A practical, water-soluble, ionic scavenger for the solution-phase syntheses of amides

Article abstract of DOI:10.1002/hlca.200690056

A new ionic, water-soluble scavenger for acyl chlorides, 1-(2-aminoethyl)pyridinium bromide (1), has been investigated. Compound 1 was used for the rapid and simple purification of a series of benzamides and sulfonamides (Table) obtained by solution-phase synthesis from the corresponding amines (Scheme). The inexpensive scavenger, which can be prepared on large scale, was shown to readily 'eliminate' excess acyl chlorides (reagent) by simple aqueous extraction. The amides purified in this way were obtained in excellent yields and purities (Table), which makes 1 a versatile new reagent, especially for the combinatorial solution-phase synthesis of amide libraries.

Full text of DOI:10.1002/hlca.200690056

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Helvetica Chimica Acta – Vol. 89 (2006)
A Practical, Water-Soluble, Ionic Scavenger for the Solution-Phase Syntheses
of Amides
by Ming Lei, Xiao-Le Tao, and Yan-Guang Wang*
Department of Chemistry, Zhejiang University, Hangzhou 310027, P.R. China
(e-mail: orgwyg@zju.edu.cn)
A new ionic, water-soluble scavenger for acyl chlorides, 1-(2-aminoethyl)pyridinium bromide (1),
has been investigated. Compound 1 was used for the rapid and simple purification of a series of benz-
amides and sulfonamides (Table) obtained by solution-phase synthesis from the corresponding amines
(Scheme). The inexpensive scavenger, which can be prepared on large scale, was shown to readily ‘elim-
inate’ excess acyl chlorides (reagent) by simple aqueous extraction. The amides purified in this way were
obtained in excellent yields and purities (Table), which makes 1 a versatile new reagent, especially for the
combinatorial solution-phase synthesis of amide libraries.
Introduction. – Solution-phase combinatorial chemistry for library generation has
been receiving increased attention as a powerful tool for lead discovery and optimiza-
tion in drug development [1]. Solution-phase synthetic techniques offer many advan-
tages over solid-phase approaches such as unlimited scale, simple manipulation, and
cost effectiveness. However, with solution-phase syntheses, the rapid purification or
isolation of desired compound from a reaction mixture is difficult, and represents the
‘
bottleneck’ in the synthetic process.
Recently, polymer-supported scavengers have been developed for compound puri-
fication in solution-phase combinatorial chemistry [2]. These scavengers allow the
removal of excess reagents and side products by simple filtration, but low loading
capacity and high costs have, so far, limited their application for large-scale library
preparation. Although several high-loading solid scavenger reagents have been devel-
oped, they suffer from slow exchange at the solid–liquid interface [3]. An efficient so-
lution to these problems is replacement of the polymer-supported scavenger with small-
molecule reagents such as Girard’s reagent T [4], N-methyltris(2-aminoethyl)amine
[
5], N-Boc-iminodiacetic anhydride [6], and potassium sarcosinate [7] to generate
water-soluble byproducts, which can be separated, together with the excess scavengers,
from the products by liquid–liquid extraction.
Recently, Song and co-workers [8] reported an amino-functionalized ionic liquid,
i.e., 1-aminoethyl-3-methylimidazolium hexafluorophosphate ([2-aemim][PF ]), as an
6
electrophile scavenger for solution-phase synthesis; the scavenging products were sep-
arated by extraction with the ionic liquid [bmim][PF ].
6
Herein, we describe the application of the practical, ionic, water-soluble scavenger
1-(2-aminoethyl)pyridinium bromide (1) for the solution-phase synthesis of libraries of
amides and sulfonamides.
©
2006 Verlag Helvetica Chimica Acta AG, Zürich

Helvetica Chimica Acta – Vol. 89 (2006)
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Results and Discussion. – We chose the pyridinium salt 1 as a model of an ionic
scavenger since it is highly water-soluble, inexpensive, and can be readily prepared
and purified, even on large scale, from pyridine and 2-bromoethylamine hydrobromide
(Scheme 1). Next, 1 was reacted with benzoyl chloride (BzCl) and toluene-4-sulfonyl
chloride (TsCl) to afford the corresponding benzamide 2 and sulfonamide 3, respec-
tively. As expected, both compounds are water soluble, which ensured that the scav-
enger 1 is capable of trapping excess reagent (acid chloride) to generate water-soluble
byproducts (such as 2 and 3), which, in turn, can be removed by washing.
Scheme 1
The ionic scavenger 1 was evaluated in the purification of various amides prepared
by benzoylation of the corresponding amines 4 (Scheme 2). Typically, an amine (1
mmol) was reacted with excess BzCl (2 mmol) in CH Cl (5 ml) in the presence of
2
2
excess base (Et N or pyridine) at room temperature. After completion of the reaction,
3
compound 1 (1.2 mmol) was added, the mixture was stirred for 6 h, diluted with
AcOEt, and washed with brine. The organic layers were passed through a short pad
of anhydrous Na SO , and, finally, evaporated to afford the desired benzamides 5 in
2
4
good-to-excellent yields (86–92%) and high purities (95–99%; Table).
Next, we tested the reaction of different amines with TsCl instead of BzCl. When
the same procedure was applied, with 1 acting as a scavenger of excess TsCl, and
using pyridine instead of Et N as base, similarly high yields and purities were achieved
3
(Table).
In summary, we have developed a practical, water-soluble, ionic scavenger for the
purification of amide or sulfonamide libraries prepared by solution-phase synthesis.
The scavenger 1 can be easily prepared on large scale, and efficiently removes excess

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Helvetica Chimica Acta – Vol. 89 (2006)
Scheme 2
Table. Amines for the Synthesis of the Corresponding Amides 5 and 6 Purified with the Aid of the Ionic
1
Scavenger 1. All products were identified by GC/MS and H-NMR (data not shown). For synthetic
details, see Exper. Part.
Amine
Benzamide 5
Sulfonamide 6
Yield [%]
Purity [%]a)
Yield [%]
Purity [%]a)
Aniline
N-Ethylaniline
87
89
92
86
86
86
88
88
87
90
97
99
99
95
95
99
97
98
99
97
89
88
93
85
85
87
90
88
87
90
95
97
96
95
98
99
96
99
95
95
4
4
-Methoxyaniline
-Nitroaniline
Benzylamine
Cyclohexylamine
Dodecylamine
Morpholine
Piperidine
Toluidine )
b
a) Determined by GC/MS. ) 2-Toluidine for 5, 3-toluidine for 6.
b
reagents (acid chlorides) by generating water-soluble byproducts that can be removed
by simple extraction. Since compound 1 is high loading and cost effective, it should
prove useful in solution-phase combinatorial chemistry.
Experimental Part
General. All chemicals were reagent grade, and used as purchased. M.p.: WRS-1B digital melting-
1
13
point apparatus; uncorrected. H- and C-NMR Spectra: Bruker Avance-500 or Avance-400 spectrome-
1
13
1
ters; at 500 ( H) and 125 MHz ( C), or at 400 MHz ( H); d in ppm, J in Hz. GC/MS: Hewlett-Packard
HP-6890 gas chromatograph coupled to a mass spectrometer; in m/z.
1-(2-Aminoethyl)pyridinium Bromide (1). A soln. of 2-bromoethylamine hydrobromide (20.49 g, 0.1
mol) in freshly dist. pyridine (50 ml) was heated at reflux for 24 h. Excess pyridine was removed in vacuo,
the solid residue was dissolved in a minimal amount of H O, and the pH was adjusted to ca. 8 by adding
2
solid KOH in small portions. The aq. soln. was extracted with AcOEt (2×30 ml), and evaporated to dry-
ness. The resulting solid residue was extracted with MeCN. The combined MeCN extracts were concen-
trated to afford 1 (18.3 g, 90%) as a solid. M.p. 227.9–229.68. IR (KBr): 3555, 3481, 3418, 1637, 1618, 1079,

Helvetica Chimica Acta – Vol. 89 (2006)
535
1
1
(
1
036. H-NMR (500 MHz, D O): 3.43 (t, J=6.0, 2 H); 4.80 (t, J=6.0, 2 H); 8.09–8.12 (m, 2 H); 8.56–8.59
2
13
m, 1 H); 8.89–8.90 (m, 2 H). C-NMR (125 MHz, D O): 40.89; 61.43; 128.98; 145.00; 146.76. ESI-MS:
2
+
23 ([MÀBr] ).
1
-[2-(Benzoylamino)ethyl]pyridinium Bromide (2). To a soln. of BzCl (211 mg, 2 mmol) in CH Cl
2
2
(
5 ml) was added 1 (203 mg, 1 mmol) and Et N (2 mmol). The mixture was stirred at r.t. for 2 h, and
3
then diluted with H O (5 ml). The aq. layer was extracted with CH Cl (2×5 ml), and concentrated.
2
2
2
The resulting residue was purified by column chromatography (SiO ; CH Cl /MeOH 5 :2) to afford 2
2
2
2
(
252 mg, 82% based on 1) as a yellow solid. M.p. 241.1–242.78. IR (KBr): 3424, 3018, 2999, 2820,
1
1
7
8
1
637, 1492, 1328, 1158, 1095. H-NMR (500 MHz, D O): 3.76 (t, J=5.2, 2 H); 4.62 (t, J=5.2, 2 H);
2
.19–7.22 (m, 2 H); 7.28–7.32 (m, 1 H); 7.37–7.39 (m, 2 H); 7.78–7.81 (m, 2 H); 8.29–8.33 (m, 1 H);
1
3
.66–8.68 (m, 2 H). C-NMR (125 MHz, D O): 40.35; 61.30; 127.29; 128.55; 129.16; 132.65; 132.83;
2
+
44.91; 146.48; 170.61. ESI-MS: 227 ([MÀBr] ).
1
-(2-{[(4-Methylphenyl)sulfonyl]amino}ethyl)pyridinium Bromide (3). Prepared in analogy to 2 (see
above), but from TsCl and pyridine. Yield of 3: 85% (based on 1). Yellow solid. M.p. 234.3–235.68. IR
1
(
KBr): 3448, 3029, 2972, 1633, 1489, 1316, 1159, 1092. H-NMR (500 MHz, D O): 2.33 (s, 1 H); 3.47 (t,
2
J=5.2, 2 H); 4.61 (t, J=5.2, 2 H); 7.29–7.31 (m, 2 H); 7.51–7.53 (m, 2 H); 7.94–7.98 (m, 2 H);
1
3
8
1
.45–8.47 (m, 1 H); 8.70–8.72 (m, 2 H). C-NMR (125 MHz, D O): 20.85; 42.93; 61.18; 126.70;
2
+
28.40; 135.11; 144.92; 145.47; 146.43. ESI-MS: 277 ([MÀBr] ).
General Procedure for the Synthesis of Benzamides 5. To a soln. of the appropriate amine 4 (1 mmol)
in CH Cl (3 ml) was added BzCl (2 mmol), and Et N or pyridine (3 mmol), and the mixture was stirred
2
2
3
at r.t. The progress of the reaction was monitored by GC analysis. After completion of the reaction, the
scavenger 1 (1.2 mmol) was added, the mixture was stirred at r.t. for 6 h, diluted with AcOEt (10 ml), and
2 4
washed with brine (2×10 ml). The org. layers were passed through a short pad of anh. Na SO , and
1
evaporated to afford the benzamides 5. Their purities were determined by GC/MS analysis and H-
NMR spectroscopy.
General Procedure for the Synthesis of Sulfonamides 6. To a soln. of the amine 4 (1 mmol) in CH
3 ml) was added TsCl (2 mmol) and pyridine (3 mmol), and the mixture was stirred at r.t. The progress
of the reaction was monitored by GC analysis. After completion of the reaction, the scavenger 1
1.2 mmol) was added at r.t., the mixture was stirred for 6 h, diluted with AcOEt (10 ml), and washed
with brine (2×10 ml). The org. layers were passed through a short pad of anh. Na SO , and evaporated
2 2
Cl
(
(
2
4
1
to afford the sulfonamides 6. Their purities were determined by GC/MS analysis and H-NMR spectros-
copy.
This work was financially supported by the National Natural Science Foundation of China (No.
2
0272051) and the Teaching and Research Award Program for Outstanding Young Teachers in Higher
Education Institutions of the Ministry of Education, P.R. China
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Received November 15, 2005