Synthesis of monoimidazole/polyamine amides

Article abstract of DOI:10.1081/SCC-120030748

A facile and efficient route has been reported to selectively prepare a series of unsymmetrical monoimidazole/polyamine amides without protection process of the polyamines. These amides are versatile building blocks for the synthesis of DNA sequence recognition ligands and other biologically functional molecules.

Full text of DOI:10.1081/SCC-120030748

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Synthesis of Monoimidazole/Polyamine Amides
a b
a
a
Changjin Zhu
a
, Yanfeng Jiang & Yufen Zhao
Key Laboratory for Bioorganic Phosphorus Chemistry of Ministry of Education,
Department of Chemistry, School of Life Science and Engineering, Tsinghua University,
Beijing, 100084, China
b
School of Chemical Engineering and Environment, Beijing Institute of Technology,
Beijing, China
Published online: 16 Aug 2006.
To cite this article: Changjin Zhu , Yanfeng Jiang & Yufen Zhao (2004) Synthesis of Monoimidazole/Polyamine Amides,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 34:9,
1609-1615, DOI: 10.1081/SCC-120030748
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w
SYNTHETIC COMMUNICATIONS
Vol. 34, No. 9, pp. 1609–1615, 2004
Synthesis of Monoimidazole/Polyamine
Amides
1
,2
1
Changjin Zhu, Yanfeng Jiang, and Yufen Zhao
1,*
1
Key Laboratory for Bioorganic Phosphorus Chemistry of Ministry of
Education, Department of Chemistry, School of Life Science and
Engineering, Tsinghua University, Beijing, China
2
School of Chemical Engineering and Environment, Beijing Institute of
Technology, Beijing, China
ABSTRACT
A facile and efficient route has been reported to selectively prepare a
series of unsymmetrical monoimidazole/polyamine amides without pro-
tection process of the polyamines. These amides are versatile building
blocks for the synthesis of DNA sequence recognition ligands and other
biologically functional molecules.
Key Words: Polyamine; Monoimidazole; Spermine; Amides.
*
Correspondence: Yufen Zhao, Key Laboratory for Bioorganic Phosphorus Chemistry
of Ministry of Education, Department of Chemistry, School of Life Science and
Engineering, Tsinghua University, Beijing 100084, China; Fax: þ86-10-62781695;
E-mail: tp-dch@mail.tsinghua.edu.cn.
1
609
DOI: 10.1081/SCC-120030748
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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1
610
Zhu, Jiang, and Zhao
INTRODUCTION
A number of studies have shown that natural polyamines and polyamine
[
1–4]
amides play a profound role in cellular processes.
conditions, polycations of these structures bind tightly to anionic cellular com-
Under physiological
[5,6]
ponents, such as DNA, and strongly modulate their functions.
synthesis and exploration of the biological activities of such amides and
Thus, the
[7–11]
their analogs has attracted much attention.
In the present study, a facile and efficient method was developed for
the synthesis of a series of unsymmetrical polyamine amides 3a–h. These
amides are all new compounds and potential analogs for channel blocking
[
12,13]
toxins.
the design and synthesis of diverse netropsin and distamycin analogs or related
They are also important building blocks or intermediates for
[14–18]
conjugates having DNA-binding activity or multiple functions.
0
Typically, the synthesis of 3a was initiated with 3,3 -diamino-N-methyl-
dipropylamine 2a (Sch. 1), which has been frequently used for the design
[14,19–24]
and synthesis of sequence-specific DNA binding molecules.
employed imidazole acyl donor, 4-nitro-1-methyl-2-trichloroacetylimidazole
The
[25]
1
, was prepared from N-methyl-imidazole as described previously.
Because 1 is very reactive with amines,
[25,26]
it was expected to react with
triamine 2a to readily produce the undesired bisimidazole amide 4a. However,
we found that the desired monoimidazole N-acylated polyamine conjugate
(
monoimidazole amide) 3a could be selectively obtained. This selectivity
exhibited a remarkable solvent-dependence but was insensitive to tempera-
ture. Thus, although low yields (,60%) were obtained in tetrahydrofuran,
dioxane, or chloroform, impressive yields were obtained in dichloromethane.
Therefore, we decided to apply this method for the preparation of a series of
the targeted molecules 2a–h as described below and in Sch. 1.
Scheme 1.

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Synthesis of Monoimidazole/Polyamine Amides
1611
Reaction of imidazole 1 with 2a (2 equiv.) in CH Cl gave a crude resul-
2
2
ting mixture, which was separated by column chromatography over silica gel
to afford monoimidazole amide 3a and the bisimidazole amide by-product 4a
in 80% and 3% yields, respectively. By the same method, amides 3b–g were
also obtained in good selectivity and yields as summarized in Table 1. For the
triamine of spermidine 2g, there is a secondary amino group situated between
the two primary terminal amino groups. Owing to the higher nucleophilicity
of the secondary amino group than the primary amino groups, its preferential
N-acylation by 1 was expected. However, this was not observed, presumably
because the nucleophilicity of the secondary amine is masked by the greater
[
7,27]
steric hindrance of spermidine 2g.
unsymmetrical, its reaction with 1 was expected to give two kinds of mono-
Additionally, since spermidine 2g is
[28]
imidazole amides. However, on the basis of identification
of the products
by electrospray ionization tandem mass spectrometry (ESI-MS/MS), it was
found that only one monoimidazole amide, 3g, was produced (72%) together
with some bisimidazole amide 4g (12%), suggesting the regio-selective
N-acylation of spermidine by imidazole 1.
It is worth noting that the reaction of imidazole 1 with spermine 2h
always produced the bisimidazole amide 4h predominantly, together with
only a little amount of the desired monoimidazole amide 3h as checked by
TLC. To solve this problem, imidazole 1 was converted to its methyl ester
0
1 followed by aminolysis by spermine 2h (Sch. 1) to achieve the mono N-acyl-
ation, affording 3h in 66% yield.
By the same method, monopyrrole N-acylated polyamine conjugates
monopyrrole amides), which are potential compounds for the design of
(
a
Table 1. Production yields of the reactions of 1 with polyamine 2a–h.
Polyamine 2
equiv.)
Monoimidazole
b
amide 3 (%)
Bisimidazole
b
amide 4 (%)
(
Solvent
a (2)
b (2)
c (2)
d (4)
e (2)
f (4)
g (2)
h (2)
CH
CH
2
Cl
Cl
2
2
2
2
2
2
2
a (83)
b (80)
c (88)
d (84)
e (87)
f (93)
g (73)
h (66)
a (1)
b (8)
c (2)
d (3)
e (4)
2
CH Cl
2
CH
CH
CH
2
Cl
2
Cl
2
Cl
c
f (nd )
g (12)
h (10)
CH Cl
2
MeOH
a
The reactions were conducted at rt.
b
Based on isolated product.
Not detected.
c

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1
612
Zhu, Jiang, and Zhao
can also be easily synthesized from 4-nitro-1-
[
14,16]
DNA binding molecules,
methyl-2-trichloroacetylpyrrole.
EXPERIMENTAL
0
00
N-[3 -N,N-(3 -Aminopropylmethyl)-aminopropyl]-4-nitro-1-methyl-
imidazole-2-carboxamide 3a. To a solution of 2a (103 mg, 0.79 mmol) in
CH Cl (4 mL) with stirring was added 4 mL CH Cl solution of 1 (114 mg,
2
2
2
2
0.42 mmol) dropwise during 2 hr at rt. The reaction mixture was stirred at
the same temperature overnight, concentrated under reduced pressure, and
chromatographied by column over silica gel (CHCl /MeOH ¼ 10 : 3) to
3
1
give 3a as white powder in 83%. H NMR (CDCl , 500 MHz): 8.84 (br,
3
1
H), 7.78 (s, 1H), 4.15 (s, 3H), 3.48 (s, 2H), 2.79 (t, J ¼ 6.9 Hz, 2H), 2.50
(dd, J ¼ 11.9, 5.9 Hz, 2H), 2.44 (dd, J ¼ 7.9, 6.8 Hz, 2H), 1.71–1.78
(m, 6H); ESI MS (rel. int.): m/z 321 (3), 299 (100), 282 (16), 254 (4), 242
(4), 211 (7), 172 (3); Hi-resolution (HR)-FABMS: m/z calcd for
C H N O (M þ 1) 299.1826, found 299.1822.
1
2 23 6 3
Using the same procedure, 3b–g were also synthesized.
0
1
N-(7 -Aminoheptyl)-4-nitro-1-methyl-imidazole-2-carboxamide 3b. H
NMR (CDCl , 500 MHz): 7.84 (s, 1H), 7.40 (br, 1H), 4.15 (s, 3H), 3.39 (dd,
3
J ¼ 13.8, 6.9 Hz, 2H), 2.69 (t, J ¼ 6.9 Hz, 2H), 1.57–1.63 (m, 2H), 1.42–
1.47 (m, 4H), 1.35–1.37 (m, 6H); ESI MS (rel. int.): m/z 284 (100), 267 (3),
1
83 (4).
0
1
N-(5 -Aminopentyl)-4-nitro-1-methyl-imidazole-2-carboxamide 3c. H
NMR (CDCl , 500 MHz): 7.80 (s, 1H), 7.43 (br, 1H), 4.16 (s, 3H), 3.40 (dd,
3
J ¼ 13.8, 6.9 Hz, 2H), 2.71 (t, J ¼ 6.9 Hz, 2H), 1.62–1.66 (m, 2H), 1.46–1.50
(m, 2H), 1.39–1.44 (m, 2H), 1.31 (br, 2H); ESI MS (rel. int.): m/z 256 (100),
2
39 (8), 183 (2).
0
1
N-(4 -Aminobutyl)-4-nitro-1-methyl-imidazole-2-carboxamide 3d. H
NMR (CDCl , 500 MHz): 7.81 (s, 1H), 7.71 (br, 1H), 4.17 (s, 3H), 3.42
3
(
dd, J ¼ 12.8, 6.9 Hz, 2H), 2.75 (t, J ¼ 6.9 Hz, 2H), 1.63–1.69 (m, 2H),
1
.51–1.56 (m, 2H), 1.28 (br, 2H); ESI MS (rel. int.): m/z 242 (100), 225
(
36), 183 (3).
0
1
N-(3 -Aminopropyl)-4-nitro-1-methyl-imidazole-2-carboxamide 3e. H
NMR (CDCl , 500 MHz): 7.87 (br, 1H), 7.79 (s, 1H), 4.16 (s, 3H), 3.51 (dd,
3
J ¼ 12.8, 5.9 Hz, 2H), 2.83 (t, J ¼ 6.9, 5.9 Hz, 2H), 1.75 (dd, J ¼ 12.8,
6
.9Hz, 2H), 1.47 (br, 2H); ESI MS (rel. int.): m/z 228 (100), 211 (98), 183 (10).
0
1
N-(2 -Aminoethyl)-4-nitro-1-methyl-imidazole-2-carboxamide 3f. H
NMR (CDCl , 500 MHz): 7.80 (s, 1H), 7.65 (br, 1H), 4.18 (s, 3H), 3.46
3
(
dd, J ¼ 11.8, 5.9 Hz, 2H), 2.93 (t, J ¼ 5.9 Hz, 2H), 1.32 (br, 2H); ESI MS
rel. int.): m/z 236 (16), 214 (100), 197 (96).
(

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Synthesis of Monoimidazole/Polyamine Amides
1613
0
00
N-[3 -N-(4 -Aminobutyl)- aminopropyl]-4-nitro-1-methyl-imidazole-
1
-carboxamide 3g. H NMR (CDCl , 500 MHz): 8.58 (br, 1H), 7.80
2
3
(
s, 1H), 4.15 (s, 3H), 3.49 (dd, J ¼ 7.8, 5.8 Hz, 2H), 2.80 (t, J ¼ 6.8 Hz,
2
1
H), 2.72 (dd, J ¼ 9.8, 13.8 Hz, 2H), 2.65 (dd, J ¼ 7.9, 13.8 Hz, 2H), 1.67–
.81 (m, 4H), 1.55–1.66 (m, 2H), 1.49–1.53 (m, 2H); ESI MS (rel. int.):
m/z 321 (7), 299 (100), 282 (49), 211 (3), 155 (3); MS/MS: m/z 299 (5),
82 (100), 228 (6), 211 (4), 155 (3); HR-FABMS: m/z calcd for
C H N O (M þ 1) 299.1826, found 299.1824.
2
1
2 23 6 3
1
0
0
0
N -(4 -Nitro-1 -methyl-imidazole-2 -carboxyl)-1,12-diamino-4,9-di-
azadodecane 3h. A solution of 1 (102 mg, 0.37 mmol) in MeOH (4 mL) was
0
stirred for 1 hr to give methyl 4-nitro-1-methyl-imidazole-2-carboxylate (1 ),
which was checked by ESI MS and MS/MS. The resulting solution was
added dropwise to a solution of spermine 2h (168 mg, 0.83 mmol) in 4 mL
MeOH. The reaction mixture was stirred overnight and concentrated under
reduced pressure to give a residue, which was dissolved in a mixed solvent
(
MeOH/3% aq.HCl ¼ 10 : 1) and separated by column chromatography
over ODS gel (H O/MeOH ¼ 7 : 3) to produce 3h in 66% yield. RP-HPLC
2
1
analysis: 3.2 min (96%) and 6.7 min (4%). H NMR (D O, 500 MHz): 8.14
2
(
s, 1H), 3.93 (s, 3H), 3.40 (t, J ¼ 13.8, 6.9 Hz, 2H), 3.02–3.06 (m, 10H),
1
.98–2.00 (m, 2H), 1.91–1.96 (m, 2H), 1.69 (m, 4H); ESI MS (rel. int.):
m/z 378 (2), 356 (100), 282 (60), 211 (8), 156 (13), 129 (17); HR-FABMS:
m/z calcd for C H N O (M þ 1) 356.2404, found 356.2404.
1
5
30
7
3
ACKNOWLEDGMENT
We thank the National Natural Science Foundation of China (No.
0132020 and No. 20372009) for financial support.
2
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Received in the UK March 21, 2003

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