Synthesis of polymer-bound 4-acetoxy-3-phenylbenzaldehyde derivatives: Applications in solid-phase organic synthesis

Article abstract of DOI:10.1021/jo061328z

(Chemical Equation Presented) Aminomethyl polystyrene resin was reacted with 4-(5′-formyl-2′-hydroxyphenyl)benzoic acid and 4-(5′-formyl-2′-hydroxyphenyl)phenyl propionic acid, respectively, in the presence of 1-hydroxybenzotriazole and 1,3-diisopropylcarbodiimide to yield polymer-bound benzaldehydes. The phenolic group in resins was acetylated with acetic anhydride to afford two polymer-bound 4-acetoxybenzaldehydes. The reductive amination of polymer-bound linkers by amines and sodium triacetoxyborohydride, followed by sulfonylation with arylsulfonyl chloride derivatives in the presence of pyridine and the cleavage with TFA/DCM/H ₂O, produced pure sulfonamides.

Full text of DOI:10.1021/jo061328z

Therefore, the polymer-bound linkers that have application in
producing pure final products are preferred. Stable polymer-
bound linkers are needed that provide the concomitant cleavage
of pure and various products and removal of the linker group
without any loss in overall synthetic efficiency. Furthermore,
for the synthesis of a diverse number of compounds, such as
organosulfur and organophosphorus compounds, polymer-bound
linkers have not been developed extensively.
To explore further the synthetic utility of the polymer-bound
linkers as tools for the synthesis of a diverse number of
compounds without the need of purification in the final cleavage
step, two new polymer-bound linkers of p-acetoxybenzaldehyde,
1a and 1b, were synthesized (Figure 1).
Synthesis of Polymer-Bound
4-Acetoxy-3-phenylbenzaldehyde Derivatives:
Applications in Solid-Phase Organic Synthesis
Anil Kumar,†,‡ Guofeng Ye,† Yousef Ahmadibeni,† and
Keykavous Parang*,†
Department of Biomedical and Pharmaceutical Sciences,
College of Pharmacy, The UniVersity of Rhode Island, Kingston,
Rhode Island 02881, and Chemistry Group, Birla Institute of
Technology and Science, Pilani, Rajasthan, India 333031
kparang@uri.edu
ReceiVed June 27, 2006
Because of the proximity of the amino group and the
p-acetoxy group in the previously reported polymer-bound
linkers of p-acetoxybenzyl alcohol,20,23,24 the intramolecular
reactions caused uncontrolled partial release of some intermedi-
ates before further modifications on attached moieties (X)
(Scheme 1). Therefore, the yield of the final products was lower
than expected.
Polymer-bound p-acetoxybenzaldehydes 1a and 1b offered
several advantages compared to other polymer-bound linkers
reported by us and others.20,23,24 First, a large separation between
the nitrogen atom in amide and the p-acetoxy group was
introduced in new polymer-bound linkers 1a and 1b. The
presence of the nitrogen atom in the amide form and the large
distance between the amide bond and the p-acetoxy group
minimized the intramolecular reaction between these functional
Aminomethyl polystyrene resin was reacted with 4-(5′-
formyl-2′-hydroxyphenyl)benzoic acid and 4-(5′-formyl-2′-
hydroxyphenyl)phenyl propionic acid, respectively, in the
presence of 1-hydroxybenzotriazole and 1,3-diisopropylcar-
bodiimide to yield polymer-bound benzaldehydes. The
phenolic group in resins was acetylated with acetic anhydride
to afford two polymer-bound 4-acetoxybenzaldehydes. The
reductive amination of polymer-bound linkers by amines and
sodium triacetoxyborohydride, followed by sulfonylation
with arylsulfonyl chloride derivatives in the presence of
pyridine and the cleavage with TFA/DCM/H2O, produced
pure sulfonamides.
(6) Kenner, G. W.; McDermott, J. R.; Sheppard, R. C. Chem. Commun.
1971, 12, 636-637.
(7) Backes, B. J.; Ellman, J. A. J. Am. Chem. Soc. 1994, 116, 11171-
11172.
(8) Backes, B. J.; Ellman, J. A. J. Org. Chem. 1999, 64, 2322-2330.
(9) Backes, B. J.; Dragoli, D. R.; Ellman, J. A. J. Org. Chem. 1999, 64,
5472-5478.
(10) Link, A.; van Calenbergh, S.; Herdewijn, P. Tetrahedron Lett. 1998,
39, 5175-5176.
Solid-phase organic synthesis has emerged as a powerful tool
to generate large molecular libraries1-3 of small-sized molecules
and to accelerate lead discovery and optimization processes.
The challenge now is to extend the ability of solid-phase
chemistry to generate a large number of structurally diversified
compounds by developing suitable polymer-bound reagents4,5
that accommodate the synthesis of various compounds.
(11) Golisade, A.; Herforth, C.; Wieking, K.; Kunick, C.; Link, A. Bioorg.
Med. Chem. Lett. 2001, 11, 1783-1786.
(12) Routledge, A.; Abell, S.; Balasubramanian, S. Tetrahedron Lett.
1997, 38, 1227-1230.
(13) Lee, H. B.; Balasubramanian, S. J. Org. Chem. 1999, 64, 3454-
3460.
(14) Wade, W. S.; Yang, F.; Sowin, T. J. J. Comb. Chem. 2000, 2, 266-
275.
The reagents have to be attached to the polymer through a
linker. Linkers that can generate different compounds depending
on the attached compounds and the cleavage conditions are
needed. A number of polymer-bound linkers have been used
for the synthesis of different compounds.5-29 In some cases,
the purification of final products is still needed because of the
instability of polymer-bound linkers in different reaction condi-
tions and/or the leakage of different materials upon cleavage.
(15) Hulme, B.; Peng, J.; Morton, G.; Salvino, J. M.; Herpin, T.;
Labaudiniere, R. Tetrahedron Lett. 1998, 39, 7227-7230.
(16) Panke, G.; Frank, R. Tetrahedron Lett. 1998, 39, 17-18.
(17) Nicolaou, K. C.; Winssinger, N.; Hughes, R.; Smethurst, C.; Cho,
S. Y. Angew. Chem., Int. Ed. 2000, 39, 1084-1088.
(18) Scicinski, J. J.; Congreve, M. S.; Ley, S. V. J. Comb. Chem. 2004,
6, 375-384.
(19) Estep, K. G.; Neipp, C. E.; Stramiello, L. M. S.; Adam, M. D.;
Allen, M. P.; Robinson, S.; Roskamp, E. J. J. Org. Chem. 1998, 63, 5300-
5301.
(20) Chitkul, B.; Atrash, B.; Bradley, M. Tetrahedron Lett. 2001, 42,
6211-6214.
† The University of Rhode Island.
‡ Birla Institute of Technology and Science.
(21) Parang, K.; Fournier, E. J.-L.; Hindsgaul, O. Org. Lett. 2001, 3,
307-309.
* Corresponding author. Phone: +1-401-874-4471. Fax: +1-401-874-5787.
(1) Gallop, M. A.; Barret, R. W.; Dower, W. J.; Fodor, S. P. A.; Gordon,
E. M. J. Med. Chem. 1994, 37, 1233-1251.
(22) Parang, K. Bioorg. Med. Chem. Lett. 2002, 12, 1863-1866.
(23) Ahmadibeni, Y.; Parang, K. J. Org. Chem. 2005, 70, 1100-1103.
(24) Ahmadibeni Y.; Parang, K. Org. Lett. 2005, 7, 5589-5592.
(25) Ahmadibeni, Y.; Parang, K. J. Org. Chem. 2006, 71, 5837-5839.
(26) Ahmadibeni, Y.; Parang, K. Org. Lett. 2005, 7, 1955-1958.
(27) Kan, J.; Toy, P. J. Sulfur Chem. 2005, 26, 509-540.
(28) McAllister, L. A.; McCormick, R. A.; Procter, D. J. Tetrahedron
2005, 61, 11527-11576.
(2) Gordon, E. M.; Barret, R. W.; Dower, W. J.; Fodor, S. P. A.; Gallop,
M. A. J. Med. Chem. 1994, 37, 1385-1401.
(3) Terrett, N. K.; Gardner, M.; Gordon, D. W.; Kobylecki, R. J.; Steele,
J. Tetrahedron 1995, 51, 8135-8173.
(4) James, I. W. Tetrahedron 1999, 55, 4855-4946.
(5) Backes, B. J.; Virgilio, A. A.; Ellman, J. A. J. Am. Chem. Soc. 1996,
118, 3055-3056.
(29) Ahmadibeni, Y.; Parang, K. J. Org. Chem. 2006, 71, 6693-6696.
10.1021/jo061328z CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/07/2006
J. Org. Chem. 2006, 71, 7915-7918
7915

FIGURE 1. Polymer-bound linkers of p-acetoxybenzaldehyde, 1a and 1b.
SCHEME 1. Intramolecular Reaction in Polymer-Bound Intermediates Derived from Polymer-Bound p-Acetoxybenzyl Alcohol
Reducing the Efficiency in Solid-Phase Synthesis Because of the Partial Loss and Release of Some of the Unmodified
Intermediates
SCHEME 2. Synthesis of Building Block Linkers 5a and 5b
groups. The polymer-bound intermediates were stable even in
basic conditions. Second, 1a and 1b were designed to produce
final products without the need for purification. The final
products were synthesized in a short period, high yields, and
parallel format and were easily separated from the resin-bound
linkers. Finally, 1a and 1b were stable in basic conditions (e.g.,
pyridine). This allows the potential use of 1a and 1b for the
synthesis of diverse classes of compounds by converting them
to polymer-bound amines through reductive amination and
further substitution of amino functional groups. To demonstrate
this, their application in solid-phase organic synthesis of sulfon-
amides is shown here. Presumably, 1a and 1b can be reduced
to polymer-bound benzyl alcohols and then be used for the syn-
thesis of monophosphorylated compounds as shown previously
for other polymer-bound linkers of p-acetoxybenzyl alcohol.21-25
For the synthesis of polymer-bound p-acetoxybenzaldehydes
1a and 1b, building block linkers, 4-(5′-formyl-2′-hydroxyphe-
nyl)benzoic acid (5a) and 4-(5′-formyl-2′-hydroxyphenyl)phenyl
propionic acid (5b), were required for the attachment to
aminomethyl polystyrene resin. The reaction of 3-bromo-4-
hydroxybenzaldehyde (4) with 4-(4,4,5,5-tetramethyl-1,3,2-
bioxaborolan-2-yl)benzoic acid (3a) in toluene/ethanol/water and
with [4-(2-carboxyethyl)phenyl]boronic acid (3b) in methanol/
water, respectively, in the presence of tetrakis(triphenylphos-
phine)palladium (Pd(Ph3P)4) afforded 5a (83%) and 5b (92%)
(Scheme 2). Compound 3a was synthesized quantitatively by
the reaction between 2,3-dimethyl-2,3-butanediol (pinacol) and
4-carboxylphenylboronic acid (2) in THF/toluene (Scheme 2).
Although compound 2 can be used directly in reaction with 4,
we used the protected form of boronic acid 3a. It appears that
the protection of boronic acid is not essential because 5b was
produced from unprotected 3b in a slightly higher yield when
compared to that of 5a from protected 3a.
Building block linkers 5a and 5b were used for the synthesis
of 1a and 1b, respectively (Scheme 3). The reaction of
aminomethyl polystyrene resin 6 with 5a and 5b, respectively,
in the presence of 1-hydroxybenzotriazole (HOBt) and 1,3-
diisopropylcarbodiimide (DIC) afforded 7a,b. Polymer-bound
p-acetoxybenzaldehydes, 1a,b, were synthesized by the reaction
of 7a,b with acetic anhydride in the presence of pyridine
(Scheme 3).
7916 J. Org. Chem., Vol. 71, No. 20, 2006

SCHEME 3. Synthesis of Solid-Phase Polymer-Bound Linkers of 4-Acetoxy-3-phenylbenzaldehyde (1a,b)
SCHEME 4. Synthesis of Sulfonamides
We investigated whether developed polymer-bound linkers
can have potential application for the synthesis of sulfonamides.
Sulfonamides are currently used as therapeutic agents, such as
sulfa antibiotics (e.g., sulfathiazole) or serotonin antagonists
(e.g., antimigraine Sumatriptan).30 Isoquinoline sulfonamides
inhibit protein kinases by competing with ATP.31-33 Although
sulfonamides can be synthesized through solution-phase meth-
ods, the synthesis of a large library of sulfonamides using these
strategies is cumbersome because a large number of final
products need to be purified. Several solid-phase routes have
been reported for the synthesis of sulfonamides.34,35 We
examined polymer-bound linkers of p-acetoxybenzaldehyde
(1a,b) for the synthesis of sulfonamides to demonstrate their
general application.
aldehydes 1a,b by amines (8) (e.g., aniline, 4-chloroaniline,
benzylamine, 4-methoxybenzylamine) and sodium triacetoxy-
borohydride (NaBH(OAc)3) afforded 9-12a and 9-12b. Sulfon-
ylation of resin-bound amines 9-12a and 9-12b with arylsul-
fonyl chloride derivatives (e.g., p-toluenesulfonyl chloride, 3,5-
dimethoxybenzene-1-sulfonyl chloride, 3-nitrobenzenesulfonyl
chloride) in the presence of pyridine gave polymer-bound
sulfonamides 13-24a and 13-24b. The sulfonamide remained
bound to the polymer-bound linker under basic conditions. The
activation step by hydrolysis of the acetyl group and cleavage
of the products from the resins in TFA/DCM/H2O (74:24:2 v/v/
v) produced pure sulfonamides 26-37 (>98%) (Scheme 4). In
total, by using different combinations of amines and sulfonyl
chlorides, 12 compounds were synthesized using both polymer-
bound linkers (overall yield 60-83%, calculated from 1a,b).
Compounds 27, 30, 33, and 36 are novel compounds.
The cleavage mechanism of the final sulfonamides from 13-
24a and 13-24b is shown in Scheme 4. The multistep cleavage
mechanism is shown in one step here for simple demonstration.
The linkers remained covalently bound on the resins using both
polymer-bound linkers, which facilitated the separation of the
final products by filtration.
Figure 2 shows the chemical structures of the synthesized
compounds. The final products were characterized by nuclear
magnetic resonance spectra (1H NMR and 13C NMR) and high-
resolution time-of-flight electrospray mass spectrometry.
The solid-phase synthetic strategy of sulfonamides consisted
of three steps (Scheme 4): reductive amination, sulfonylation,
and cleavage. The reductive amination of polymer-bound
(30) Meng, C. Q. Curr. Med. Chem. 1997, 4, 385-404.
(31) Xu, R. M.; Carmel, G.; Kuret, J.; Cheng, X. Proc. Natl. Acad. Sci.
U.S.A. 1996, 93, 6308-6313.
(32) Hidaka, H.; Inagaki, M.; Kawamoto, S.; Sasaki, Y. Biochemistry
1984, 23, 5036-5041.
(33) Ricouart, A.; Gesquiere, J. C.; Tartar, A.; Sergheraert, C. J. Med.
Chem. 1991, 34, 73-78.
(34) Fivush, A. M.; Willson, T. M. Tetrahedron Lett. 1997, 38, 7151-
7154.
(35) Raju, A.; Kogan, T. P. Tetrahedron Lett. 1997, 38, 3373-3376.
J. Org. Chem, Vol. 71, No. 20, 2006 7917

FIGURE 2. Structures of synthesized sulfonamides.
TABLE 1. Overall Isolated Yields and Final Cleavage Yields of
Products for Sulfonamides (26-37)
Experimental Section
As a representative example, resin 1a (1.62 g, 0.78 mmol/g) was
swelled in 1,2-dichloroethane (30 mL) and was shaken at room
temperature for 15 min. Aniline (0.6 mL, 6.4 mmol) was added to
the swelled resin. The mixture was shaken for 1 h at room
temperature. NaBH(OAc)3 (1.35 g, 6.4 mmol) was added to the
reaction mixture. After 6 h of shaking at room temperature, the
resin was collected by filtration and washed with water (2 × 30
mL), DCM (2 × 30 mL), and MeOH (2 × 30 mL), respectively,
and dried under vacuum to give 9a (1.71 g, 94%, 0.70 mmol/g).
Polymer-bound aniline 9a (550 mg, 0.70 mmol/g) was swelled in
cold dry pyridine (30 mL). To the swelled resin was added
p-toluenesulfonyl chloride (1.0 g, 5.26 mmol), and the reaction was
shaken at room temperature for 6 h. The resin was washed with
water (2 × 30 mL), DCM (2 × 30 mL), and MeOH (2 × 30 mL)
and dried under vacuum for 24 h to give 13a (606 mg, 95%, 0.60
mmol/g). Polymer-bound sulfonamide 13a (606 mg, 0.60 mmol/g)
was suspended in TFA/DCM/H2O (74:24:2 v/v/v, 5 mL). After 30
min of shaking the mixture at room temperature, the resin was
collected by filtration and washed with DCM (5 mL), THF (5 mL),
and MeOH (5 mL). The filtrate was evaporated at room temperature,
and the residue was washed with water (10 mL) and extracted with
ethyl acetate (2 × 10 mL). The organic phase was dried with
anhydrous sodium sulfate and evaporated to afford pure 4-methyl-
N-phenylbenzenesulfonamide (26, 84 mg, 94%; overall yield
final cleavage final cleavage
overall yield (%) overall yield (%)
yield (%)
yield (%)
no.
calcd from 1a
calcd from 1b
from 13-24a from 13-24b
26
27
28
29
30
31
32
33
34
35
36
37
83
78
80
82
81
72
70
77
62
67
76
67
72
73
74
76
74
60
78
74
74
74
79
72
94
91
96
88
89
84
85
90
80
88
95
88
89
86
89
93
89
78
90
87
89
88
90
86
Products were compared for yield and purity. There were no
significant differences in the purity of the final products using
resin-bound linkers 1a and 1b (>98%), but most compounds
were produced from 1a in higher yields than those from 1b
(Table 1). The compounds did not need any purification (>98%
pure) compared with the previously reported solid-phase
methods for the synthesis of sulfonamides34,35 and were
produced in comparable or higher yields.
1
calculated from 1a, 83%). H NMR (CDCl3, 400 MHz, δ ppm):
In conclusion, two stable polymer-bound linkers were syn-
thesized and used for the solid-phase synthesis of sulfonamides.
The amines and sulfonyl chlorides were mixed with the polymer-
bound linkers, respectively, and were thereby “captured” as
immobilized compounds. Washing the support guaranteed that
no unreacted starting amines or sulfonyl chlorides remained.
In the final cleavage reaction, the linkers remained covalently
bound on the resins, which facilitated the separation of the final
products by filtration. This solid-phase strategy allowed the
synthesis of sulfonamides in a short synthetic route without the
need for purification of intermediates and final products.
Furthermore, this strategy offered the advantages of facile
isolation and recovery of pure final products. These polymer-
bound linkers can be used for solid-phase preparation of other
biologically important compounds.
7.70 (d, J ) 8.30 Hz, 2H), 7.30-7.21 (m, 4H), 7.19 (br s, 1H),
7.14-7.06 (m, 3H), 2.37 (s, 3H). 13C NMR (CDCl3, 100 MHz, δ
ppm): 144.3, 137.0, 136.4, 130.1, 129.7, 127.7, 125.6, 121.9, 22.0.
HR-MS (ESI-TOF) (m/z) for C13H13NO2S: calcd, 247.0667; found,
248.2760 [M + H]+.
Acknowledgment. We acknowledge the financial support
from the National Center for Research Resources, NIH, Grant
Number 1 P20 RR16457.
Supporting Information Available: Experimental procedures
and characterization of intermediates with FT-IR and final com-
pounds with 1H NMR, 13C NMR, and high-resolution mass
spectrometry. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO061328Z
7918 J. Org. Chem., Vol. 71, No. 20, 2006