); LC-MS (ESI): tR = 3.78 min (798.5
[M ϩ H]ϩ and 400.0 [M ϩ 2H]2ϩ); HRMS (ESI): m/z calcd
(C53H56N3O4) 798.4271, found 798.4294 [M ϩ H]ϩ.
(5-{2-[(3-Anthracen-9-yl-propyl)-methylamino]-ethoxy}-indol-1-
yl)-[5-(2-fluorophenyl)-pyridin-3-yl]-methanone (17d)
General procedure for activation of the safety-catch
HPLC (220–290 nm): tR = 5.20 min (>99%); IR: νmax/cmϪ1 1684;
1H NMR (400 MHz, CDCl3): δ 2.03 (2H, m), 2.42 (3H, s), 2.72
(2H, t, J = 7.0), 2.89 (2H, t, J = 5.9), 3.68 (2H, t, J = 8.0), 4.19
The acetals 15a (82 mg, 120 µmol), 15b (57 mg, 85 µmol), 16
(98 mg, 123 µmol), and 15d (145 mg, 213 µmol) were separately
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 9 8 9 – 9 9 8
996

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(2H, d, J = 5.9), 6.59 (1H, d, J = 3.8), 7.03 (1H, dd, J = 2.6 and
9.0), 7.09 (1H, d, J = 2.6), 7.25 (3H, m), 7.46 (6H, m), 7.99 (2H,
d, J = 8.0), 8.21 (1H, m), 8.32 (4H, m), 8.94 (1H, d, J = 2.2), 8.99
(1H, t, J = 1.8); 13C NMR (100 MHz, CDCl3): δ 165.1, 155.7,
151.4, 147.8, 136.0, 134.2, 131.2, 131.0 (3C), 130.2, 130.1, 130.0,
129.7, 129.0 (2C), 128.5 (2C), 126.8, 125.0, 124.8 (3C), 124.3,
124.1 (3C), 123.8 (2C), 116.6, 115.8 (1C, d, 2JC,F = 22.2), 113.7,
109.1, 104.1, 66.1, 57.5, 55.6, 42.3, 28.2 and 24.9; LC-MS (ESI):
tR = 3.97 min (608.6 [M ϩ H]ϩ); HRMS (ESI): m/z calcd
(C40H35N3O2F) 608.2713, found 608.2709 [M ϩ H]ϩ.
5.2), 7.34 (1H, dd, J = 1.2 and 3.6), 7.40 (2H, d J = 8.0), 7.62
(2H, d, J = 8.0);. 13C NMR (100 MHz, CDCl3): δ 169.3, 142.8,
134.8, 134.6, 127.5, 127.0 (2C), 125.1 (2C), 124.8, 123.0, 48.2,
42.6, 25.9, 25.0, and 23.9; LC-MS (ESI): tR = 4.23 min (272.4
[M ϩ H]ϩ); HRMS (ESI): m/z calcd (C16H17NOSNa) 294.0929,
found 294.0917 [M ϩ Na]ϩ.
4Ј-[(Benzyl-methylamino)-methyl]-biphenyl-4-carboxylic acid
propylamide (21a)
A suspension of indolyl amide resin 20a (130 mg, 0.31 mmol
g
Ϫ1, 40 µmol) in 20% propylamine solution in THF (2 ml) was
General procedure for Diels–Alder cycloaddition with PS-
shaken at room temperature for 16 h. The mixture was filtered,
and the resin was washed with THF (3×). The combined
filtrates were concentrated in vacuo to give propylamide 21a as a
white solid (12.3 mg, 82%). HPLC (254 nm): tR = 3.44 min
(98%); 1H NMR (400 MHz, CDCl3): δ 0.98 (3H, t, J = 7.6), 1.66
(2H, tq, J = 6.7 and 7.6), 2.21 (3H, s), 3.44 (2H, q, J = 6.7), 3.54
(2H, s), 3.56 (2H, s), 6.18 (1H, brs), 7.25 (1H, m), 7.34 (4H, m),
7.45 (2H, d, J = 8.0), 7.56 (2H, d, J = 8.0), 7.64 (2H, d, J = 8.0),
7.82 (2H, d, J = 8.0); 13C NMR (100 MHz, CDCl3): δ 166.6,
143.3, 138.7, 138.6, 138.0, 132.7, 128.8 (2C), 128.3 (2C), 127.6
(2C), 126.7 (2C), 126.4 (2C), 126.4 (2C), 126.3, 61.2, 60.8,
41.7, 41.1, 22.3 and 10.8;. LC-MS (ESI): tR = 3.12 min (373.6
[M ϩ H]ϩ); HRMS (EI): m/z calcd (C25H28N2O) 372.2202,
found 372.2198 [M]ϩ.
maleimide resin
To a reaction tube (30 ml) containing swollen maleimide resin
(1.5 eq. ∼1.2 mmol gϪ1) in toluene (3 ml), was added a solution
of anthracene 17c (68 mg, 95 µmol) or 17d (114 mg, 188 µmol)
in toluene (3 ml). The mixtures were stirred at 100 ЊC for 16 h
and then the resins were thoroughly washed with CH2Cl2, and
dried under high vacuum to give the Diels–Alder adducts
brown beads 20a (308 mg, quant.) and 20b (355 mg, quant.) as
brown beads. Under these conditions, no starting materials
remained in solution according to HPLC analysis.
2Ј-Fluoro-biphenyl-4-carboxylic acid methylamide (18a)
Indolyl amide 17a (26 mg, 43 µmol) was dissolved in 1 M
methylamine solution in THF (4 ml). The resulting solution
was stirred at room temperature for 16 h and then concentrated
in vacuo. The residue was loaded onto a pre-washed SCX-2
cartridge (500 mg), and the cartridge was eluted with methanol
(3 ml). The eluant was concentrated in vacuo to give the methyl-
amide 18a as a solid (9.6 mg, 96%). HPLC (254 nm): tR = 4.46
{4Ј-[(Benzyl-methylamino)-methyl]-biphenyl-4-yl}-piperidin-1-yl-
methanone (21b)
A suspension of indolyl amide resin 20a (130 mg, ∼0.31 mmol
g
Ϫ1, 40 µmol) in 20% piperidine solution in THF (2 ml) was
heated at 65 ЊC for 48 h. The mixture was filtered, and the resin
was washed with THF (3 × 2 ml). The combined filtrates were
concentrated in vacuo to give piperidinylamide 21b (12.7 mg,
79%). HPLC (254 nm): tR = 3.70 min (96%); 1H NMR
(400 MHz, CDCl3): δ 1.62 (6H, brs), 2.21 (3H, s), 3.40 (2H, br),
3.54 (2H, s), 3.56 (2H, s), 3.72 (2H, brs), 7.25 (1H, m), 7.35 (4H,
m), 7.45 (4H, m), 7.54 (2H, d, J = 8.0), 7.60 (2H, d, J = 8.0);
13C NMR (100 MHz, CDCl3): δ 169.5, 141.5, 138.6, 138.3 (2C),
134.4, 128.8 (2C), 128.3 (2C), 127.6 (2C), 126.7 (2C), 126.3
(5C), 61.2, 60.8, 48.2, 42.5, 41.7, 25.9, 25.0 and 24.0; LC-MS
(ESI): tR = 3.21 min (399.6 [M ϩ H]ϩ); HRMS (EI): m/z calcd
(C27H30N2O) 398.2358, found 398.2354 [M]ϩ.
1
min (>99%); H NMR (400 MHz, CDCl3): δ 3.03 (3H, d, J =
5.2), 6.24 (1H, brs), 7.18 (1H, m), 7.34 (1H, m), 7.43 (1H, m),
7.61 (2H, d J = 8.2), 7.81 (2H, d, J = 8.2); 13C NMR (100 MHz,
CDCl3): δ 167.2, 159.0 (1C, d, 1JC,F = 277.1), 138.2, 133.0, 130.0
3
4
(1C, d, JC,F = 2.8), 129.0 (1C, d, JC,F = 8.3), 128.5 (2C), 127.3
2
3
(1C, d, JC,F = 13), 126.3 (2C), 123.8 (1C, d, JC,F = 3.3), 115.6
2
(1C, d, JC,F = 22.5), and 26.3; LC-MS (ESI): tR = 3.85 min
(230.4 [M ϩ H]ϩ); HRMS (EI): m/z calcd (C14H12NOF)
229.0903, found 229.0903 [M]ϩ.
2Ј-Fluoro-biphenyl-4-carboxylic acid methyl ester (18b)
To a solution of indolyl amide 17a (26 mg, 43 µmol) in a
mixture of THF and methanol (2 ml/2 ml), was added DMAP
(50 mg, 0.41 mmol). The resulting mixture was refluxed for 48 h
and then loaded onto a pre-washed SCX-2 cartridge (2 g). The
cartridge was eluted with methanol (8 ml), and the eluate was
concentrated in vacuo to give methyl ester 18b as a white solid
5-(2-Fluorophenyl)-N-methyl-nicotinamide (21c)
A suspension of indolyl amide resin 20b (150 mg, 0.52 mmol
g
Ϫ1, 78 µmol) in 2 M methylamine solution in THF (2 ml) was
shaken at room temperature for 16 h. The suspension was
filtered, and the resin was washed with THF (3×). The com-
bined filtrates were concentrated in vacuo to give methylamide
21c as a white solid (14.1 mg, 79%). HPLC (254 nm): tR = 2.58
min (98%); 1H NMR (400 MHz, CDCl3): δ 3.04 (3H, d, J = 4.8),
6.50 (1H, brs), 7.22 (2H, m), 7.42 (2H, m), 8.27 (1H, s), 8.87
(1H, s), 8.94 (1H, s); 13C NMR (100 MHz, CDCl3): δ 165.5,
159.1 (1C, d, 1JC,F = 247.5), 151.2 (1C, d, 3JC,F = 3.4), 146.0 (2C),
134.6, 131.0, 129.9 (1C, d, 4JC,F = 8.2), 129.4, 124.2 (1C, d, 3JC,F
= 3.4), 123.9 (1C, d, 2JC,F = 13.2), 115.7 (1C, d, 2JC,F = 22.1) and
26.3; LC-MS (ESI): tR = 3.33 min (231.4 [M ϩ H]ϩ); HRMS
(EI): m/z calcd (C13H11N2OF) 230.0855, found 230.0861 [M]ϩ.
1
(7.6 mg, 76%). HPLC (254 nm): tR = 5.90 min (>99%); H
NMR (400 MHz, CDCl3): δ 3.94 (3H, s), 7.19 (1H, m), 7.35
(1H, m), 7.45 (1H, m), 7.62 (2H, d J = 8.2), 8.11 (2H, d, J = 8.2);
1
13C NMR (100 MHz, CDCl3): δ 166.3, 159.1 (1C, d, JC,F
=
247.1), 139.7, 130.0 (1C, d, 3JC,F = 2.7), 129.2 (1C, d, 4JC,F = 8.3),
2
129.0 (2C), 128.6, 128.3 (2C), 127.3 (1C, d, JC,F = 13.2), 123.9
(1C, d, 3JC,F = 3.2), 115.6 (1C, d, 2JC,F = 22.5), and 51.5; LC-MS
(ESI): tR = 4.55 min (231.4 [M ϩ H]ϩ); HRMS (EI): m/z calcd
(C14H11O2F) 230.0743, found 230.0736 [M]ϩ.
Piperidin-1-yl-(4-thiophen-2-yl-phenyl)-methanone (18c)
5-(2-Fluorophenyl)-nicotinic acid (21d)
Indolyl amide 17b (40 mg, 68 µmol) was dissolved in 20% piper-
idine solution in acetonitrile (2.5 ml). The resulting solution
was stirred at 80 ЊC for 16 h, and then concentrated in vacuo.
The residue was loaded onto a pre-washed SCX-2 cartridge
(500 mg), the cartridge was eluted with methanol, and the
eluate was concentrated in vacuo to give piperidinyl amide 18c
(13.8 mg, 75%). HPLC (254 nm): tR = 5.24 min (97%); 1H NMR
(400 MHz, CDCl3): δ 1.60 (6H, brs), 3.38 (2H, brs), 3.70 (2H,
brs), 7.08 (1H, dd, J = 3.6 and 5.2), 7.31 (1H, dd, J = 1.2 and
Caesium hydroxide (5 mg, 30 µmol) was added to a suspension
of indolyl amide resin 20b (150 mg, 0.52 mmol gϪ1, 78 µmol) in
a mixture of THF and water (1.9 ml/0.1 ml). The resulting
mixture was shaken at room temperature for 16 h when
saturated brine (2 ml) was added. The mixture was extracted
with ethyl acetate (3 × 2 ml), and the combined organic layer
was concentrated in vacuo to give the carboxylic acid 17g as a
1
white solid. HPLC (254 nm): tR = 3.16 min (>99%); H NMR
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 9 8 9 – 9 9 8
997

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7 (a) A. M. Hay, S. Hobbs-Dewitt, A. A. MacDonald and R. Ramage,
Synthesis, 1999, 1979; (b) J. S. Warmus and M. I. da Silva, Org. Lett.,
2000, 2, 1807.
8 K. Itami, T. Nokami and J. Yoshida, Angew. Chem., Int. Ed., 2001,
40, 1074.
9 S. Zhang, K. Fukase and S. Kusumoto, Tetrahedron Lett., 1999, 40,
7479.
10 (a) H. Perrier and M. Labelle, J. Org. Chem., 1999, 64, 2110; (b)
D. J. Gravert and K. D. Janda, Chem. Rev., 1997, 97, 489.
11 S. V. Ley, A. Massi, F. Rodriguez, D. C. Horwell, R. A. Lewthwaite,
M. C. Pritchard and A. M. Reid, Angew. Chem., Int. Ed., 2001, 40,
1053.
12 (a) Review: W. Zhang, Tetrahedron, 2003, 59, 4475; (b) FluoroFlash:
D. P. Curran, Synlett, 2001, 1488; (c) D. P. Curran, D. P. Curran
and Y. Oderaotoshi, Tetrahedron, 2001, 57, 5243; (d ) D. Schwinn
and W. Bannwarth, Helv. Chim. Acta, 2002, 85, 255; (e)
D. Schwinn, H. Glatz and W. Bannwarth, Helv. Chim. Acta, 2003,
86, 188.
(400 MHz, DMSO): δ 7.36 (2H, m), 7.49 (1H, m), 7.66 (1H, m),
8.36 (1H, s), 8.96 (1H, s), 9.06 (1H, s); 13C NMR (100 MHz,
CDCl3): δ 165.8, 159.1 (1C, d, 1JC,F = 245.2), 152.5, 149.1 (2C),
136.4 (1C, d, 3JC,F = 2.8), 130.7 (1C, d, 4JC,F = 8.3), 130.6, 126.3,
3
2
125.1 (1C, d, JC,F = 3.0), 123.8 (1C, d, JC,F = 12.9), and
2
116.0 (1C, d, JC,F = 22.1); LC-MS (ESI): tR = 3.85 min (218.4
[M ϩ H]ϩ); HRMS (EI): m/z calcd (C12H8NO2F) 217.0539,
found 217.0537 [M]ϩ.
Acknowledgements
We thank GlaxoSmithKline for financial support of this work.
References
1 (a) E. M. Gordon, M. A. Gallop and D. V. Patel, Acc. Chem. Res.,
1996, 29, 144; (b) J. Li, C. W. Murray, B. Waszkowycz and
S. C. Young, Drug Discovery Today, 1998, 3, 105; (c) B. A. Kenny,
M. Bushfield, D. J. Parry-Smith, S. Fogarty and J. M. Treherne,
Prog. Drug Res., 1998, 51, 245; (d ) A. Golebiowski,
S. R. Klopfenstein and D. E. Portlock, Curr. Opin. Chem. Biol.,
2001, 5, 273.
2 (a) J. Yoshida and K. Itami, Chem. Rev., 2002, 102, 3693; (b)
A. Ganesan, Drug Discovery Today, 2002, 7, 47; (c) F. Z. Dörwald,
Organic Synthesis on Solid Phase, Wiley-VCH, Weinheim, 2000; (d )
D. Obrecht and J. M. Villalgordo, Solid-Supported Combinatorial
and Parallel Synthesis of Small-Molecular-Weight Compound
Libraries, Pergamon, Oxford, 1998.
3 (a) N. Bailey, A. W. J. Cooper, M. J. Deal, A. W. Dean, A. L. Gore,
M. C. Hawes, D. B. Judd, A. T. Merritt, R. Storer, S. Travers and
S. P. Watson, Chimia, 1997, 51, 832; (b) I. Hughes and D. Hunter,
Curr. Opin. Chem. Biol., 2001, 5(3), 243.
4 (a) D. H. Drewry, D. M. Coe and S. Poon, Med. Res. Rev., 1999, 19,
97; (b) S. V. Ley, I. R. Baxendale, R. N. Bream, P. S. Jackson,
A. G. Leach, D. A. Longbottom, M. Nesi, J. S. Scott, R. I. Storer
and S. J. Taylor, Chem. Soc., Perkin Trans. 1, 2000, 3815; (c)
A. Kirschning, H. Monenschein and R. Wittenberg, Angew. Chem.,
Int. Ed., 2001, 40, 650; (d ) D. L. Flynn, S. C. Berk and
G. M. Makara, Curr. Opin. Drug Discovery Dev., 2002, 5, 580; (e)
S. V. Ley and I. R. Baxendale, Nat. Rev. Drug Discovery, 2002, 1, 573.
5 (a) L. A. Thompson, Curr. Opin. Chem. Biol., 2000, 4, 324; (b)
D. L. Flynn, Med. Res. Rev., 1999, 19, 408.
13 S. P. Andrews and M. Ladlow, J. Org. Chem., 2003, 68, 5525.
14 X. Li, C. Abell and M. Ladlow, J. Org. Chem., 2003, 68, 4189.
15 (a) M. E. Bunnage and K. C. Nicolaou, Angew. Chem., Int. Ed.,
1996, 35, 1110; (b) M. E. Bunnage and K. C. Nicolaou, Chem. Eur.
J., 1997, 3, 187.
16 (a) E. Arai, H. Tokuyama, M. S. Linsell and T. Fukuyama,
Tetrahedron Lett., 1998, 39, 71; (b) M. H. Todd, S. F. Oliver and
C. Abell, Org. Lett., 1999, 1, 1149.
17 A. S. B. Prasad, J. V. B. Kanth and M. Periasamy, Tetrahedron, 1992,
48, 4623.
18 K. Hanaya, T. Muramatsu, H. Kudo and Y. L. Chow, J. Chem Soc.,
Perkin Trans. 1, 1979, 10, 2409.
19 For example: (a) S. Peukert, J. Brendel, B. Pirard, A. Brüggemann,
P. Below, H.-W. Kleemann, H. Hemmerle and W. Schmidt, J. Med.
Chem., 2003, 46, 486; (b) D. Lesuisse, E. Albert, F. Bouchoux,
E. Cérède, J.-M. Lefrançois, M.-O. Levif, S. Tessier, B. Tric and
G. Teutsch, Bioorg. Med. Chem. Lett., 2001, 11, 1713; (c)
S. Takekawa, A. Asami, Y. Ishihara, J. Terauchi, K. Kato,
Y. Shimomura, M. Mori, H. Murakoshi, K. Kato, N. Suzuki,
O. Nishimura and M. Fujino, Eur. J. Pharmacol., 2002, 438, 129.
20 Isolute SCX-2 (alkylsulfonic acid) cartridges were obtained from
Jones Chromatography (e.g. Cat. No. 532-0100-C).
21 The polymer-supported maleimide resin was prepared on a 1–2%
cross-linked polystyrene and was determined to have a loading of
approximately 1.2 mmol gϪ1 according to N combustion analysis.
22 K. Valko, C. M. Du, C. Bevan, D. P. Reynolds and M. H. Abraham,
Curr. Med. Chem., 2001, 8, 1137.
6 (a) P. Lan, J. A. Porco Jr., M. S. South and J. J. Parlow, J. Comb.
Chem., 2003, 5, 660; (b) X. Wang, J. J. Parlow and J. A. Porco Jr.,
Org. Lett., 2001, 2, 3509.
23 HPLC retention times tR were measured using a wide polarity
reverse phase method with an 7 min total gradient time as described
in the Experimental section.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 9 8 9 – 9 9 8
998