Versatile Acylation of N-Nucleophiles Using a New Polymer-Supported 1-Hydroxybenzotriazole Derivative

Article abstract of DOI:10.1021/jo961761g

The synthesis of a new polymer-supported coupling reagent derived from 1-hydroxybenzotriazole is described. An aminomethylated polystyrene was functionalized by reaction with 3-nitro-4- chlorobenzenesulfonyl chloride (2) followed by treatement with hydrazine hydrate, to give the polymeric N-benzyl-1-hydroxybenzotriazole-6-sulfonamide (4).The polymeric reagent 4 was shown to be highly efficient for the synthesis of amides. The efficiency of 4 could be attributed to its high acidity, conferred by the sulfonyl moiety. The procedure for amide synthesis involves the formation of an activated ester on the derivatized polymer followed, in a second step, by treatment with an amine to generate the amide in solution. Simple filtration allows the separation of the product from the polymeric reagent which in this case plays the role of leaving group. An optimization study of this two-step procedure was performed. As amides are obtained in solution free of reaction byproducts, this method can be used in an automated procedure to recover them directly into a 96 well plate, ready to be used in high throughput screening assays. Thus 4 was shown to be particularly suitable for the high throughput parallel synthesis of amides libraries.

Full text of DOI:10.1021/jo961761g

2594
J . Org. Chem. 1997, 62, 2594-2603
Ver sa tile Acyla tion of N-Nu cleop h iles Usin g a New
P olym er -Su p p or ted 1-Hyd r oxyben zotr ia zole Der iva tive
Iuliana E. Pop,† Benoˆıt P. De´prez,† and Andre´ L. Tartar*,‡
CEREP, 1 rue du Pr. Calmette, 59 019 Lille Ce´dex, France and Chimie des Biomole´cules,
URA CNRS 1309, Institut Pasteur de Lille, Faculte´ de Pharmacie,1 rue du Pr. Calmette,
59 019 Lille Ce´dex, France
Received September 13, 1996X
The synthesis of a new polymer-supported coupling reagent derived from 1-hydroxybenzotriazole
is described. An aminomethylated polystyrene was functionalized by reaction with 3-nitro-4-
chlorobenzenesulfonyl chloride (2) followed by treatement with hydrazine hydrate, to give the
polymeric N-benzyl-1-hydroxybenzotriazole-6-sulfonamide (4).The polymeric reagent 4 was shown
to be highly efficient for the synthesis of amides. The efficiency of 4 could be attributed to its high
acidity, conferred by the sulfonyl moiety. The procedure for amide synthesis involves the formation
of an activated ester on the derivatized polymer followed, in a second step, by treatment with an
amine to generate the amide in solution. Simple filtration allows the separation of the product
from the polymeric reagent which in this case plays the role of leaving group. An optimization
study of this two-step procedure was performed. As amides are obtained in solution free of reaction
byproducts, this method can be used in an automated procedure to recover them directly into a 96
well plate, ready to be used in high throughput screening assays. Thus 4 was shown to be
particularly suitable for the high throughput parallel synthesis of amides libraries.
In tr od u ction
soluble polymers can also be used not only as supports
for the growing molecule but also as tethers for reagents
or catalysts. In this case, unlike classical solid phase
syntheses, the reagents remain attached to the insoluble
matrix, while the desired product generated in solution
is easily recovered by filtration. Reagents such as
nitrophenol,10-13 HOBt (1-hydroxybenzotriazole),14-16 car-
bodiimides,17,18 DMAP (4-(dimethylamino)pyridine)19 or
triphenylphosphine,20-22 which have been synthesized on
polymeric beads, should meet a renewed interest for the
synthesis of small organic molecules, especially for two-
or three-step routes.
Recent advances in molecular biology and automation
have led to a dramatic increase in the throughput of the
biological screening. Consequently, the rapid generation
of large arrays of chemically diverse compounds has
become a major tool in the search for novel lead struc-
tures. Large numbers of oligomeric compounds have
been synthesized rapidly by repetitive coupling reactions,
using both solid phase techniques and automated syn-
thesizers which were developed for peptide and oligo-
nucleotide synthesis during the past three decades. The
limited number of building blocks from which they stem
limits their chemical diversity. In this context, the
synthesis of diverse small organic molecules has received
much attention during the recent years.
Taking into account that commercially available amines
and carboxylic acids give access to a wide structural
diversity space, our aim was to design a reaction scheme
One of the major difficulties encountered during the
synthesis of large chemical libraries is conciliating the
need for highly diverse arrays of compounds with their
heterogeneous behavior either from physical or from
chemical points of view. Organic synthesis by solid phase
methods is therefore emerging as a powerful tool for clean
generation of structurally diverse small organic mol-
ecules. Tethering starting materials or reagents to an
insoluble polymer allows great simplifications in all
handling steps, rendering the automation process readily
feasible. Heterocycles as benzodiazepines, diketopiper-
azines, and hydantoins were synthesized on insoluble
polymers.1-3 A wide range of organic reactions such as
Mitsunobu,4 Still,5,6 Heck,7,8 Horner-Emmons9 have
already been performed on solid phase. However, in-
(7) Yu, K.-L.; Deshpande, M. S.; Vyas, D. M. Tetrahedron. Lett. 1994,
35, 8919.
(8) Hiroshige, M.; Hauske, J . R.; Zhou, P. Tetrahedron. Lett. 1995,
36, 4567.
(9) Chen, C.; Ahlberg Randall, L. A.; Miller, R. B.; J ones, A. D.;
Kurth, M. J . J . Am. Chem. Soc. 1994, 116, 2661.
(10) Fridkin, M.; Patchornic, A.; Katchalski, E. J . Am. Chem. Soc.
1965, 87, 4646.
(11) Fridkin, M.; Patchornic, A.; Katchalski, E. J . Am. Chem. Soc.
1966, 88, 3164.
(12) Kalir, R.; Fridkin, M.; Patchornic, A. Eur. J . Biochem. 1974,
42, 151.
(13) Fridkin, M.; Hazum, E.; Kalir, R.; Rotman, M.; Koch, Y. J . Solid-
Phase Biochem. 1977, 2, 175.
(14) Kalir, R.; Warshawsky, A.; Fridkin, M.; Patchornic, A. Eur. J .
Biochem. 1975, 59, 55.
(15) Mokotoff, M.; Patchornic, A Int. J . Pept. Protein Res. 1983, 21,
145.
(16) Mokotoff, M.; Zhao, M.; Roth, S. M.; Slavosky, J . N; Shelley, J .
A. J . Med. Chem. 1990, 33, 354.
(17) Weinshenker, A.; Shen, C.-M. Tetrahedron Lett. 1972, 3281.
(18) Desai, M. C.; Stephens Straminello, L. M. Tetrahedron Lett.
1993, 34, 7685.
(19) Shai, Y.; J acobson, K. A.; Patchornic, A. J . Am. Chem. Soc. 1985,
107, 4249.
(20) McKenzie, W. M.; Sherrington, D. C. J ournal of Polymer
Science: Polymer Chemistry Edition; J ohn Wiley & Sons, Inc., 1982;
Vol. 20.
(21) Harrison, C. R.; Hodge, P.; Hunt, B. J .; Khoshedel, E.; Rich-
ardson, G. J . Org. Chem. 1983, 48, 3721.
(22) Caputo, R.; Cassano, E.; Longobardo, L.; Mastroiani, D.;
Palumbo, G. Synthesis 1995, 141.
† CEREP.
‡ Institut Pasteur de Lille.
X Abstract published in Advance ACS Abstracts, March 1, 1997.
(1) Bunin, B. A.; Ellman, J . A. J . Am. Chem. Soc. 1992, 114, 10997.
(2) Hobbs DeWitt, S.; Kiely, J . S.; Stankovic, C. J .; Schroeder, M.
C.; Reynolds Cody, D. M.; Pavia, M. R. Proc. Natl. Acad. Sci. U.S.A.
1993, 90, 6909.
(3) Hobbs DeWitt, S.; Schroeder, M. C.; Stankovic, C. J .; Strode, J .
E.; Czarnic, A. W. Drug Dev. Res. 1994, 33, 116.
(4) Rano, T. A.; Chapman, K. T. Tetrahedron Lett. 1995, 36, 3789.
(5) Deshpande, M. S. Tetrahedron Lett. 1994, 35, 5613.
(6) Forman, F. W.; Sucholeiki, I. J . Org. Chem. 1995, 60, 523.
S0022-3263(96)01761-6 CCC: $14.00 © 1997 American Chemical Society

Versatile Acylation of N-Nucleophiles
J . Org. Chem., Vol. 62, No. 8, 1997 2595
Sch em e 1a
for the synthesis of large arrays of amides, easily imple-
mentable in a robotic system. The need for a clean
activation procedure led us first to focus on the use of
the previously described polymeric carbodiimide.18 No
additional soluble reagent is needed when activating
acids with this polymeric carbodiimide. Nevertheless, we
encountered two major difficulties associated with this
functionalized polymer. The described synthesis of this
polymeric reagent lacks reproducibility and is not easily
monitored, neither is the final reagent easily character-
ized.23 Considering these difficulties, we decided to
develop a procedure involving a soluble activating re-
agent and a polymeric nucleophile, likely to form reactive
isolable esters with most of the carboxylic acids. Poly-
meric nitrophenol and 1-hydroxybenzotriazole (HOBt)
were already used in peptide synthesis; however, the
most successful for the amide bond creation was a HOBt-
containing polymer.10-16 HOBt is well known for its
efficiency in coupling amino acids, improving reactions
kinetics, and decreasing racemization. On these bases,
our interest has been devoted to the synthesis of an
improved polymer-supported HOBt.
a
(a) Et3N, CH2Cl2, rt, 5 h; (b) NH2NH2, EtOH, reflux, 5 h; (c)
HCl, dioxane.
Sch em e 2a
The previously described14 functionalization of poly-
styrene beads via a Friedel-Crafts alkylation is rather
delicate and moreover, is limited to aryl-containing
polymers. Our aim was to design a more versatile
anchoring scheme of the HOBt moiety, suitable for any
kind of amino-functionalized polymer such as polyethyl-
ene oxide-grafted polystyrene, polymethacrylate, func-
tionalized polyethylene, or polypropylene. In this paper
we describe the synthesis and evaluation of a new
polymer-supported HOBt derivative, and we explore the
reactivity of this polymeric coupling reagent toward a
variety of carboxylic acids and N-nucleophiles.
a
(a) Et3N, CH2Cl2, rt, 2.5 h; (b) NH2NH2, EtOH, reflux, 5 h; (c)
aqueous HCl, pH 0.9.
Resu lts a n d Discu ssion
materials, but also allows the introduction of the required
electron-withdrawing group. An aminomethylated di-
vinylbenzene cross-linked polystyrene charged with 1.6
mmol of amino-groups/g was reacted with the sulfonyl
chloride 2 at room temperature in the presence of Et3N
to give the sulfonamide-derivatized polymer 3 (Scheme
1). The reaction went to completion within 5 h, as
determined by a quantitative ninhydrin test.29 Reacting
3 with hydrazine hydrate under reflux of ethanol and
subsequent treatment with a dioxane solution of hydro-
chloric acid afforded the polymer-bound 1-hydroxy-
benzotriazole-6-sulfonamide (4) under neutral form. The
loading of 4 was determined by acetylation of the hy-
droxyl groups on the polymer followed by aminolysis of
the polymer-bound activated ester with benzylamine and
subsequent quantification of the unreacted amine in the
reaction mixture. A substitution level of 0.8-1 mmol of
hydroxyl-groups/g of polymer was found.
Highly efficient HOBt-derived soluble coupling re-
agents have recently been reported.24-27 The increased
effectiveness of these novel coupling reagents was ob-
tained by incorporating electron-withdrawing substitu-
ents on the benzotriazole ring (although, in the case of
the 1-hydroxy-7-azabenzotriazole (HOAt) an intramo-
lecular base catalysis was also suspected). In this
context, incorporating an electron-withdrawing substitu-
ent in the polymer-supported benzotriazole ring was
expected to enhance its reactivity. Syntheses of several
HOBt derivatives were already described.28 Among
them, N-ethyl-1-hydroxybenzotriazole-6-sulfonamide (1)
was selected for the derivatization of an aminofunction-
alized polymer. Indeed, a polymer-supported derivative
In order to evaluate its properties, the soluble N-ben-
zyl-1-hydroxybenzotriazole-6-sulfonamide (6) was also
1
synthesized (Scheme 2). pKa and H NMR studies were
performed to compare the acidities of the following
compounds: 6, HOBt (7), HOSu (1-hydroxysuccinimide)
(8), and 2-nitrophenol (9). The pKa values found for 7-9
were in good agreement with the literature.30 Both the
pKa and chemical shifts of the hydroxyl proton indicated
a higher acidity of 6 (Table 1). This is explained by the
strong electron-withdrawing effect induced by the sulfo-
nyl moiety. The acidity of 6 (pKa ) 3.59) is close to that
of 1 is not only easy to obtain from commercially available
(23) The synthesis and use of a polymer-bound carbodiimide cationic
derivative, which seems to overcome these difficulties, was meanwhile
reported.18
(24) Carpino, L. A. J . Am. Chem. Soc. 1993, 115, 4397.
(25) J ensen, T.-H.; Olsen, C. A.; Holm, A. J . Org. Chem. 1994, 59,
1257.
(26) Carpino, L. A.; Faham, A. -E.; Minor, C. A.; Albericio, F. J .
Chem. Soc., Chem. Commun. 1994, 201.
(27) Wijkmans, J . C. H. M.; Blok, F. A. A.; van der Marel, G. A.;
van Boom, J . H.; Bloemhoff, W. Tetrahedron Lett. 1995, 36, 4643.
(28) Ko¨nig, W.; Geiger, R. Chem. Ber. 1970, 103, 788.
(29) Sarin, V. K.; Kent, B. H.; Tam, J . P.; Merrifield, R. B. Anal.
Biochem. 1981, 117, 147.

2596 J . Org. Chem., Vol. 62, No. 8, 1997
Pop et al.
Ta ble 1. p Ka Va lu es a n d Ch em ica l Sh ift of th e Acid
P r oton for 6-9
requires large volumes of solvents. This problem could
be only partially overcome using DIC (data not shown).
On the contrary, PyBrOP is highly soluble, as well as
the byproducts generated during the activation. PyBrOP
was shown to be highly effective for difficult couplings
in the field of peptide synthesis.31,32 It was thus selected
and submitted to further experimentation to determine
the most suitable activating conditions.
2. Op tim iza tion of th e Activa tion Step Usin g
P yBr OP a s Solu ble Activa tin g Rea gen t. To this aim,
three acids were used: 5-methyl-2-nitrobenzoic acid (a ),
2-(p-toluoyl)benzoic acid (b), and diphenylacetic acid (c).
The efficiency of the activation was determined in each
case by the amount of amide formed upon reaction of the
resulting polymer-bound species with benzylamine. Single
and double activation procedures were tested, as well as
different amounts of acid with respect to the polymer-
bound reagent 4 (Table 2). The best results were
obtained when using a double activation procedure
(entries 3, 5, and 8 in Table 2). Attempts to improve the
activation by increasing the activation time were unsat-
isfactory (entries 1, 3, and 5 in Table 3). The reaction
time was optimized to allow the reaction of less reactive
species and to minimize the decomposition of the polymer-
bound esters.33 The conditions for an effective activation
when using PyBrOP as soluble activating reagent were
found to be: 2 × 3 h activating time using 3 equiv of
acid for each activation step.
B. Cou p lin g Step . Op tim iza tion of th e Cou p lin g
Tim e. The reaction time of the polymer-bound esters
with N-nucleophiles was then investigated. In initial
experiments, reactions of benzylamine and 2-aminoben-
zothiazole with the polymer-bound active ester of 5-methyl-
2-nitrobenzoic acid (10a ) were used to determine the
optimum coupling time. While benzylamine was quan-
titatively acylated within 1 h, used under the same
conditions, 2-aminobenzothiazole reacted more slowly, a
maximal conversion of 68% being obtained after 25 h. In
the meantime, 20% of the activated ester was decom-
posed, as indicated by the presence of free carboxylic
derivative in the solution (Table 4). The optimum
coupling time was found to be 20 h. Further increase of
the coupling time was not likely to improve coupling
yields, as we have previously shown33 that in the absence
of nucleophile, 62% of the polymer-bound ester is hydro-
lyzed in DMF solution during that period of time.
C. Scop e of th e Meth od . Commercially available
carboxylic acids and N-nucleophiles (about 700 different
structures in each group) were divided into several
classes, according to criteria based on structural and
reactivity parameters. Representative structures were
chosen for each class and were tested under the condi-
tions previously defined, to establish the range of ap-
plicability of this method to the synthesis of amides.
1. Rea ctivity of Ca r boxylic Acid s tow a r d th e
P olym er -Bou n d Rea gen t 4. The following compounds
were chosen to investigate the reactivity of the different
compd
pKa
chemical shift (ppm)a
6
7
8
9
3.59
4.64
6.00
7.15
14.0
13.6
11.0
10.6
1H NMR spectra were performed in C6D6.
a
of HOAt (pKa ) 3.47), which is known to be a highly
efficient coupling reagent in the peptide synthesis. Ac-
cording to the general assumption that the electrophi-
licity of an active ester is related to the acidity of the
parent alcohol,30 these findings should indicate a great
effectiveness of 4 in promoting amide bond formation.
Gen er a l Op tim iza tion of Am id es Syn th esis Usin g
th e P olym er ic Rea gen t 4. Our aim was to adapt the
use of 4 to the coupling of the largest array of carboxylic
acids and N-nucleophiles, in the view of its further use
in parallel combinatorial synthesis. Synthesis of amides
using 4 requires a two-step procedure: first, the esteri-
fication of the polymer-bound HOBt with the carboxylic
acid by the mean of a soluble activating reagent. After
removal of the reagent in excess, the next step involves
the reaction of the N-nucleophile and subsequent release
of the acylated product in a soluble form (Scheme 3).
Systematic optimization of both steps was performed.
DMF was found to be the solvent of choice for the
synthesis, according to the solubility studies performed
on a representative cross section of a large set of
compounds (about 700 carboxylic acids and 700
amines): 86% of the amines were soluble at 0.1 M
concentration in DMF while only 55% were soluble at
the same concentration in CH2Cl2, and 84% of the
carboxylic acids were soluble at 0.75 M concentration in
DMF. Moreover, DMF is easily handled in an automated
process, due to its high boiling point and viscosity.
A. Activa tion Step . The soluble activating reagent,
activating time, and excess of reagents were studied to
define a general procedure to activate carboxylic acids
via the polymer-bound reagent 4.
1. Ch oice of th e Solu ble Activa tin g Rea gen t. The
use of activating reagents, such as HBTU (2-(1H-benzo-
triazole-1-yl)tetramethyluronium hexafluorophosphate)
or BOP (benzotriazol-1-yloxy)tris(dimethylamino)phos-
phonium hexafluorophosphate), that generate nucleo-
philic species likely to compete with the nucleophilic
polymer was avoided. Preliminary studies were per-
formed using DCC (N,N′-dicyclohexylcarbodiimide), DIC
(N,N′-diisopropylcarbodiimide), and PyBrOP (bromo-
trispyrrolidinophosphonium hexafluorophosphate). Dif-
ficulties were encountered when using DCC because of
the poorly soluble dicyclohexylurea generated during the
activation. Thus, the separation of the polymer from the
reagents in excess and byproducts becomes difficult and
(31) Fre´rot, E.; Coste, J .; Pantaloni, A.; Dufour, M.-N.; J ouin, P.
Tetrahedron 1991, 47, 259.
(32) Coste, J .; Fre´rot, E.; J ouin, P. Tetrahedron Lett. 1991, 32, 1967.
(33) Stability studies of the polymer-bound activated ester 10a
showed that, in suspension in neat DMF and in the presence of
N-ethyldiisopropylamine, 62% of 10a is decomposed during 25 h to
give the starting polymer 4 and the free carboxylic acid in solution.
Stored under appropriate conditions, the activated esters of 4 were
quite stable. After storage in dry form for two months at +4 °C and
under nitrogen, 10a still gave quantitative yield when reacted with
phenethylamine.
(30) Koppel, I.; Koppel, J .; Leito, I.; Pihl, V.; Grehn, L.; Ragnarsson,
U. J . Chem. Res. (S) 1993, 446.

Versatile Acylation of N-Nucleophiles
J . Org. Chem., Vol. 62, No. 8, 1997 2597
Sch em e 3
Ta ble 2. In flu en ce of th e Qu a n tity of Acid on th e
Activa tion Step a
Ta ble 4. Con ver sion a n d Decom p osition of th e
P olym er -Bou n d Ester 10a d u r in g Cou p lin g With
2-Am in oben zoth ia zolea
time (min)
5
10
20
30
60
90 1500 2940
compd 14 (%)b 7.6 16.7 25.2 32.5 44.9 45.9 68.3 68.0
acid (%)c
1.3
1.6
2.0
2.6
4.0
4.8 17.7 19.5
a
10a was obtained under the optimized activating conditions
previously defined. For the coupling step, 0.16 M DMF solution
of 2-aminobenzothiazole, in equimolar quantity with respect to 10a
b
was used. Yield was determined by HPLC using calibration
curves. c Free acid found in the solution due to the decomposition
of 10a , determined by HPLC using calibration curves.
isolated amide were obtained when reacting benzoic type
acids a , b, and d , as well as sterically hindered acids e
and f (entries 1, 2, and 4-6 in Table 5). Moderate yields
were obtained when activating acids c and g, while no
reaction took place for acid h (entries 3, 7, and 8 in Table
5). For the polymer-bound esters of acids c and h , under
the basic conditions of the activation, the acidity of the
R proton is likely to be responsible for the formation of a
ketene, in which the polymer plays the role of leaving
group. For the nicotinic acid g, the nucleophilic pyridine
ring is likely to be acylated, leading to the cleavage of
the activated ester bond. In this latter case, the activa-
tion could be improved to 55% by reducing the activation
time at 1 h (when activating 2 × 3 h, only 37% yield in
isolated amide was obtained). It is noteworthy that
carboxylic acids showing particular reactivities as c, g,
and h , which should be eliminated when synthesizing a
library of amides by this method, represent about 25%
of the commercially available carboxylic acids. Neverthe-
less, the large number of the commercially available
carboxylic acids tolerated by this chemistry would allow
the synthesis of a very large numbered library of amides.
Ta ble 3. In flu en ce of th e Rea ction Tim e on th e
Activa tion Step a
activating
entry
compd
equiv of acid
time (h)
yield (%)
1
2
3
4
5
6
11
11
12
12
13
13
3 + 3
3 + 3
3 + 3
3 + 3
3 + 3
3 + 3
5 + 15
3 + 3
33
84
73
87
13
50
5 + 15
3 + 3
2. Rea ctivity of N-Nu cleop h iles tow a r d th e P oly-
m er -Bou n d Activa ted Ester s 10. In the next step,
compounds belonging to different classes of N-nucleo-
philes were tested to determine their reactivity toward
the polymer-bound esters. N-nucleophiles were reacted
with the polymer-bound ester 10a . Reactions were
followed by HPLC, and conversions were determined
using calibration curves (Table 6). Good conversions and
excellent purities were obtained when coupling phen-
ethylamine, N,O-dimethylhydroxylamine, 2-amino-5-
methyl-1,3,4-thiadiazole, ethyl 4-aminobenzoate, benzo-
phenonehydrazone, and 5-nitroindazole (entries 1-6 in
Table 6). Only traces of free acid generated by decom-
position of the polymer-bound ester or nonreacted nu-
cleophile were in some cases detected in the reaction
mixture. Interestingly, coupling of 5-nitroindazole (entry
6 in Table 6) required the presence of a base, due to the
fact that in this particular case the reactive species is
5 + 15
3 + 3
a
For each activation step, 0.27 M DMF solutions of acids and
an equimolar quantity of PyBrOP with respect to the acid were
used. For the coupling step, 0.16 M DMF solutions of benzylamine
were used, in equimolar quantity with respect to the polymer-
bound ester.
classes of carboxylic acids toward the reagent 4: the
benzoic-type acids a , b, and d , possessing different
substituents on the aromatic ring; acids e and f, for which
the carboxyl moiety is linked to a hindered aliphatic
carbon; acid g, possessing a nucleophilic group, and acids
c and h , containing an acidic R proton (Table 5). Their
reactivity was estimated by quantifying the amount of
amide formed upon reaction of the corresponding polymer-
bound esters with benzylamine. Very good yields in

2598 J . Org. Chem., Vol. 62, No. 8, 1997
Ta ble 5. Syn th esis of Am id es Usin g Ca r boxylic Acid s a -h a n d Ben zyla m in ea
Pop et al.
Ta ble 6. Rea ction of P olym er -Bou n d Ester 10a w ith Differ en t N-Nu cleop h iles
the anion formed by deprotonation. 2-Aminopyridine
Con clu sion
showed only a poor reactivity (entry 7 in Table 6), while
4-nitroaniline and 2-aminopyrimidine did not react with
10a (entries 8 and 9 in Table 6). Thus highly deactivated
anilines, 2-aminopyrimidines, or 2-aminopyridines should
be eliminated as being too poor nucleophiles to generate
amides by this method. Results in Table 6 show that a
large variety of N-nucleophiles: primary and secondary
amines, moderately deactivated anilines, as well as other
nucleophiles such as hydrazones can be succesfully used
for the synthesis of amides, good to excellent purities of
the crude products being obtained.
A small library of amides was synthesized under the
optimized conditions (Table 7). In most cases good yields
in isolated products were obtained. An excellent selectiv-
ity for the amide formation was found when coupling an
amino alcohol (entries 6 and 10 in Table 7). No traces of
ester or polymeric species were found in these cases in
the reaction mixture, the amide being the sole product.
Satisfactory yields were also obtained when coupling
some less usual N-nucleophiles (entries 1-4 and 9 in
Table 7), which introduce a larger diversity into the
amide library.
A novel HOBt derivative-tethered polymer has been
synthesized. This polymer was designed for the rapid
and clean synthesis of large combinatorial arrays of
amides and related compounds. Optimization studies of
this two-step synthesis, carried out on a wide variety of
carboxylic acids and N-nucleophiles, allowed the choice
of standard reaction conditions. Amides generated in
solution showed in most cases good to excellent purities.
This should allow their direct use in the biological
screenings, without purification. The chemistry de-
scribed in this work should be of broad utility in the
multiple simultaneous synthesis of amide libraries in a
soluble form.
Exp er im en ta l Section
Gen er a l Meth od s. All commercial reagents and solvents
were used without further purification. The aminomethylated
divinylbenzene cross-linked polystyrene used to synthesize 4
was obtained as described,18 starting from a Merrifield resin
(1.7 mmol/g) purchased from Fluka. The PyBrOP was pur-
chased from Nova Biochem. Melting points are uncorrected.

Versatile Acylation of N-Nucleophiles
J . Org. Chem., Vol. 62, No. 8, 1997 2599
Ta ble 7. Syn th esis of Am id es Usin g Va r iou s Ca r boxylic Acid s a n d N-Nu cleop h iles
HPLC analyses were performed using a 250 × 4 mm2 reversed-
phase Vydac C18 5 µm column. A gradient starting from 100%
H2O/0.05% TFA and going to 100% H2O/80% CH3CN/0.0425%
TFA within 30 min at 1 mL/min flow rate was used. Elemen-
tal analyses were determined by Service Central d’Analyse,
Vernaison, France.
temperature. The acetylated resins were reacted with differ-
ent amounts of 0.195 M benzylamine in DMF (19.5 µmol, 29.25
µmol, 33.15 µmol, 35.1 µmol, 46.8 µmol, and 58.5 µmol). After
shaking at room temperature for 4 h, the polymeric beads were
filtered, and the solutions were diluted with DMF. The
amount of unreacted amine was determined for each reaction
mixture using a quantitative ninhydrin test.
P olym er -Bou n d
1-H yd r oxyb en zot r ia zole-6-su lfon -
a m id e (4). 4-Chloro-3-nitrobenzenesulfonyl chloride (2) (59.0
g, 230.7 mmol) in CH2Cl2 (800 mL) was added to an amino-
methylated divinylbenzene cross-linked polystyrene (47.2 g,
76.9 mmol) preswollen with CH2Cl2 (300 mL). Et3N was added
(32 mL, 230.7 mmol), and the reaction mixture was gently
stirred at room temperature. After 5 h the resin was filtered,
washed with CH2Cl2 (1500 mL), DMF (1000 mL), DMF/water
(1/1, V/V, 1000 mL), water (1500 mL), 95% EtOH (1000 mL),
and diethyl ether (1000 mL) and dried at room temperature
to give the polymer 3, for which a coupling level of 99% of the
amino groups was determined using a quantitative ninhydrin
procedure.29 Polymer 3 (67.2 g) was then treated with hydra-
zine hydrate (134 mL) in 95% EtOH (200 mL). The reaction
mixture was gently stirred under reflux. After 5 h, the resin
was washed with EtOH (1500 mL), water (1500 mL), DMF/
water (1/1, V/V, 500 mL), DMF (500 mL), CH2Cl2 (500 mL),
1% HCl in dioxane (1000 mL), dioxane (500 mL), and diethyl
ether (500 mL) and was dried at room temperature to give
59.6 g (95.6% yield with respect to the starting amino-
methylated resin) of polymer 4.
N-Ben zyl-4-ch lor o-3-n itr oben zen esu lfon a m id e (5). A
mixture of benzylamine (5.45 mL, 50 mmol) and Et3N (6.95
mL, 50 mmol) in CH2Cl2 (300 mL) was added dropwise to a
solution of 4-chloro-3-nitrobenzenesulfonyl chloride (12.8 g, 50
mmol) in CH2Cl2 (50 mL). The mixture was stirred at room
temperature for 2.5 h. The solvent was removed by rotary
evaporation, leaving a yellow powder which was taken up in
EtOAc (300 mL), washed with water (3 × 200 mL), and dried
(Na2SO4), and the solvent was removed under reduced pres-
sure to give 12.95 g (79.4%) of crude N-benzyl-4-chloro-3-
nitrobenzenesulfonamide (5): mp 90 °C; C18 RP HPLC (215/
254 nm) tR ) 29.7 min; 1H NMR (300 MHz, DMSO-d6) δ 8.61-
8.67 (t, J ) 6.26 Hz, NH, 1H), 8.30 (d, J ) 2.0 Hz, ArH, 1 H),
8.01-7.97 (dd, J ) 2.0, 8.46 Hz, ArH, 1 H), 7.95-7.92 (d, J )
8.45 Hz, ArH, 1 H), 7.27-7.19 (m, ArH, 5 H), 4.12 (d, J ) 6.24
Hz, CH2, 2 H); 13C NMR δ 147.9, 141.9, 137.70, 133.8, 132.2,
129.9, 129.07, 128.7, 128.1, 124.9, 47.1.
N-Ben zyl-1-h yd r oxyben zot r ia zole-6-su lfon a m id e (6).
To a solution of 5 (12 g, 36.7 mmol) in 95% EtOH (400 mL)
was added hydrazine hydrate (80 mL), and the mixture was
stirred under reflux. After 5 h, the solvent was removed by
rotary evaporation to give a dark yellow oil which was taken
up in water (500 mL) and acidified with aqueous HCl (pH 0.9).
The crude product precipitated and was separated by filtration
and dried under vacuum to give 10.7 g (95.8%) of crude 6. Upon
crystallization from EtOH (113 mL)/water (100 mL), the
Su bstitu tion Level of P olym er 4. Samples of polymer 4
were introduced into six tubes (30 mg, 37.0 µmol theoretical,
in each tube) and suspended into 0.2 mL of 2 M acetic
anhydride in CH2Cl2. After shaking for 2.5 h at room tem-
perature, the six samples were washed with DMF (20 mL) and
diethyl ether (8 mL) and dried under vacuum at room

2600 J . Org. Chem., Vol. 62, No. 8, 1997
Pop et al.
product was obtained as pale yellow crystals (9.2 g, 86.8%
yield): mp 200-205 °C; C18 RP HPLC (215/254 nm) tR ) 22.3
min; 1H NMR (300 MHz, DMSO-d6) δ 14.12 (s, OH, 1 H), 8.42
(t, J ) 6.3 Hz, NH, 1 H), 8.20-8.17 (dd, J ) 8.8, 0.5 Hz, ArH,
1 H), 8.09 (m, ArH, 1 H), 7.78-7.75 (dd, J ) 1.6, 8.8 Hz, ArH,
1 H), 7.25-7.14 (m, ArH, 5 H), 4.06 (d, J ) 6.3 Hz, CH2, 2 H);
13C NMR δ 144.6, 140.54, 138.1, 129.0, 128.5, 127.9, 127.80,
122.9, 121.5, 110.5, 47.1; TOF-MS m/ z 304.5 (M+). Anal.
Calcd for C13H12N4O3S: C, 51.31; H, 3.95; N, 18.42; O, 15.79;
S, 10.53. Found: C, 50.87; H, 3.91; N, 18.10; O, 15.59; S, 10.71.
the general procedure to give 24.1 mg (50%) of crude 13: mp
125 °C; C18 RP HPLC (215/254 nm) tR ) 30.5 min; H NMR
(300 MHz, DMSO-d6) δ 8.78 (t, J ) 5.80 Hz, NH, 1 H), 7.35-
7.19 (m, ArH, 15 H), 5.02 (s, CH, 1 H), 4.31 (d, J ) 5.81 Hz,
CH2, 2 H); MS(EI) m/ z 301 (M•+), 167, 91.
P r ep a r a t ion of N-(2-Ben zot h ia zolyl)-5-m et h yl-2-n i-
tr oben za m id e (14). By the general procedure, the reaction
of 5-methyl-2-nitrobenzoic acid (a ) (0.652 g, 3.6 mmol) and
PyBrOP (1.678 g, 3.6 mmol) in the presence of diisopropyl-
ethylamine (1.255 mL, 7.2 mmol) in DMF (5 mL) with the resin
4 (1.5 g, 1.2 mmol) gave the polymer-bound activated ester
which was reacted with 2-aminobenzothiazole (0.162 g, 1.08
mmol) and diisopropylethylamine (0.376 mL, 1.08 mmol) in
DMF (5 mL). The supernatant was collected and combined
with the DMF solutions used to wash the resin. DMF was
removed by rotary evaporation. The residue was taken up in
EtOAc (250 mL), the solution was washed with 0.1 M aqueous
1
p Ka Mea su r em en ts for Com p ou n d s 6, 7, 8, a n d 9.
2
mM hydroalcoholic solutions (9% MeOH in water) of 6-9 were
prepared. These solutions (15 mL) were titrated with aqueous
NaOH (2 mM), and the pH was followed using a 3 M KCl/
AgCl electrode. pKa values were determined from the titration
plots.
Gen er a l P r oced u r e for th e P r ep a r a tion of P olym er -
Bou n d Activa ted Ester s 10. One equivalent of PyBrOP and
two equivalents of diisopropylethylamine with respect to the
acid were used. The acid was taken up in a DMF solution of
PyBrOP, and diisopropylethylamine was added next. The
resin 4, preswollen with DMF, was reacted with this mixture
at room temperature for 3 h (unless otherwise noted). After
the first activation step the resin was washed with DMF (three
times). The second activation step was performed under the
same conditions as the first one (unless otherwise noted), and
the resin was washed with DMF (five times).
Gen er a l P r oced u r e for th e P r ep a r a tion of Com p ou n d s
11-38. One equivalent of N-nucleophile with respect to the
resin 4 was generally used. The amine was taken up in DMF,
and diisopropylethylamine was added to this solution if
necessary. The polymer-bound activated ester was reacted
with this mixture at room temperature. After 20 h, the
supernatant was separated from the resin by filtration. The
polymeric beads were washed with DMF (three times), the
washing solutions were recovered and combined with the
supernatant previously recovered, and the solvent was re-
moved under vacuum. The residue was taken up in tert-butyl
alcohol, and the solution was frozen and lyophilized to give
the crude products (unless otherwise noted).
N-Ben zyl-5-m eth yl-2-n itr oben za m id e (11). By the gen-
eral procedure, the reaction of 5-methyl-2-nitrobenzoic acid (a )
(0.087 g, 0.48 mmol) and PyBrOP (0.224 g, 0.48 mmol) in the
presence of diisopropylethylamine (0.223 mL, 0.96 mmol) in
DMF (1.5 mL) with the resin 4 (0.2 g, 0.16 mmol) gave the
polymer-bound activated ester which was reacted with ben-
zylamine (17 µL, 0.16 mmol) in DMF (1 mL) at room temper-
ature. The product was recovered by the general procedure
to give 36.3 mg (84%) of crude 11: mp 156 °C; C18 RP HPLC
(215/254 nm) tR ) 20.5 min; 1H NMR (300 MHz, DMSO-d6) δ
9.15 (t, J ) 5.80 Hz, NH, 1 H), 7.96 (d, J ) 8.24 Hz, ArH, 1
H), 7.50-7.46 (m, ArH, 2 H), 7.37 (m, ArH, 4 H), 7.29-7.25
(m, ArH, 1 H), 4.46 (d, J ) 5.95 Hz, CH2, 2 H), 2.44 (s, CH3, 3
H); MS(CI) m/ z 271 (MH +), 165, 106, 91. Anal. Calcd for
C15H14N2O3: C, 66.66; H, 5.18; N, 10.37. Found: C, 66.66; H,
5.00; N, 10.18.
N-Ben zyl-2-(p-tolu oyl)ben za m id e (12). By the general
procedure, the reaction of 2-(p-toluoyl)benzoic acid (b) (0.115
g, 0.48 mmol) and PyBrOP (0.224 g, 0.48 mmol) in the presence
of diisopropylethylamine (0.223 mL, 0.96 mmol) in DMF (1.5
mL) with the resin 4 (0.2 g, 0.16 mmol) gave the polymer-
bound activated ester which was reacted with benzylamine
(17 µL, 0.16 mmol) in DMF (1 mL). The product was recovered
by the general procedure to give 46.1 mg (87%) of crude 12:
mp 152 °C; C18 RP HPLC (215/254 nm) tR ) 25.3 min; 1H
NMR (300 MHz, DMSO-d6) δ 7.74-7.71 (m, ArH, 1 H), 7.56-
7.49 (m, ArH, 2 H), 7.27-7.07 (m, ArH, NH, 11 H), 4.49 (d, J
) 15.47 Hz, CH2, 1 H), 4.18 (d, J ) 15.47 Hz, CH2, 1 H), 2.24
(s, CH3, 3 H); MS(CI) m/ z 330 (MH +), 223, 106, 91.
N-Ben zyld ip h en yla ceta m id e (13). By the general pro-
cedure, the reaction of diphenylacetic acid (c) (0.101 g, 0.48
mmol) and PyBrOP (0.224 g, 0.48 mmol) in the presence of
diisopropylethylamine (0.223 mL, 0.96 mmol) in DMF (1.5 mL)
with the resin 4 (0.2 g, 0.16 mmol) gave the polymer-bound
activated ester which was reacted with benzylamine (17.5 µL,
0.16 mmol) in DMF (1 mL). The product was recovered by
NaHCO3
(three times) and with 0.37 M aqueous HCl (three
times) and dried (Na2SO4), the solvent was removed by rotary
evaporation, and the residue was taken up in tert-butyl alcohol
(10 mL), frozen, and lyophilized to give 0.183 g (54%) of crude
14: mp 205-210 °C (dec); C18 RP HPLC (215/254 nm) tR
)
28.9 min; 1H NMR (600 MHz, DMF-d7) δ 8.36 (d, J ) 8.45 Hz,
ArH, 1 H), 8.27 (d, J ) 7.60 Hz, ArH, 1 H), 7.98 (d, J ) 8.03
Hz, ArH, 1 H), 7.96 (d, J ) 1.04 Hz, ArH, 1 H), 7.88 (dd, J )
8.44, 1.06 Hz, ArH, 1 H), 7.68 (td, J ) 7.66, 1.16 Hz, ArH, 1
H), 7.58 (td, J ) 7.63, 1.02 Hz, ArH, 1 H), 2.74 (s, CH3, 3 H);
MS(EI) m/ z 313 (M•+), 267, 164, 149.
N-Ben zyl-3-ch lor oben za m id e (15). By the general pro-
cedure, the reaction of 3-chlorobenzoic acid (d ) (0.279 g, 1.78
mmol) and PyBrOP (0.831 g, 1.78 mmol) in the presence of
diisopropylethylamine (0.622 mL, 3.56 mmol) in DMF (3.80
mL) with the resin 4 (0.7 g, 0.59 mmol) gave the polymer-
bound activated ester which was reacted with benzylamine
(64.9 µL, 0.59 mmol) in DMF (5.95 mL). The supernatant was
collected and combined with the DMF solutions coming from
the washings of the resin. This solution was concentrated by
rotary evaporation. The residual solution was purified by
preparative RP HPLC (column Vydac C18, 5 µm, 500 × 20
mm2), using as eluents water/0.050% TFA and aqueous aceto-
nitrile (80%)/0.045% TFA (grad) at 4 mL/min flow rate and
detecting at 254/280 nm. The pure fractions were combined,
and the solvent was removed by rotary evaporation to give
0.124 g (85%) of 15: mp 89 °C; C18 RP HPLC (215/254 nm) tR
) 27.7 min; 1H NMR (300 MHz DMSO-d6) δ 9.18 (t, J ) 5.83
Hz, NH, 1 H), 7.95 (t, J ) 1.97, ArH, 1 H), 7.87 (dt, J ) 1.38,
7.67, ArH, 1 H), 7.62 (ddd, J ) 2.12, 7.99 Hz, ArH, 1 H), 7.52
(t, J ) 7.83 Hz, ArH, 1 H), 7.38-7.32 (m, ArH, 4 H), 7.28-
7.22 (m, ArH, 1 H), 4.50 (d, J ) 5.98 Hz, CH2, 2 H); MS(EI)
m/ z 245-247 (M•+), 139-141, 111-113, 106, 91. Anal. Calcd
for C14H12NOCl: C, 67.88; H, 4.85; N, 5.66. Found: C, 67.69;
H, 4.87; N, 5.77.
N-Ben zyl-3-(4-ch lor op h en yl)-1-cyclop r op a n eca r b ox-
a m id e (16). By the general procedure, the reaction of 3-(4-
chlorophenyl)-1-cyclopropanecarboxylic acid (e) (94 mg, 0.48
mmol) and PyBrOP (0.224 g, 0.48 mmol) in the presence of
diisopropylethylamine (0.223 mL, 0.96 mmol) in DMF (1.5 mL)
with the resin 4 (0.2 g, 0.16 mmol) gave the polymer-bound
activated ester which was reacted with benzylamine (17.5 µL,
0.16 mmol) in DMF (1 mL). The product was recovered by
the general procedure to give 37.2 mg (81%) of crude 16: mp
1
107 °C; C18 RP HPLC (215/254 nm) tR ) 25.3 min; H NMR
(300 MHz, C6D6) δ 7.21-7.07 (m, ArH, 5 H), 7.05-7.00 (m,
ArH, 2 H), 6.87-6.83 (m, ArH, 2 H), 5.40 (br s, NH, 1 H), 4.27
(d, J ) 6.10 Hz, CH2, 2 H), 1.88-1.84 (m, CH2, 2 H), 0.81-
0.77 (m, CH2, 2 H); MS(EI) m/ z 285-287 (M•+), 194-196,
180-182, 151-153, 91.
N-Ben zyl-2,2′-d ip h en ylp r op ion a m id e (17). By the gen-
eral procedure, the reaction 2, 2′-diphenylpropionic acid (f)
(0.156 g, 0.69 mmol) and PyBrOP (0.322 g, 0.69 mmol) in the
presence of diisopropylethylamine (0.241 mL, 1.38 mmol) in
DMF (2 mL) with the resin 4 (0.4 g, 0.23 mmol) gave the
polymer-bound activated ester which was reacted with ben-
zylamine (25 µL, 0.23 mmol) in DMF (2 mL). The product was
recovered by the general procedure to give 62.1 mg (86%) of
crude 17. mp 95-97 °C; C18 RP HPLC (215/254 nm) tR
)

Versatile Acylation of N-Nucleophiles
J . Org. Chem., Vol. 62, No. 8, 1997 2601
1
32.1 min; H NMR (300 MHz, DMSO-d6) δ 7.93 (t, J ) 5.96
The residue was taken up in tert-butyl alcohol (12 mL), frozen,
and lyophilized to give 0.273 g (77%) of 24: mp 210-215 °C;
C18 RP HPLC (215/254 nm) tR ) 31.3 min; 1H NMR (600 MHz,
DMF-d7) δ 9.01 (d, J ) 2.15 Hz, ArH, 1 H), 8.76 (d, J ) 9.10
Hz, ArH, 1 H), 8.72 (s, ArH, 1 H), 8.68 (dd, J ) 9.07, 2.21 Hz,
ArH, 1 H), 8.35 (d, J ) 8.48 Hz, ArH, 1 H), 7.92 (d, J ) 1.09
Hz, ArH, 1 H), 7.80 (dd, J ) 8.47, 1.14 Hz, ArH, 1 H), 2.76 (s,
CH3, 3 H); MS(CI) m/ z 327 (MH +), 280, 164.
Hz, NH, 1 H), 7.33-7.15 (m, ArH, 15 H), 4.30 (d, J ) 5.99 Hz,
CH2, 2 H), 1.90 (s, CH3, 3 H);. MS(EI) m/ z 315 (M•+), 181,
167, 103, 91, 77.
N-Ben zyln icotin a m id e (18). The reaction of nicotinic acid
(g) (85 mg, 0.69 mmol) and PyBrOP (0.322 g, 0.69 mmol) in
the presence of diisopropylethylamine (0.241 mL, 1.38 mmol)
in DMF (2 mL) with the resin 4 (0.4 g, 0.23 mmol) twice for 1
h each time gave the polymer-bound activated ester which was
reacted with benzylamine (25 µL, 0.23 mmol) in DMF (2 mL).
The product was recovered by the general procedure to give
29.4 mg (60%) of crude 18 which was purified by preparative
TLC (MN-Kieselgel G/UV254 glass plate; eluent: CH2Cl2/
MeOH/H2O/AcOH 9/1/0.1/0.05) to give 20.5 mg of 18: mp 120-
N-P h en eth yl-2,2′-d ip h en ylp r op ion a m id e (26), N-((â)R-
H yd r oxy-(r)S-m et h ylp h en et h yl)-5-m et h yl-2-n it r ob en z-
a m id e (27), a n d 2,2′-Dip h en ylp r op a n ilid e (28). By the
general procedure, the reaction of 2,2′-diphenylpropionic acid
(f) (1.627 g, 7.2 mmol) and PyBrOP (3.355 g, 7.2 mmol) in the
presence of diisopropylethylamine (2.51 mL, 14.4 mmol) in
DMF (18 mL) with the resin 4 (3 g, 2.4 mmol) gave the
polymer-bound activated ester. The resin beads were washed
with DMF (three times) and with CH2Cl2 (twice) and dried
under vacuum. A portion of the polymer-bound activated ester
(0.48 mmol) was reacted with phenethylamine (60.0 µL, 0.48
mmol) in DMF (4.8 mL). The supernatant was collected and
combined with the DMF solutions used to wash the resin. DMF
was removed by rotary evaporation. The residue was taken
up in CH2Cl2, the solution was washed with 0.1 M aqueous
NaHCO3 (three times) and with 0.37 M aqueous HCl (three
times) and dried (Na2SO4), and the solvent was removed by
rotary evaporation. The residue was taken up in tert-butyl
alcohol (12 mL), frozen, and lyophilized to give 129.5 mg (82%)
of 26. By the same procedure, reaction of the polymer-bound
activated ester (0.48 mmol) with (1R,2S)-(-)-norephedrine
(79.2 mg, 0.52 mmol) in DMF (4.8 mL) gave 128 mg (74%) of
27. By the same procedure, reaction of the polymer-bound
activated ester (0.48 mmol) with aniline (45.5 mg, 0.48 mmol)
in DMF (4.8 mL) gave 82.6 mg (64%) of 28. Data for compound
26: mp 63-66 °C; C18 RP HPLC (215/254 nm) tR ) 32.3 min;
1H NMR (300 MHz, DMSO-d6) δ 7.32-7.10 (m, NH, ArH, 16
H), 3.35 (m, CH2, 2 H), 2.74 (t, J ) 7.19 Hz, CH2, 2 H), 1.83 (s,
CH3, 3 H); MS(EI) m/ z 329 (M•+), 181, 167, 103, 91, 77. Data
for compound 27: mp 60-62 °C; C18 RP HPLC (215/254 nm)
tR ) 29.9 min; 1H NMR (300 MHz, DMSO-d6) δ 7.31-7.23 (m,
ArH, 11 H), 7.10 (m, ArH, 2 H), 6.94 (m, ArH, 2 H), 6.63 (d, J
) 8.68 Hz, NH, 1 H), 5.41 (d, J ) 4.59 Hz, OH, 1 H), 4.53 (m,
CH, 1 H), 4.10 (m, CH, 1 H), 1.78 (s, CH3, 3 H), 0.97 (d, J )
6.67 Hz, CH3, 3 H); MS(EI) m/ z 341 (M•+- 18), 253, 181, 165,
103, 77. Data for compound 28: mp 110 °C; C18 RP HPLC
(215/254 nm) tR ) 32.2 min; 1H NMR (300 MHz, DMSO-d6) δ
9.19 (s, NH, 1 H), 7.62 (d, J ) 1.24 Hz, ArH, 2 H), 7.38-7.24
(m, ArH, 12 H), 7.06 (t, J ) 1.24 Hz, ArH, 1 H), 2.06 (s, CH3,
3 H); MS(EI) m/ z 301 (M•+), 181, 167, 103, 77.
1
130 °C; C18 RP HPLC (215/254 nm) tR ) 17.8 min; H NMR
(300 MHz, DMF-d7) δ 9.42 (br s, NH, 1 H), 9.38 (dd, J ) 0.78,
2.30 Hz, ArH, 1 H), 8.93 (dd, J ) 1.66, 4.81 Hz, ArH, 1 H),
8.54 (dt, J ) 1.99, 7.94 Hz, ArH, 1 H), 7.75-7.70 (m, ArH, 1
H), 7.62-7.45 (m, ArH, 5 H), 4.80 (d, J ) 5.93 Hz, CH2, 2 H);
MS(CI) m/ z 213 (MH +), 106, 91.
N-(2-(5-Met h yl-1,3,4-t h ia d ia zolyl))-5-m et h yl-2-n it r o-
ben za m id e (21). By the general procedure, the reaction of
5-methyl-2-nitrobenzoic acid (a ) (0.326 g, 1.8 mmol) and
PyBrOP (0.839 g, 1.8 mmol) in the presence of diisopropyl-
ethylamine (0.627 mL, 3.6 mmol) in DMF (2.5 mL) with the
resin 4 (0.75 g, 0.6 mmol) gave the polymer-bound activated
ester which was reacted with 2-amino-5-methyl-1,3,4-thiadi-
azole (62 mg, 0.6 mmol) in DMF (2 mL). The supernatant was
collected and combined with the DMF solutions used to wash
the resin. DMF was removed by rotary evaporation. The
residue was taken up in EtOAc (150 mL), the solution was
washed with 0.1 M aqueous NaHCO3 (three times) and with
0.37 M aqueous HCl (three times) and dried (Na2SO4), the
solvent was removed by rotary evaporation, and the residue
was taken up in tert-butyl alcohol (10 mL), frozen, and
lyophilized to give 0.106 g (71%) of crude 21: mp 226 °C; C18
RP HPLC (215/254 nm) tR ) 22.9 min; 1H NMR (300 MHz,
DMSO-d6) δ 13.03 (s, NH, 1 H), 8.12 (d, J ) 8.34 Hz, ArH, 1
H), 7.64 (s, ArH, 1 H), 7.60 (d, J ) 8.42 Hz, ArH, 1 H), 2.67 (s,
CH3, 3 H), 2.47 (s, CH3, 3 H); MS(CI) m/ z 279 (MH +), 164.
Ben zop h en on e (5-Met h yl-2-n it r ob en zoyl)h yd r a zon e
(23). By the general procedure, the reaction of 5-methyl-2-
nitrobenzoic acid (a ) (0.543 g, 3 mmol) and PyBrOP (1.398 g,
3 mmol) in the presence of diisopropylethylamine (1.05 mL, 6
mmol) in DMF (4 mL) with the resin 4 (1.25 g, 0.8 mmol) gave
the polymer-bound activated ester which was reacted with
benzophenone hydrazone (0.196 g, 1 mmol) in DMF (6 mL).
The supernatant was collected and combined with the DMF
solutions used to wash the resin. DMF was removed by rotary
evaporation. The residue was taken up in EtOAc (30 mL),
the solution was washed with 0.1 M aqueous NaHCO3 (three
times) and with 0.37 M aqueous HCl (three times) and dried
(Na2SO4), and the solvent was removed by rotary evaporation
to give 0.253 g (70%) of crude 23 which was crystallized from
EtOAc (4 mL) to give 99 mg of pure 23 (2 isomers 2.13/1): mp
N-(1-Ad a m a n tyl)-2,2′-d ip h en ylp r op ion a m id e (29). By
the general procedure, the reaction of 2,2′-diphenylpropionic
acid (f) (0.638 g, 2.40 mmol) and PyBrOP (1.118 g, 2.40 mmol)
in the presence of diisopropylethylamine (0.837 mL, 4.80
mmol) in DMF (7 mL) with the resin 4 (1 g, 0.8 mmol) gave
the polymer-bound activated ester which was reacted with
1-adamantanamine chlorhydrate (0.15 g, 0.8 mmol) and di-
isopropylethylamine (0.139 mL, 0.8 mmol) in DMF (4 mL). The
supernatant was collected and combined with the DMF
solutions used to wash the resin. DMF was removed by rotary
evaporation. The residue was taken up in CH2Cl2, the solution
was washed with 0.1 M aqueous NaHCO3 (three times) and
with 0.37 M aqueous HCl (three times) and dried (Na2SO4),
and the solvent was removed by rotary evaporation. The
residue was taken up in tert-butyl alcohol (20 mL), frozen, and
lyophilized to give 0.144 g (50%) of 29: mp 103-107 °C; C18
RP HPLC (215/254 nm) tR ) 38.9 min; 1H NMR (300 MHz,
DMSO-d6) δ 7.21-7.00 (m, ArH, 10 H), 5.65 (s, NH, 1 H), 1.84-
1.45 (m, 18 H); MS(CI) m/ z 360 (MH +), 182, 135, 103.
1
204-206 °C; C18 RP HPLC (215/254 nm) tR ) 31.7 min; H
NMR (600 MHz, DMSO-d6) δ 10.83 (s, NH, 1 Ha), 10.45 (s,
NH, 1 Hb), 8.15 (d, J ) 8.38 Hz, ArH, 1 Hb), 8.02 (d, J ) 8.38,
ArH, 1 Ha), 7.60-7.25 (m, ArH, 11 Ha, 10 Hb), 7.06 (d, J )
7.35, ArH, 1 Hb), 2.49 (s, CH3, 3 Hb), 2.42 (s, CH3, 3 Ha); MS(EI)
m/ z 359 (M•+), 195, 180, 165, 77. Anal. Calcd for
C21H17N3O3: C, 70.19; H, 4.74; N, 11.70. Found: C, 69.83; H,
4.80; N, 11.88.
1-(5-Met h yl-2-n it r ob en zoyl)-5-n it r oin d a zole (24). By
the general procedure, the reaction of 5-methyl-2-nitrobenzoic
acid (a ) (0.652 g, 3.6 mmol) and PyBrOP (1.678 g, 3.6 mmol)
in the presence of diisopropylethylamine (1.255 mL, 7.2 mmol)
in DMF (5 mL) with the resin 4 (1.5 g, 1.2 mmol) gave the
polymer-bound activated ester which was reacted with 5-ni-
troindazole (0.196 g, 1.2 mmol) and diisopropylethylamine
(0.418 mL, 2.4 mmol) in DMF (3 mL). The supernatant was
collected and combined with the DMF solutions used to wash
the resin. DMF was removed by rotary evaporation. The
residue was taken up in EtOAc (250 mL), the solution was
washed with 0.1 M aqueous NaHCO3 (three times) and dried
(Na2SO4), and the solvent was removed by rotary evaporation.
N′-(5-Meth yl-2-n itr oben zoyl)-2-fu r oich yd r a zid e (30).
By the general procedure, the reaction of 5-methyl-2-nitroben-
zoic acid (a ) (0.608 g, 3.36 mmol) and PyBrOP (1.565 g, 3.36
mmol) in the presence of diisopropylethylamine (1.171 mL,
6.72 mmol) in DMF (5 mL) with the resin 4 (1.4 g, 1.12 mmol)
gave the polymer-bound activated ester. The resin beads were
washed with DMF (three times), with diethyl ether (twice) and
dried under vacuum.
A portion of the polymer-bound

2602 J . Org. Chem., Vol. 62, No. 8, 1997
Pop et al.
activated ester (0.08 mmol) was reacted with 2-furoic hy-
drazide (10.1 mg, 0.08 mmol) in the presence of diisopropyl-
ethylamine (27.9 µL, 0.16 mmol) in DMF (0.5 mL). The
supernatant was collected and combined with the DMF
solutions used to wash the resin. DMF was removed by rotary
evaporation. The crude product was purified by column
chromatography (silica gel, pentane/EtOAc 1/1) to give 11.5
mg (50%) of 30: mp 194-202 °C dec; C18 RP HPLC (215/254
nm) tR ) 18.7 min; 1H NMR (300 MHz, DMSO-d6) 10.61 (s,
NH, 1 H), 10.57 (s, NH, 1 H), 8.04-8.01 (d, J ) 8.30 Hz, ArH,
1 H), 7.93 (d, J ) 3.16 Hz, ArH, 1 H), 7.58-7.55 (d, J ) 8.39
Hz, ArH, 1 H), 7.52 (s, ArH, 1 H), 7.32-7.31 (d, J ) 3.11 Hz,
ArH, 1 H), 6.69-6.68 (q, J ) 1.73 Hz, ArH, 1 H), 2.48 (s, CH3,
3 H); m/ z 290 (MH+), 164, 149.
the resin. DMF was removed by rotary evaporation. The
residue was taken up in CH2Cl2 (30 mL), the solution was
washed with 0.1 M aqueous NaHCO3 (three times) and with
0.37 M aqueous HCl (three times) and dried (Na2SO4), and
the solvent was removed by rotary evaporation. The residue
was taken up in tert-butyl alcohol (20 mL), frozen, and
lyophilized to give 0.161 g (70%) of 34: mp 156-159 °C; C18
RP HPLC (215/200 nm) tR ) 34.7 min; 1H NMR (600 MHz,
DMSO-d6) δ 7.83 (t, J ) 1.75 Hz, ArH, 1 H), 7.76-7.74 (m,
ArH, NH, 2 H), 7.57-7.55 (m, ArH, 1 H), 7.46 (t, J ) 7.86 Hz,
ArH, 1 H), 2.07 (s, CH, 9 H), 1.66 (s, CH, 6 H); MS(EI) m/ z
289-291 (M•+), 232-234, 139-141, 111-113. Anal. Calcd for
C17H20NOCl: C, 70.47; H, 6.91; N, 4.83. Found: C, 70.27; H,
6.99; N, 4.63.
N -((â)R -H yd r oxy-(r)S -m e t h ylp h e n e t h yl)-3-ch lor o-
ben za m id e (31). By the general procedure, the reaction of
3-chlorobenzoic acid (d ) (0.279 g, 1.78 mmol) and PyBrOP
(0.831 g, 1.78 mmol) in the presence of diisopropylethylamine
(0.622 mL, 3.56 mmol) in DMF (3.80 mL) with the resin 4 (0.7
g, 0.59 mmol) gave the polymer-bound activated ester which
was reacted with (1R,2S)-(-)-norephedrine (89.8 mg, 0.595
mmol) in DMF (5.95 mL). The product was recovered and
purified by preparative RP HPLC, as described for compound
15, to give 0.135 g (79%) of 31: mp 140 °C; C18 RP HPLC
(215/254 nm) tR ) 25.6 min; 1H NMR (300 MHz, DMSO-d6) δ
8.37 (d, J ) 8.32 Hz, NH, 1 H), 7.83 (t, J ) 1.74 Hz, ArH, 1
H), 7.74 (dt, J ) 7.67, 1.39 Hz, ArH, 1 H), 7.58 (ddd, J ) 7.99,
1.08 Hz, ArH, 1 H), 7.48 (t, J ) 7.80, ArH, 1 H), 7.40 (m, ArH,
2 H), 7.31 (m, ArH, 2 H), 7.24-7.18 (m, ArH, 1 H), 5.46 (d, J
) 4.84 Hz, OH, 1 H), 4.71 (t, J ) 5.13 Hz, CH, 1 H), 4.19-
4.12 (m, CH, 1 H), 1.11 (d, J ) 6.77 Hz, CH3, 3 H); MS(CI)
m/ z 272-274 (M+ - OH), 183-185, 139-141.
N-ter t-Bu tyl-3-ch lor oben za m id e (35). By the general
procedure, the reaction of 3-chlorobenzoic acid (d ) (0.376 g,
2.40 mmol) and PyBrOP (1.118 g, 2.40 mmol) in the presence
of diisopropylethylamine (0.837 mL, 4.80 mmol) in DMF (7 mL)
with the resin 4 (1 g, 0.8 mmol) gave the polymer-bound
activated ester which was reacted with tert-butylamine (84 µL,
0.8 mmol) in DMF (4 mL). The supernatant was collected and
combined with the DMF solutions used to wash the resin. DMF
was removed by rotary evaporation. The residue was taken
up in CH2Cl2, the solution was washed with 0.1 M aqueous
NaHCO3 (three times) and with 0.37 M aqueous HCl (three
times) and dried (Na2SO4), and the solvent was removed by
rotary evaporation. The residue was taken up in tert-butyl
alcohol (10 mL), frozen, and lyophilized to give 0.086 g (51%)
of 35: mp 99-101 °C; C18 RP HPLC (215/200 nm) tR ) 27.9
1
min; H NMR (600 MHz, DMSO-d6) δ 7.90 (s, NH, 1 H), 7.85
(t, J ) 1.81 Hz, ArH, 1 H), 7.76 (dt, J ) 7.72, 1.20 Hz, ArH, 1
H), 7.57 (m, ArH, 1 H), 7.47 (t, J ) 7.86 Hz, ArH, 1 H), 1.38
(s, CH3, 9 H); MS(EI) m/ z 211-213 (M•+), 196-199, 156-158,
139-141, 111- 113. Anal. Calcd for C11H14NOCl: C, 62.41;
H, 6.62; N, 6.62. Found: C, 62.53; H, 6.64; N, 6.43.
3-Ch lor oben za n ilid e (32). By the general procedure, the
reaction of 3-chlorobenzoic acid (d ) (0.279 g, 1.78 mmol) and
PyBrOP (0.831 g, 1.78 mmol) in the presence of diisopropyl-
ethylamine (0.622 mL, 3.56 mmol) in DMF (3.80 mL) with the
resin 4 (0.7 g, 0.59 mmol) gave the polymer-bound activated
ester which was reacted with aniline (55 mg, 0.595 mmol) in
DMF (5.95 mL). The product was recovered and purified by
preparative RP HPLC, as described for compound 15, to give
0.109 g (79%) of 32: mp 134-136 °C; C18 RP HPLC (215/254
N-Eth yl-N-p h en yl-3-ch lor oben za m id e (36). By the gen-
eral procedure, the reaction of 3-chlorobenzoic acid (d ) (0.376
g, 2.40 mmol) and PyBrOP (1.118 g, 2.40 mmol) in the presence
of diisopropylethylamine (0.837 mL, 4.80 mmol) in DMF (7 mL)
with the resin 4 (1 g, 0.8 mmol) gave the polymer-bound
activated ester which was reacted with N-ethylaniline (100
µL, 0.8 mmol) in DMF (4 mL). The supernatant was collected
and combined with the DMF solutions used to wash the resin.
DMF was removed by rotary evaporation. The residue was
taken up in CH2Cl2, the solution was washed with 0.1 M
aqueous NaHCO3 (three times) and with 0.37 M aqueous HCl
(three times) and dried (Na2SO4), and the solvent was removed
by rotary evaporation. The residue was taken up in tert-butyl
alcohol (12 mL), frozen, and lyophilized to give 0.178 g (86%)
of 36: oil; C18 RP HPLC (215/254 nm) tR
1
nm) tR ) 28.6 min; H NMR (300 MHz, DMSO-d6) δ 10.36 (s,
NH, 1 H), 8.02 (t, J ) 1.83 Hz, ArH, 1 H), 7.93 (dt, J ) 7.70,
1.38 Hz, ArH, 1 H), 7.80-7.76 (m, ArH, 2 H), 7.67 (ddd, J )
8.02, 1.08 ArH, 1 H), 7.58 (t, J ) 7.86, ArH, 1 H), 7.41-7.34
(m, ArH, 2 H), 7.16- 7.10 (m, ArH, 1 H); MS(EI) m/ z 231-233
(M•+), 139-141, 111-113.
N-(3-Ch lor oben zoyl)p ip er id in e (33). By the general
procedure, the reaction of 3-chlorobenzoic acid (d ) (0.376 g,
2.40 mmol) and PyBrOP (1.118 g, 2.40 mmol) in the presence
of diisopropylethylamine (0.837 mL, 4.80 mmol) in DMF (7 mL)
with the resin 4 (1 g, 0.8 mmol) gave the polymer-bound
activated ester which was reacted with piperidine (79 µL, 0.8
mmol) in DMF (4 mL). The supernatant was collected and
combined with the DMF solutions used to wash the resin. DMF
was removed by rotary evaporation. The residue was taken
up in CH2Cl2, the solution was washed with 0.1 M aqueous
NaHCO3 (three times) and with 0.37 M aqueous HCl (three
times) and dried (Na2SO4), and the solvent was removed by
rotary evaporation. The residue was taken up in tert-butyl
alcohol , frozen, and lyophilized to give 0.128 g (72%) of 33:
) 29.9 min; 1H NMR
(300 MHz, DMSO-d6) δ 7.33-7.16 (m, ArH, 9 H), 3.86 (q, J )
7.10 Hz, CH2, 2 H), 1.11 (t, J ) 7.10 Hz, CH2, 3 H); MS(EI)
m/ z 259-261 (M•+), 139-141, 120, 111-113. Anal. Calcd for
C15H14NOCl: C, 69.36; H, 5.39; N, 5.39. Found: C, 69.11; H,
5.67; N, 5.42.
N-(1-Ad a m a n tyl)-1-a d a m a n ta n a ceta m id e (37). By the
general procedure, the reaction of 1-adamantanacetic acid
(0.466 g, 2.40 mmol) and PyBrOP (1.118 g, 2.40 mmol) in the
presence of diisopropylethylamine (0.837 mL, 4.80 mmol) in
DMF (7 mL) with the resin 4 (1 g, 0.8 mmol) gave the polymer-
bound activated ester which was reacted with 1-adamantan-
amine chlorhydrate (0.15 g, 0.8 mmol) and diisopropylethyl-
amine (0.139 mL, 0.8 mmol) in DMF (4 mL). The supernatant
was collected and combined with the DMF solutions used to
wash the resin. DMF was removed by rotary evaporation. The
residue was taken up in CH2Cl2 (50 mL), the solution was
washed with 0.1 M aqueous NaHCO3 (three times) and with
0.37 M aqueous HCl (three times) and dried (Na2SO4), and
the solvent was removed by rotary evaporation. The residue
was taken up in tert-butyl alcohol (25 mL), frozen, and
lyophilized to give 0.170 g (65%) of 37: mp 254-260 °C; C18
RP HPLC (215/200 nm) tR ) 39.1 min; 1H NMR (300 MHz,
CD3OD) δ 7.14 (s, NH, 1 H), 2.05-1.97 (m, 12 H), 1.86 (s, CH2,
2 H), 1.74-1.65 (m, 18 H); MS (EI) m/ z 327 (M•+), 270, 151,
94, 79, 67, 135. Anal. Calcd for C22H33NO: C, 80.73; H, 10.09;
N, 4.28. Found: C, 80.53; H, 10.23; N, 4.19.
1
mp 44-48 °C; C18 RP HPLC (215/200 nm) tR ) 27.1 min; H
NMR (300 MHz, CD3CN) δ 7.48-7.39 (m, ArH, 3 H), 7.32-
7.29 (m, ArH, 1 H), 3.63 (br s, 2 H), 3.29 (br s, 2 H), 1.72-1.52
(br m, 6 H); MS(CI) m/ z 224-226 (MH+), 188, 139-141. Anal.
Calcd for C12H14NOCl: C, 64.42; H, 6.26; N, 6.26. Found: C,
64.38; H, 6.31; N, 6.18.
N-(1-Ad a m a n tyl)-3-ch lor oben za m id e (34). By the gen-
eral procedure, the reaction of 3-chlorobenzoic acid (d ) (0.376
g, 2.40 mmol) and PyBrOP (1.118 g, 2.40 mmol) in the presence
of diisopropylethylamine (0.837 mL, 4.80 mmol) in DMF (7 mL)
with the resin 4 (1 g, 0.8 mmol) gave the polymer-bound
activated ester which was reacted with 1-adamantanamine
chlorhydrate (0.15 g, 0.8 mmol) and diisopropylethylamine
(0.139 mL, 0.8 mmol) in DMF (4 mL). The supernatant was
collected and combined with the DMF solutions used to wash

Versatile Acylation of N-Nucleophiles
J . Org. Chem., Vol. 62, No. 8, 1997 2603
N-(1-Ad a m a n tyl)cycloh exa n eca r boxa m id e (38). By the
general procedure, the reaction of cyclohexanecarboxylic acid
(0.307 g, 2.40 mmol) and PyBrOP (1.118 g, 2.40 mmol) in the
presence of diisopropylethylamine (0.837 mL, 4.80 mmol) in
DMF (7 mL) with the resin 4 (1 g, 0.8 mmol) gave the polymer-
bound activated ester which was reacted with 1-adamantan-
amine chlorhydrate (0.15 g, 0.8 mmol) and diisopropylethyl-
amine (0.139 mL, 0.8 mmol) in DMF (4 mL). The supernatant
was collected and combined with the DMF solutions used to
wash the resin. DMF was removed by rotary evaporation. The
residue was taken up in CH2Cl2 (50 mL), the solution was
washed with 0.1 M aqueous NaHCO3 (three times) and with
0.37 M aqueous HCl (three times) and dried (Na2SO4), and
the solvent was removed by rotary evaporation. The residue
was taken up in tert-butyl alcohol (25 mL), frozen, and
lyophilized to give 0.136 g (65%) of 38: mp 189-192 °C; C18
RP HPLC (215/200 nm) tR ) 33.6 min; 1H NMR (600 MHz,
DMSO-d6) δ 7.04 (s, NH, 1 H), 2.05 (tt, J ) 11.50, 3.40 Hz, 1
H), 1.99 (s, 3 H), 1.90 (m, 6 H), 1.70-1.61 (m, 11 H), 1.31-
1.13 (m, 5 H); MS (EI) m/ z 261 (M•+), 206, 135, 94, 79, 67.
Anal. Calcd for C17H27NO: C, 78.16; H, 10.34; N, 5.36.
Found: C, 77.82; H, 10.18; N, 5.20.
Ack n ow led gm en t . We thank the GlaxoWellcome
Laboratories for financial support. We thank Christelle
Biville and Vale´rie Thorel for their assistance in the
synthesis and physical characterization of the com-
pounds in this study.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra
and HPLC chromatograms for all the compounds described
in the Experimental Section (54 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
J O961761G