A novel anthracenyl tagged protecting group for "phase-switching" applications in parallel synthesis

Article abstract of DOI:10.1021/jo034219i

A new "phase-switching" protecting group 1 that facilitates the parallel synthesis of carboxylic acids, esters, and carboxamides is described. Its use permits chemistries to be performed in solution, which may be conveniently monitored with conventional a

Full text of DOI:10.1021/jo034219i

A Novel An th r a cen yl Ta gged P r otectin g Gr ou p for
“P h a se-Sw itch in g” Ap p lica tion s in P a r a llel Syn th esis
Xin Li, Chris Abell, and Mark Ladlow*,†
University Chemical Laboratory, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, U.K,
and GSK Cambridge Technology Center, University Chemical Laboratory, University of Cambridge,
Lensfield Road, Cambridge, CB2 1EW, U.K.
mark.2.ladlow@gsk.com
Received February 19, 2003
A new “phase-switching” protecting group 1 that facilitates the parallel synthesis of carboxylic
acids, esters, and carboxamides is described. Its use permits chemistries to be performed in solution,
which may be conveniently monitored with conventional analytical techniques, followed by
subsequent immobilization onto a solid-phase support to aid compound purification. Carboxylic
acids, esters, and carboxamides are then cleaved from the solid support following activation of the
“safety-catch” and treatment with the desired nucleophile.
In tr od u ction
ated with other chromophores that may be present
thereby facilitating quantitative reaction monitoring by
HPLC.
In recent years, solid-phase organic synthesis (SPOS)
has emerged as a powerful method for the preparation
of compound libraries for use in high throughput screen-
ing campaigns.1,2 However, SPOS often suffers from the
disadvantage of requiring tedious reaction optimization
prior to library synthesis and this is compounded by the
inability to use many conventional solution phase ana-
lytical techniques. In contrast, solution phase synthesis
may suffer from difficulties associated with compound
purification, although the application of polymer sup-
ported reagents and scavenger resins is proving beneficial
in this respect.3 An attractive alternative would be to
combine the attributes of both solid and solution phase
methodologies in a single synthetic strategy whereby the
substrate may be moved between different phases to aid
both synthesis and final purification. Such a strategy may
be realized in practice by “tagging” the substrate with a
protecting group that enables “phase-switching”.4 For
example, Parlow has reported the use of an anthracenyl
tag that may be readily attached to the solid phase
following a Diels-Alder reaction with a resin-bound
maleimide to facilitate the synthesis of esters.5 In addi-
tion, the anthracenyl moiety has been shown to be a
useful analytical “tag” that allows the convenient moni-
toring of chemistries on solid phase following initial
cleavage into solution.6 The anthracenyl substituent was
found to be comparatively unreactive and, importantly,
absorbs in a remote region of the UV spectrum (380-
390 nm), which is typically free from absorptions associ-
Herein, we describe a new solution phase protecting
group 1 that extends the scope of the anthracenyl “phase-
switch” concept. The protecting group 1 incorporates an
anthracenyl “tag” in combination with Fukuyama’s anili-
no protecting group for carboxylic acids.7 When im-
mobilized on resin, this latter protecting group has also
been used as a “safety-catch” linker for solid-phase
synthesis.8 Amides derived from acylation of 1 are stable
toward basic or nucleophilic reagents. However, upon
ring closure to the corresponding more electrophilic
indolylamides 2, compound release can be effected by
nucleophilic cleavage under mild conditions. The utility
of 1 is demonstrated by the preparation of carboxylic
acids, esters, and carboxamides, using a “phase-switch-
ing” approach.
Resu lts a n d Discu ssion
Syn th esis of th e An th r a cen yl-Ta gged Lin k er 1.
The anthracenyl-tagged linker 1 may be conveniently
prepared as outlined in Scheme 1. Alkylation of com-
† Address correspondence to this author at GSK Cambridge Tech-
nology Center.
(1) Yoshida, J .; Itami, K. Chem. Rev. 2002, 102, 3693-3716.
(2) Do¨rwald, F. Z. In Organic Synthesis on Solid Phase; Wiley-
VCH: Weinheim, Germany, 2000.
(3) Ley, S. V.; Baxendale, I. R.; Bream, R. N.; J ackson, P. S.; Leach,
A. G.; Longbottom, D. A.; Nesi, M.; Scott, J . S.; Storer, R. I.; Taylor, S.
J . J Chem. Soc., Perkin Trans. 1 2000, 23, 3815-4196.
(4) Flynn, D. L. Med. Res. Rev. 1999, 19, 408-431.
(5) Wang, X.; Parlow, J . J .; Porco, J . A. Org. Lett. 2000, 2, 3509-
3512.
(6) Congreve, M. S.; Ladlow, M.; Marshall, P.; Parr, N.; Scicinski,
J . J .; Sheppard, T.; Vickerstaffe, E.; Carr, R. A. E. Org. Lett. 2001, 3,
507-510.
(7) Arai, E.; Tokuyama, H.; Linsell, M. S.; Fukuyama, T. Tetrahe-
dron Lett. 1998, 39, 71-74.
(8) Todd, M. H.; Oliver, S. F.; Abell, C. Org. Lett. 1999, 1, 1149-
1151.
10.1021/jo034219i CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/29/2003
J . Org. Chem. 2003, 68, 4189-4194
4189

Li et al.
a
a
SCHEME 1
SCHEME 2
a
Reagents and conditions: (i) 3-methyl-4-nitrophenol, K2CO3,
DMF, 90 °C, 99%; (ii) (a) dimethylformamide dimethyl acetal,
DMF, reflux, (b) 10% HCl aqueous solution, diethyl ether, reflux,
73%; (iii) trimethyl orthoformate, p-TsOH, MeOH, reflux, 100%;
(iv) NaBH4, Cu(acac)2, CH2Cl2/MeOH/i-PrOH, reflux, 74%.
mercially available 3-methyl-4-nitrophenol with 9-(3-iodo-
propyl)anthracene 3 gave the desired ether 4 in high yield.
The ether 4 was heated with dimethylformamide
dimethyl acetal to afford the intermediate unstable vinyl
dimethylamine, which was hydrolyzed in the presence
of 10% HCl to give the phenyl acetaldehyde 5. Upon
exposure to trimethyl orthoformate the aldehyde 5 was
protected as the dimethyl acetal 6. To avoid the risk of
concomitant reduction of the anthracenyl moiety, the
nitro substituent in 6 was reduced with sodium borohy-
dride in the presence of copper(II) acetonylacetonate9 at
40 °C to provide the desired aniline 1 in 53% overall yield.
Con str u ction of a Nin e-Mem ber Libr a r y w ith 1.
To demonstrate the utility of the new protecting group 1
in synthesis, a small library containing 9 compounds was
constructed by using a “phase-switching” strategy (Scheme
2).
Thus, acylation of 1 with 4-bromobenzoyl chloride was
performed in solution in the presence of diisopropylethy-
lamine on polystyrene (PS-DIPEA). The use of the
polymer supported base reduced the workup to a simple
filtration. Reaction progress was monitored by HPLC
with UV detection at 386 nm under which conditions only
anthracenyl tagged material was visible (Figure 1a). The
time-course data indicated that, under the experimental
conditions employed, amidation of 1 was complete after
5 h (Figure 1b). Extending the reaction time or the use
of a large excess of the acylating reagent led to diacyla-
tion of the aniline. Any residual acid chloride could be
readily removed by filtration of the reaction mixture
a
Reagents and conditions: (i) 4-bromobenzoyl chloride, CH2Cl2,
PS-DIPEA, 99%; (ii) maleimide resin, toluene, 100 °C; (iii) Ar-
B(OH)2, Pd(PPh3)4, Cs2CO3, DME, 80 °C; (iv) PPTS, THF, 50 °C;
(v) NuH, solvent.
through an Isolute-NH2 cartridge to afford the anthra-
cenyl tagged amide 7 in almost quantitative yield.
Next, we addressed the homologation of the carbox-
amide 7 using a palladium-mediated Suzuki coupling
reaction. We observed that competing reduction of the
aryl bromide to the corresponding phenyl derivative was
sometimes a problem under solution phase Suzuki condi-
tions and we therefore decided to effect a “phase-switch”
at this stage and conduct the Suzuki reaction on solid-
phase. This also greatly simplified reaction workup since
residual palladium contaminants and excess reagents
could be readily washed away. Therefore, according to
Parlow’s procedure5,10 maleimide functionalized polysty-
rene resin was prepared and heated with the amide 7 in
toluene to promote the Diels-Alder reaction, affording
the resin-bound bromide 8. The progress of the reaction
was again monitored by the disappearance of the an-
thracenyl UV absorption at 386 nm and the kinetic plot
is shown in Figure 2. Whereas the “phase-switch” takes
approximately 7 h at 90 °C, the process is complete in
only 4 h at 100 °C. In addition, although the resin-bound
(10) The maleimide resin was prepared on 1-2% cross-linked
polystyrene and determined to have a loading of ∼1.2 mmol/g according
to N combustion analysis.
(9) Hanaya, K.; Muramatsu, T.; Kudo, H.; Chow, Y. L. J . Chem. Soc.,
Perkin Trans. 1 1979, 2409.
4190 J . Org. Chem., Vol. 68, No. 11, 2003

A Novel Anthracenyl Tagged Protecting Group
F IGUR E 2. Time-course plot to show the temperature
dependence for the Diels-Alder “phase-switch” reaction of 7
with PS-maleimide resin to afford 8. Monitored by HPLC
analysis of the supernatant solution at 386 nm.
TABLE 1. P u r ities a n d Yield s of Ben zoic Acid
Der iva tives 13 P r ep a r ed by Nu cleop h ilic Clea va ge fr om
Resin s 11a -c
F IGURE 1. Acylation of aniline 1 with 4-bromobenzoyl
chloride to afford carboxamide 7. (a) Time course to show the
disappearance of 1 and the appearance of 7 at room temper-
ature monitored by HPLC at 386 nm. (b) Normalized kinetic
plot for the conversion of 1 into 7 obtained by HPLC monitor-
ing at 386 nm.
boronic acid
(ArB(OH)2)
nucleophile
(NuH)
purity,
%
yield,
%
a
b
product
13a c
13bc
13cc
13d d
13ed
13fd
13ge
13h e
13ie
4-methoxophenyl-
4-fluorophenyl-
3-thiophenyl-
4-methoxyphenyl-
4-fluorophenyl-
3-thiophenyl-
4-methoxyphenyl-
4-fluorophenyl-
3-thiophenyl-
nPrNH2
nPrNH2
nPrNH2
MeOH
MeOH
MeOH
H2O
98
95
92
97
95
98
94
98
97
75
74
80
70
65
66
77
70
77
maleimide was used in excess, the gel-phase FT-IR
spectrum obtained after the Diels-Alder reaction showed
a significant decrease in intensity of the cis-(HCdCH)
vinylic wagging band at 828 cm-1 and the appearance of
a new carboxamide N-H stretching band was observed
H2O
H2O
at 3346 cm-1
.
HPLC purity with UV detection at 254 nm. b 1H NMR yield
obtained by integration vs residual protio-DMSO peaks in d6-
DMSO calibrated with 4-nitrophenol as an external standard.12
a
Further evidence for the formation of the resin-bound
Diels-Alder adduct 8 was obtained from examination of
the gel-phase 1H HRMAS NMR spectrum. First, to
provide a model compound for comparison, the adduct 9
was prepared by subjecting the carboxamide 7 to a Diels-
Alder reaction with N-Me maleimide in solution. Distinc-
tive signals for the amidic proton and the dimethoxy
groups were observed at 9.44 and 3.46 ppm, respectively,
in the solution phase 1H NMR spectrum of 9 and
corresponding signals were observed at 9.54 and 3.51
d
c 20% propylamine in THF, rt, 16 h. NaNH2, MeOH/THF (1:4),
rt, 16 h. e CsOH‚H2O, H2O/THF (1:10), rt, 16 h.
The Suzuki coupling reaction of resin 8 was carried
out with three different boronic acids (cf. Scheme 2) in
degassed DME at 80 °C, using Pd(PPh3)4 as the catalyst
and cesium carbonate as the base to afford the resins
10a -c. Under these conditions competing reduction of
the aryl bromide did not occur to any significant extents
as was evident from the high purities of the final
compounds obtained following cleavage from the resin
(Table 1). Similarly, consistent with the observations of
Abell et al.,8 the high cleavage yields obtained demon-
strate that the “safety-catch” linker is resistant to
premature nucleophilic cleavage, even in the presence of
aqueous cesium carbonate at 80 °C for up to 2 days. It is
unlikely that a simple ester linkage would have remained
intact under these conditions. Excess reagents and the
1
ppm in the H HRMAS NMR spectrum of resin 8.
J . Org. Chem, Vol. 68, No. 11, 2003 4191

Li et al.
palladium residues that often prove to be problematic
contaminants in solution phase were readily removed
from the solid phase by thorough washing of the resin.
Finally, activation of the “safety-catch” prior to nu-
cleophilic cleavage of the desired substrates from resin
was performed by heating the resins 10a -c with PPTS
in THF at 50 °C for 16 h to give the resin-bound
indolylamides 11a -c. These conditions were determined
for a model study in which the resin-bound carboxamide
8 was converted to the corresponding bromide 12. The
disappearance of both the band at 3346 cm-1 in the gel-
phase FT-IR and the amidic and dimethoxyl signals at
9.60 and 3.56 ppm, respectively, in the gel-phase 1H
HRMAS NMR spectra for 12 indicated that conversion
to the resin-bound indolylamide went to completion under
these conditions. In addition the signals at 106.5, 54.1,
and 36.8 ppm in the gel-phase 13C NMR for 8 disappeared
and were replaced by signals at 108.5 and 104.0 ppm
which correspond to the sp2 centers at the C-2 and C-3
positions of the newly formed indole ring in 12.
transformations is currently underway in our laboratory
and these results will be reported in due course.
Exp er im en ta l Section
9-[3-(3-Meth yl-4-n itr op h en oxy)p r op yl]a n th r a cen e (4).
A suspension of 9-(3-iodopropyl)anthracene (3, 18.3 g, 52.9
mmol), 3-methyl-4-nitrophenol (9.9 g, 64.6 mmol), and K2CO3
(21.1 g, 64.8 mmol) in DMF (180 mL) was heated at 90 °C
under nitrogen for 3 h. The reaction mixture was concentrated
in vacuo and the residue was partitioned between 2 M Na2-
CO3 aqueous solution (200 mL) and ethyl acetate (200 mL).
The organic layer was separated, washed with 2 M Na2CO3
aqueous solution and saturated brine, and dried (Na2SO4). The
solvent was evaporated in vacuo to afford 4 as a yellow solid
(19.6 g, 99%). Mp 132-133 °C. HPLC (254 nm): tR ) 7.95 min
(100%). IR: υmax 1587, 1330 cm-1 1H NMR (400 MHz,
.
CDCl3): δ 2.34 (2H, tt, J ) 5.8 and 7.6 Hz), 2.62 (3H, s), 3.84
(2H, t, J ) 7.6 Hz), 4.10 (2H, t, J ) 5.8 Hz), 6.80 (2H, m), 7.45
(4H, m), 8.01 (2H, m), 8.08 (1H, d, J ) 8.4 Hz), 8.27 (2H, m),
8.37 (1H, s). 13C NMR (100 MHz, CDCl3): δ 161.8, 141.5, 136.4,
132.6, 131.0, 129.1, 128.6, 126.9, 125.5, 125.1, 124.2, 123.4,
117.3, 111.7, 67.1, 29.7, 23.3, 21.0. HRMS (ESI): m/z calcd
(C24H21NO3Na) 394.1419, found 394.1412 [M + Na]+. Anal.
Calcd for C24H21NO3: C, 77.61; H, 5.70; N, 3.77. Found: C,
77.67; H, 5.61; N, 3.69.
[5-(3-An th r a cen -9-ylp r op oxy)-2-n itr op h en yl]a ceta ld e-
h yd e (5). To a solution of anthracene 4 (19.6 g, 52.8 mmol) in
DMF (200 mL) was added N,N-dimethylformamide dimethyl
acetal (10.9 mL, 82.3 mmol). The resulting solution was
refluxed under nitrogen for 16 h and the solvent was evapo-
rated in vacuo to leave the intermediate vinyl dimethylamine
as a dark red oil. The oil was dissolved in diethyl ether (100
mL) and treated with 10% HCl aqueous solution (25 mL), and
the resulting mixture was refluxed for 2 h. The organic layer
was separated, washed with saturated brine, and dried (Na2-
SO4). The solvent was evaporated in vacuo to leave a semisolid
that was purified by column chromatography eluting with a
mixture of ethyl acetate and hexane (1:4) to give 5 as a yellow
Each of the resins 11a -c was then subjected to
cleavage under these standard conditions in the presence
of three different nucleophiles to afford the desired
cleavage products 13a -i (Table 1).
Thus, the n-propylamides, 13a -c were obtained in
high yield and good purity following exposure of the
resins 11a -c to 20% v/v n-propylamine in THF at room
temperature for 16 h. The excess amine was removed by
evaporation under high vacuum. When nonvolatile amines
(1y, 2y, and cyclic) were used (not reported), the excess
amine could be conveniently removed by elution through
an acidic Isolute SCX-2 cartridge.
Alternatively, treatment of the resins 11a -c with
sodium amide in MeOH/THF (1:4) at room temperature
for 16 h followed by an aqueous quench of the resin with
NH4Cl solution gave the methyl esters 13d -f again in
good yield and high purity after extraction into dichlo-
romethane.
Similarly, exposure of the resins 11a -c to aqueous
cesium hydroxide gave the corresponding carboxylic acids
13g-i in high yield and excellent purities.
solid (15.5 g, 73%). Mp 139-140 °C. HPLC (254 nm): tR
)
7.10 min (100%). IR: υmax 1720, 1589, 1332 cm-1 1H NMR
.
(400 MHz, CDCl3): δ 2.34 (2H, tt, J ) 6.0 and 7.6 Hz), 3.84
(2H, t, J ) 7.6 Hz), 4.06 (2H, s), 4.10 (2H, t, J ) 6.0 Hz), 6.73
(1H, d, J ) 2.8 Hz), 6.91 (1H, dd, J ) 2.8 and 9.2 Hz), 7.46
(4H, m), 8.01 (2H, m), 8.19 (1H, d, J ) 9.2 Hz), 8.26 (2H, m),
8.36 (1H, s), 9.83 (1H, s). 13C NMR (100 MHz, CDCl3): δ 196.1,
162.4, 141.0, 132.5, 130.9, 129.1, 128.7, 127.5, 125.6, 125.1,
124.3, 123.3, 118.5, 113.0, 67.4, 48.4, 29.6, 23.2. LC-MS
(ESI): tR ) 4.98 min (m/z 400.2 [M + H]+). HRMS (ESI): m/z
calcd (C25H21NO4Na) 422.1368, found 422.1372 [M + Na]+.
Anal. Calcd for C25H21NO4: C, 75.17; H, 5.30; N, 3.51. Found:
C, 74.83; H, 5.33; N, 3.35.
9-{3-[3-(2,2-Dim eth oxyeth yl)-4-n itr op h en oxy]p r op yl}-
a n th r a cen e (6). To a solution of aldehyde 5 (8.50 g, 21.3
mmol) in CH2Cl2 (150 mL) was added p-toluenesulfonic acid
(400 mg, 2.2 mmol) and trimethyl orthoformate (50 mL). The
resulting mixture was refluxed for 30 min. The reaction
mixture was concentrated in vacuo and the residue was
partitioned between saturated NaHCO3 aqueous solution and
ethyl acetate. The organic layer was separated, washed with
saturated brine, and dried (Na2SO4). The solvent was evapo-
rated in vacuo to afford 6 as yellow oil (9.50 g, 100%). HPLC
(386 nm): tR ) 7.59 min (100%). IR: υmax 1578, 1334 cm-1. 1H
NMR (400 MHz, CDCl3): δ 2.34 (2H, m), 3.25 (2H, d, J ) 5.2
Hz), 3.35 (6H, s), 3.84 (2H, t, J ) 7.7 Hz), 4.11 (2H, t, J ) 5.9
Hz), 4.59 (1H, t, J ) 5.2 Hz), 6.82 (1H, dd, J ) 2.6 and 9.2
Hz), 6.88 (1H, d, J ) 2.6 Hz), 7.45 (4H, m), 8.00 (3H, m), 8.27
(2H, m), 8.36 (1H, s). 13C NMR (100 MHz, CDCl3): δ 161.5,
141.9, 134.4, 132.6, 130.9, 129.1, 128.6, 126.7, 125.5, 125.1,
124.2, 123.4, 118.4, 112.4, 103.9, 67.2, 53.7, 37.4, 29.6, 23.3.
LC-MS (ESI): tR ) 5.22 min (m/z 414.2 [M - MeO] -). HRMS
(ESI): m/z calcd (C27H27NO5Na) 468.1787, found 468.1795 [M
+ Na]+.
Con clu sion
In summary, we have described the preparation of a
new anthracenyl-tagged protecting group 1 and demon-
strated that it may be used to conveniently prepare
carboxylic acids, esters, and amides in good yields and
high purities by invoking a “phase-switching” strategy
in combination with PS-maleimide resin. In addition, the
monitoring of solution phase transformations of 1 is
greatly facilitated by the presence of the sensitive an-
thracenyl UV chromophore, which has absorptions in a
remote region of the UV spectrum. The development of
other tagged protected groups for “phase-switching”
4192 J . Org. Chem., Vol. 68, No. 11, 2003

A Novel Anthracenyl Tagged Protecting Group
4-(3-An t h r a cen -9-ylp r op oxy)-2-(2,2-d im et h oxyet h yl)-
p h en yla m in e (1). To a solution of 6 (9.50 g, 21.3 mmol) in a
mixture of CH2Cl2 (150 mL) and 2-propanol (30 mL) was added
copper acetylacetonate (1.12 g, 4.30 mmol) and sodium boro-
hydride (2.43 g, 64.2 mmol) with ice-water bath cooling. The
resulting mixture was stirred at room temperature for 5 min
and then MeOH (30 mL) was slowly added. The mixture was
heated under reflux for 30 min and allowed to cool to room
temperature. The reaction was quenched by slowly adding
water (30 mL). After gas evolution ceased, the mixture was
filtered through a Celite pad. The filtrate was concentrated
in vacuo and the residue was partitioned between ethyl acetate
(200 mL) and saturated brine (200 mL). The separated organic
layer was dried (Na2SO4) and the solvent was evaporated in
vacuo. The crude product was purified by column chromatog-
raphy eluting with a mixture of ethyl acetate, hexane, and
triethylamine (10: 30: 3) to give 1 as a light brown oil (6.58
g, 74%). HPLC (254 nm): tR ) 4.87 min (94%). IR: υmax 3421,
Gen er a l P r oced u r e for Activa tion of th e “Sa fety-
Ca t ch ”: P r ep a r a t ion of R esin -Bou n d In d olyla m id es
(11a -c). To a suspension of each of the biaryl resins 10a -c
(50 mg) in anhydrous THF (2 mL) under nitrogen was added
PPTS (5 mg). The reaction vessels were sealed and shaken at
50 °C for 16 h. The resins were thoroughly washed with
anhydrous CH2Cl2 and dried under high vacuum to afford
indolylamide resins 11a -c. These were used directly in the
following cleavage studies, a separate batch of resins 11a -c
being prepared prior to treatment with each nucleophile. In
all cases, yields were determined by NMR integration relative
to residual protio signals in d6-DMSO precalibrated with
p-nitrophenol.12
P r ep a r a tion of th e In d olyla m id e Resin (12). According
to the general procedure, resin 8 (300 mg) was suspended in
THF (5 mL) containing PPTS (150 mg) and gently stirred at
50 °C for 16 h to afford the resin 12 (∼300 mg). 13C NMR (100
MHz, CDCl3): δ (selected signals) 108.5, 104.0.
Gen er a l P r oced u r e for Clea va ge w ith P r op yla m in e:
P r ep a r a tion of Am id es 13a -c. The resins 11a -c (50 mg
each) were treated with 20% v/v propylamine in anhydrous
THF (2 mL) at room temperature for 16 h. The suspensions
were filtered, and resins were washed with CH2Cl2 (3 × 2 mL).
The combined filtrates were evaporated in vacuo and the
residues obtained were further dried under high vacuum to
afford amides 13a -c free of residual propylamine.
4′-Meth oxybip h en yl-4-ca r boxylic Acid P r op yla m id e
(13a ). HPLC (254 nm): tR ) 5.17 min (92%). 1H NMR (400
MHz, CDCl3): δ 0.87 (3H, t, J ) 7.4 Hz), 1.52 (2H, tq, J ) 7.2
and 7.4 Hz), 3.20 (2H, dt, J ) 5.6 and 7.2 Hz), 3.78 (3H, s),
7.01 (2H, d, J ) 9.0 Hz), 7.65 (2H, d, J ) 9.0 Hz), 7.68 (2H, d,
J ) 8.0 Hz), 7.87 (2H, d, J ) 8.0 Hz), 8.42 (1H, t, J ) 5.6 Hz).
13C NMR (100 MHz, CDCl3): δ 165.6, 159.1, 142.0, 132.6,
131.3, 127.8, 127.6, 125.6, 114.2, 55.0, 40.8, 22.2, and 11.3.
LC-MS (ESI): tR ) 4.11 min (m/z 270.2 [M + H]+). HRMS
(ESI): m/z calcd (C17H20NO2) 270.1494, found 270.1498 [M +
H]+.
4′-Flu or obiph en yl-4-car boxylic Acid P r opylam ide (13b).
HPLC (254 nm): tR ) 5.26 min (95%). 1H NMR (400 MHz,
CDCl3): δ 0.87 (3H, t, J ) 7.4 Hz), 1.51 (2H, tq, J ) 7.1 and
7.4 Hz), 3.21 (2H, dt, J ) 5.6 and 7.1 Hz), 7.29 (2H, dd, J )
8.6 and 8.6 Hz), 7.71 (2H, d, J ) 8.4 Hz), 7.75 (2H, dd, J ) 5.4
and 8.6 Hz), 7.90 (2H, d, J ) 8.4 Hz), 8.46 (1H, t, J ) 5.6 Hz).
13C NMR (100 MHz, CDCl3): δ 165.5, 141.2, 135.5, 133.3,
128.7, 128.7, 127.6, 126.2, 115.7, 115.5, 40.8, 22.2, and 11.3.
LC-MS (ESI): tR ) 4.16 min (m/z 258.2 [M + H]+). HRMS
(ESI): m/z calcd (C16H17NOF) 258.1294, found 258.1302 [M +
H]+.
N-P r op yl-4-(th iop h en -3-yl)ben za m id e (13c). HPLC (254
nm): tR ) 4.96 min (98%). 1H NMR (400 MHz, CDCl3): δ 0.87
(3H, t, J ) 7.4 Hz), 1.51 (2H, tq, J ) 7.2 and 7.4 Hz), 3.20
(2H, dt, J ) 5.6 and 7.2 Hz), 7.61 (1H, dd, J ) 1.4 and 5.2
Hz), 7.64 (1H, dd, J ) 2.8 and 5.2 Hz), 7.78 (2H, d, J ) 8.4
Hz), 7.86 (2H, d, J ) 8.4) Hz, 7.97 (1H, dd, J ) 1.4 and 2.8
Hz), 8.42 (1H, t, J ) 5.5 Hz). 13C NMR (100 MHz, CDCl3): δ
165.6, 140.4, 137.2, 132.8, 127.6, 127.1, 126.0, 125.5, 122.0,
40.8, 22.2, and 11.3. LC-MS (ESI): tR ) 4.03 min (m/z 246.1
[M + H]+). HRMS (ESI): m/z calcd (C14H16NOS) 246.0952,
found 246.0946 [M + H]+.
Gen er a l P r oced u r e for Clea va ge w ith Sod iu m Am id e:
P r ep a r a tion of Meth yl Ester s (13d -f). To a suspension of
each of the indolylamide resins 11a -c (50 mg each) in a
mixture of anhydrous MeOH and THF (1:4; 2 mL) was added
NaNH2 (2 mg). The suspensions were shaken at room tem-
perature for 16 h and the reactions were quenched by carefully
adding saturated NH4Cl aqueous solution (2 mL). The result-
ing suspensions were filtered and the resins were washed with
1
3350, 1622 cm-1. H NMR (400 MHz, CDCl3): δ 2.27 (2H, dd,
J ) 5.8 and 7.8 Hz), 2.86 (2H, d, J ) 5.4 Hz), 3.37 (6H, s),
3.82 (2H, t, J ) 7.8 Hz), 4.03 (2H, t, J ) 5.8 Hz), 4.51 (1H, t,
J ) 5.4 Hz), 6.69 (3H, m), 7.45 (4H, m), 8.00 (2H, m), 8.32
(2H, m), 8.34 (1H, s). 13C NMR (100 MHz, CDCl3): δ 151.5,
138.8, 133.6, 131.0, 129.1, 128.5, 125.2, 124.9, 124.2, 123.8,
123.4, 117.3, 116.7, 113.3, 105.9, 67.3, 53.3, 36.0, 30.2, 23.7.
LC-MS (ESI): tR ) 4.72 min (m/z 384.3 [M - MeO] -). HRMS
(ESI): m/z calcd (C27H29NO3Na) 438.2045, found 438.2038 [M
+ Na]+.
N-[4-(3-An th r a cen -9-ylp r op oxy)-2-(2,2-d im eth oxyeth -
yl)p h en yl]-4-br om oben za m id e (7). To a suspension of
4-bromobenzoyl chloride (135.6 mg, 0.62 mmol) and PS-DIPEA
(1.0 g, ∼2.2 mmol/g, ∼2.2 mmol) in CH2Cl2 (4 mL) was added
a solution of amine 1 (214 mg, 0.52 mmol) in CH2Cl2 (4 mL).
The resulting suspension was stirred at room temperature for
5 h and filtered. The resin was washed with CH2Cl2 (3 × 5
mL) and the combined filtrates were loaded onto an Isolute-
NH2 cartridge (1 g). The cartridge was eluted with CH2Cl2 (3
× 5 mL) and MeOH (3 × 5 mL) and the eluant was evaporated
in vacuo to give 7 as a pale yellow oil (310 mg, 99%). HPLC
(254 nm): tR ) 7.93 min (100%). IR: υmax 3333, 1669 cm-1. 1H
NMR (400 MHz, CDCl3): δ 2.31 (2H, tt, J ) 5.8 and 7.8 Hz),
2.95 (2H, d, J ) 5.2 Hz), 3.45 (6H, s), 3.83 (2H, t, J ) 7.8 Hz),
4.09 (2H, t, J ) 5.8 Hz), 4.52 (1H, t, J ) 5.2 Hz), 6.81 (1H, d,
J ) 2.8 Hz), 6.92 (1H, dd, J ) 2.8 and 8.8 Hz), 7.47 (4H, m),
7.63 (2H, d, J ) 8.4 Hz), 7.82 (2H, d, J ) 8.4 Hz), 7.91(1H, d,
J ) 8.8 Hz), 8.00 (2H, d, J ) 8.4 Hz), 8.31 (2H, d, J ) 8.4 Hz),
8.35 (1H, s), 9.42 (1H, s). 13C NMR (100 MHz, CDCl3): δ 163.6,
155.5, 133.34, 133.28, 131.2, 131.0, 129.3, 129.1, 129.0, 128.6,
128.0, 125.5, 125.3, 125.0, 124.7, 124.2, 123.6, 116.8, 112.6,
106.5, 66.9, 54.0, 36.7, 30.1, 23.6. LC-MS (ESI): tR ) 5.35 min
-
(m/z 598.4 [M - H] and 568.3 [M - MeO]-). HRMS (ESI):
m/z calcd (C34H32BrNO4Na) 620.1412, found 620.1440 [M +
Na]+.
P r ep a r a tion of Resin (8) by Diels-Ald er Cycloa d d i-
tion . A solution of anthracene 7 (285 mg, 0.46 mmol) in
toluene (2 mL) was added to pre-swollen PS-maleimide resin10
(0.70 g, ∼1.2 mmol/g, ∼0.84 mmol) in toluene (8 mL). The
reaction tube was sealed and stirred at 100 °C for 4 h. The
resin was thoroughly washed with CH2Cl2, and dried under
high vacuum to give brown beads of 8 (0.99 g). IR: υmax 3346,
1
1710, 828 (ω cis-CHdCH) cm-1. H HRMAS NMR (400 MHz,
CDCl3): δ (selected signals) 3.56 (s), 7.69, 7.90, and 9.60 (s).11
13C NMR (100 MHz, CDCl3): δ (selected signals) 106.5, 54.1,
and 36.8.
Gen er a l P r oced u r e for Solid -P h a se Su zu k i Cou p lin g
Rea ction (10a -c). To a suspension of resin 8 (200 mg, ∼92
µmol) in DME (2 mL), was added Pd(PPh3)4 (26 mg, 23 µmol),
2 M Cs2CO3 aqueous solution (880 µL), and the boronic acid
(10, 5 equiv) under nitrogen. The reaction vessel was sealed
and shaken at 80 °C for 48 h. The resin was thoroughly washed
(2 × THF, 2 × DMF/H2O, 3 × DMF, and 3 × CH2Cl2) and dried
under high vacuum to give brown beads of 10a -c (∼200 mg).
(11) In the 1H HRMAS NMR spectra of 1-2% polystyrenes, all
signals suffered from varying degrees of line broadening but the signals
at 9.60 and 3.56 ppm were particularly well resolved.
(12) Basso, A.; Evans, B.; Pegg, N.; Bradley, M. Tetrahedron Lett.
2000, 41, 3763-3767.
J . Org. Chem, Vol. 68, No. 11, 2003 4193

Li et al.
saturated NH4Cl aqueous solution (3 × 2 mL) and CH2Cl2 (3
× 2 mL). The separated CH2Cl2 layers were evaporated in
vacuo, and the residues obtained were further dried under high
vacuum to afford the methyl esters 13d -f.
4′-Meth oxybip h en yl-4-ca r boxylic Acid Meth yl Ester
(13d ). HPLC (254 nm): tR ) 6.05 min (97%). 1H NMR (400
MHz, CDCl3): δ 3.78 (3H, s), 3.84 (3H, s), 7.03 (2H, d, J ) 8.8
Hz), 7.68 (2H, d, J ) 8.8 Hz), 7.76 (2H, d, J ) 8.8 Hz), 7.91
(2H, d, J ) 8.8 Hz). 13C NMR (100 MHz, CDCl3): δ 165.9,
159.4, 144.1, 130.8, 129.6, 128.0, 127.4, 126.1, 114.3, 55.0, and
51.9. LC-MS (ESI): tR ) 4.53 min (m/z 243.3 [M + H] +). HRMS
(ESI): m/z calcd (C15H14O3Na) 265.0841, found 265.0844 [M
+ Na]+.
Hz), 12.94 (1H, br s). 13C NMR (100 MHz, CDCl3): δ 166.9,
143.0, 135.3, 129.7, 129.5, 128.9, 128.8, 126.5, 115.8, and 115.6.
LC-MS (ESI): tR ) 4.78 min (m/z 215.4 [M - H]-). HRMS
(ESI): m/z calcd (C13H9FO2) 216.05865, found 216.05970 [M]+.
4-Th iop h en -3-ylben zoic Acid (13i). HPLC (254 nm): tR
) 5.56 min (97%). 1H NMR (400 MHz, CDCl3): δ 7.61 (1H,
dd, J ) 1.4 and 5.2 Hz), 7.66 (1H, dd, J ) 2.8 and 5.2 Hz),
7.82 (2H, d, J ) 8.4 Hz), 7.94 (2H, d, J ) 8.4 Hz), 8.02 (1H,
dd, J ) 1.4 and 2.8 Hz), 12.90 (1H, br s). 13C NMR (100 MHz,
CDCl3): δ 166.9, 140.2, 138.8, 129.8, 129.2, 127.3, 126.0, 125.8,
and 122.6. LC-MS (ESI): tR ) 4.50 min (m/z 203.4 [M - H]-).
HRMS (ESI): m/z calcd (C11H8O2S) 204.02450, found 204.02355
[M]+.
4′-Flu or obiph en yl-4-car boxylic Acid Meth yl Ester (13e).
HPLC (254 nm): tR ) 6.01 min (95%). 1H NMR (400 MHz,
CDCl3): δ 3.85 (3H, s), 7.31 (2H, t, J ) 9.0 Hz), 7.79 (4H, m),
8.0 (2H, d, J ) 8.4 Hz). 13C NMR (100 MHz, CDCl3): δ 165.8,
163.4, 143.4, 135.1, 129.6, 129.0, 128.9, 128.2, 126.7, 115.9,
115.6, and 52.0. LC-MS (ESI): tR ) 4.53 min (m/z 231.2 [M +
H]+). HRMS (ESI): m/z calcd (C14H11O2FNa) 253.0641, found
253.0632 [M + Na]+.
P r ep a r a t ion of Ad d u ct 9: Diels-Ald er Cyclod d it ion
betw een An th r a cen e 7 a n d N-Meth ylm a leim id e. To a
solution of anthracene 7 (285 mg, 0.46 mmol) in CH2Cl2 (5 mL)
was added N-methylmaleimide (81.5 mg, 0.73 mmol). The
resulting mixture was stirred at room temperature for 48 h.
Amino-silica gel (Isolute-NH2; 4 g) was added to the reaction
mixture, and the resulting suspension was stirred at 50 °C
for 2 h. The mixture was filtered and the silica gel was
thoroughly washed with CH2Cl2 (5 × 5 mL). The combined
filtrates were evaporated in vacuo, and the residue was further
dried under high vacuum to give 9 as an oil (276 mg, 85%).
HPLC (254 nm): tR ) 6.80 min (100%). IR: υmax 3344, and
4-Th iop h en -3-ylben zoic Acid Meth yl Ester (13f). HPLC
1
(254 nm): tR ) 5.77 min (98%). H NMR (400 MHz, CDCl3):
δ 3.83 (3H, s), 7.62 (1H, dd, J ) 1.4 and 5.0 Hz), 7.67 (1H, dd,
J ) 2.8 and 5.0 Hz), 7.87 (2H, d, J ) 8.4 Hz), 7.97 (2H, d, J )
8.4 Hz), 8.06 (1H, dd, J ) 1.4 and 2.8 Hz). 13C NMR (100 MHz,
CDCl3): δ 165.8, 139.9, 139.3, 129.6, 127.7, 127.4, 126.0, 123.0,
and 51.9. LC-MS (ESI): tR ) 4.43 min (m/z 219.2 [M + H]+).
HRMS (ESI): m/z calcd (C12H10O2SNa) 241.0299, found
241.0296 [M + Na]+.
1
1698 cm-1. H NMR (400 MHz, CDCl3): δ 2.47 (5H, m), 2.86
(1H, m), 3.03 (3H, m), 3.18 (1H, d, J ) 8.8 Hz), 3.30 (1H, dd,
J ) 3.2 and 8.4 Hz), 3.46 (6H, s), 4.35 (2H, m), 4.56 (1H, t, J
) 5.2 Hz), 4.73 (1H, d, J ) 3.2 Hz), 6.90 (1H, d, J ) 2.8 Hz),
7.00 (1H, dd, J ) 2.8 and 8.8 Hz), 7.07-7.30 (6H, m), 7.38
(1H, dd, J ) 1.6 and 6.8 Hz), 7.53 (1H, d, J ) 7.0 Hz), 7.63
(2H, d, J ) 8.0 Hz), 7.82 (2H, d, J ) 8.0 Hz), 7.95 (1H, d, J )
8.8 Hz), and 9.44 (1H, s). 13C NMR (100 MHz, CDCl3): δ 176.3,
175.3, 163.6, 155.5, 142.1, 142.0, 140.8, 138.4, 133.3, 131.2,
129.4, 129.1, 128.0, 126.2, 126.0, 125.8, 125.7, 125.5, 124.8,
124.2, 123.6, 122.7, 121.6, 116.8, 112.5, 106.5, 67.8, 54.0, 47.2,
Gen er al P r ocedu r e for Cleavage with Cesiu m Hydr ox-
id e: P r ep a r a tion of Ca r boxylic Acid s 13 g-i. To a
suspension of each of the indolylamide resins 11a -c (50 mg
each) in a mixture of THF and water (10:1; 2 mL) was added
CsOH‚2H2O (2 mg) The suspensions were shaken at room
temperature for 16 h and then filtered. The resins were washed
with 10% HCl aqueous solution (3 × 2 mL) and CH2Cl2 (3 ×
2 mL). The separated organic layers were evaporated in vacuo
to leave oils which were further dried under high vacuum to
afford carboxylic acids 13g-i.
47.0, 45.5, 44.9, 36.7, 24.5, 23.7, and 23.6. LC-MS (ESI): tR
)
4.84 min (m/z 709.5 [M - H]- and 679.3 [M - MeO]-). HRMS
(ESI): m/z calcd (C39H37BrN2O6Na) 731.1733, found 731.1759
[M + Na]+.
4′-Meth oxybiph en yl-4-car boxylic Acid (13g). HPLC (254
nm): tR ) 6.07 min (94%). 1H NMR (400 MHz, CDCl3): δ 3.79
(3H, s), 7.03 (2H, d, J ) 8.8 Hz), 7.67 (2H, d, J ) 8.8 Hz), 7.72
(2H, d, J ) 8.8 Hz), 7.95 (2H, d, J ) 8.8 Hz), 12.87 (1H, br s).
13C NMR (100 MHz, CDCl3): δ 167.0, 159.3, 143.7, 131.1,
Ack n ow led gm en t. GlaxoSmithKline is gratefully
acknowledged for financial support of this work.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
129.7, 128.8, 127.9, 125.9, 114.3, and 55.0. LC-MS (ESI): tR
)
1
tal methods and copies of H NMR and 13C NMR spectra of
4.68 min (m/z 227.3 [M - H]-). HRMS (ESI): m/z calcd
compounds 1, 4, 5, 6, 7, 9, and 13a -i, and 1H HRMAS and
gel-phase 13C NMR spectra of 8 and 12. This material is
available free of charge via the Internet at http://pubs.acs.org.
(C14H13O3) 229.0864, found 229.0856 [M + H]+.
4′-F lu or obip h en yl-4-ca r boxylic Acid (13h ). HPLC (254
nm): tR ) 5.94 min (100%). 1H NMR (400 MHz, CDCl3): δ
7.30 (2H, t, J ) 9.0 Hz), 7.76 (4H, m), 7.99 (2H, d, J ) 8.8
J O034219I
4194 J . Org. Chem., Vol. 68, No. 11, 2003