Synthesis of α-chloroamides in water

Article abstract of DOI:10.1016/j.tetlet.2006.06.090

The reaction between chloroacetyl chloride and mono- or bis-aliphatic or aromatic amines in water under basic or neutral conditions gives rise to the formation of a variety of functionalized α-chloroamides. The resulting products were obtained as solids in moderate to good yields, upon precipitation and isolation by filtration.

Full text of DOI:10.1016/j.tetlet.2006.06.090

Tetrahedron Letters 47 (2006) 6321–6324
Synthesis of a-chloroamides in water
Andrew J. Harte and Thorfinnur Gunnlaugsson*
School of Chemistry, Centre for Synthesis and Chemical Biology, Trinity College Dublin, Dublin 2, Ireland
Received 26 April 2006; revised 8 June 2006; accepted 15 June 2006
Available online 18 July 2006
Abstract—The reaction between chloroacetyl chloride and mono- or bis-aliphatic or aromatic amines in water under basic or neutral
conditions gives rise to the formation of a variety of functionalized a-chloroamides. The resulting products were obtained as solids
in moderate to good yields, upon precipitation and isolation by filtration.
Ó 2006 Elsevier Ltd. All rights reserved.
Amides are important building blocks in both Nature
and in chemical synthesis.1 For the latter, such reactions
are conducted in organic solutions or in a mixture of
organic and aqueous solutions (Schotten–Baumann condi-
tions) where the organic reagents are generally dissolved
in the organic solution and treated with aqueous base.1
The development of alternative methods for achieving
amide synthesis in high yield and/or in a stereospecific
manner is of great current interest. Over the last few
years several new methods such as the use of the CuI
catalyzed transformation of alkynes, biocatalysts and
PEG supported pyridylthioesters have been employed
for amide synthesis.2 Such synthesis is also of significant
industrial importance, for example, for the synthesis of
polypeptides and amide based drugs. Recently, Bode
et al. have developed a novel method for peptide cou-
pling using decarboxylative condensation of a-ketoacids
and N-alkylhydroxylamines in organic or mixed aque-
ous solutions.3 An important family of amides are the
a-chloroamides, which have been used as alkylating
agents in a range of organic syntheses, for instance, in
the synthesis of lactams and a,b-unsaturated amides.4
Importantly, these are also valuable synthons for the
development of stable lanthanide-based macrocycles
for biological applications.5,6 We have used varieties of
a-chloroamides in the synthesis of such macrocyclic
cyclen complexes, where the amides function as pendent
arms, coordinating to lanthanide ions giving rise to
octa-coordinated supramolecular lanthanide com-
plexes.5 These can be used as potential MRI contrast
agents, as luminescent probes and as ribonuclease mim-
ics.5–10 For all of these compounds the starting point is
the synthesis of the desired pendant arms, or spacer moi-
eties in the case of the dinuclear complexes, which are
introduced by alkylation with a-chloroamides. During
the development of macrocyclic systems such as 1, 2
and 3 as MRI contrast agents,11 Figure 1, we discovered
that the classical reaction between the corresponding
amine and chloroacetyl chloride (2 equiv) in dry THF
(or CH2Cl2) at À10 °C in the presence of freshly distilled
Et3N, gave very low yields of the desired a-chloro-
amides. Furthermore, changing to solvents such as
DMF, CH2Cl2, CHCl3 or Et2O did not increase signifi-
cantly the yield of the products, and the reaction only
proceeded in EtOAc, but in low yields. For the aromatic
bis-amine 4, the reaction was even more problematic.
Hence, we turned our focus towards alternative syn-
thetic methods and found that the amide coupling could
be conducted in water in the presence of medium or
strong bases such as Et3N, KHCO3, K2CO3 or NaOH,
where the desired products were formed as solids in
R
O
H
N
H
N
N
H
O
O
O
N
N
1; R =
R
O
O
N
N
N
N
O
O
N
H
R
2; R =
3; R =
N
H
N
N
H
N
H
R
*
Corresponding author. Tel.: +353 1 608 3459; fax: +353 1 671
2826; e-mail: gunnlaut@tcd.ie
Figure 1. Macrocyclic ligands for MRI contrast agents.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.090

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A. J. Harte, T. Gunnlaugsson / Tetrahedron Letters 47 (2006) 6321–6324
H
H
O
O
O
O
N
N
Cl
Cl
Cl
Cl
Cl
Cl
N
N
N
N
N
O
O
H
H
H
H
9
7
8
10%
40%
60%
Cl
O
O
HN
O
H
H
N
Cl
Cl
N
N
N
H
nH
NH
NH
O
O
11, n=3, 30% yield
12, n=4, 39% yield
13, n=5, 42% yield
14, n=6, 42% yield
O
O
Cl
Cl
10
Cl
Cl
NO2
98%
17
64%
16
64%
15
58%
CF3
O
OH
O
HO
O
O
OH
HO
NO2
Cl
OH
Cl
Cl
HO
Cl
NH
HN
HN
O
HN
HN
HN
NH
O
O
O
O
O
O
Cl
Cl
24
88%
Cl
21
77%
22
78%
18
79%
20
23
31%
19
15%
82%
F
O
NH2
NO2
N
N
Br
O
NH
NH
NH
HN
O
N
NH
NH
O
O
O
O
O
O
Cl
Cl
Cl
Cl
31
40%
Cl
Cl
26
83%
Cl
25
64%
27
47%
28
49%
30
48%
29
37%
acceptable yields, under ambient conditions. Here, we
give a preliminary account of our investigation into
the use of this simple synthetic method for the genera-
tion of a number of a-chloroamides, which have signif-
icant value in general organic synthesis and in
developing macrocyclic ligands for targeting lanthanide
ion complexes.5–13 These ligands and the synthetic meth-
od in general, is highly applicable to industry as poten-
tial green chemistry.
as solvent and base did not yield any improvement.
The problem seemed to stem from the insolubility of
4, which was only fully soluble in alcohols and water.
Under Schotten–Baumann conditions, the formation
of HCl is neutralized with NaOH by employing a two
phase system consisting of water and CH2Cl2, or by
using excess of the amine as a base. The solvents chosen
are immiscible so that the amine and acid chloride re-
main in the lower CH2Cl2 layer, while NaOH remains
in the upper aqueous layer.12 However, due to the lack
of solubility of 4 in organic solution, we decided to carry
out a modification of this method using only water as
the solvent. Moreover, instead of using an excess of
the amine, we used 4 equiv of chloroacetyl chloride,
which was added dropwise over 1 h to the aqueous
amine solution. The solution was left to stir overnight
and the desired product 6 was isolated as a precipitate
in yields of 75% with no need for further purification.
Hence, the two-phase procedure was not necessary and
in fact this modification enabled the successful isolation
of the desired product with minimal effort. Due to the
success and simplicity of the above reaction, it was
decided to investigate its range and suitability for other
N-acylation type reactions, which would have significant
synthetic value for developing targeting lanthanide-
Initially, the acylation of p-xylylenediamine 4, to yield
1,4-bis-(2-chloro-acetylamino)-xylyene, 6 (Scheme 1)
was conducted in CHCl3 with freshly distilled Et3N.
However, this method gave a low yield of 11% of the
desired product. Varying the reaction conditions such
O
Cl
Cl
Cl
H2N
HN
5
O
O
NH2
NH
Cl
Base
4
6
Scheme 1. Acylation of p-xylylenediamine to yield 1,4–bis-(2–chloro-
acetylamino)-xylylene (6).

A. J. Harte, T. Gunnlaugsson / Tetrahedron Letters 47 (2006) 6321–6324
6323
Table 1. Effect of changing the base upon the yields of N-acylation
well as the ease of work-up are also major advantages.
The reaction has been shown to be successful for a range
of amines, both aromatic and aliphatic. Additional
investigation within our laboratory has also shown that
optimization of the above reaction can be achieved by
tuning the temperature and the base employed. We are
in the progress of exploring the scope of this method
further.
Compd NaOH (%) Et3N (%) NaHCO3 (%) No base (%)
14
16
8
32
64
8
27
69
28
39
7
85
14
17
13
74
0
6
75
9
based macrocycles. Under the same conditionsà the
a-chloroamides 7–10, were synthesized from their corre-
sponding aromatic diamines, while 11–14, were synthe-
sized from their corresponding aliphatic diamines. In
all cases, the desired products precipitated out of solu-
tion and were collected by filtration. The versatility of
this method was investigated further, by introducing
more functional groups into the starting materials such
as aryl acids, amides, halides, hydroxides and acids.
Compounds 15–31 were synthesized from such function-
alized aromatic amines, using the above procedure, and
were generally obtained in good yields. As for 6–14, the
recorded yields are that of the products isolated by sim-
ple filtration, with no further need for purification (e.g.,
no recrystallization, extraction of aqueous layer, etc.).
For those cases that gave low yields of the desired prod-
ucts, additional extraction of the aqueous layer using
CH2Cl2 gave significantly increased yields. Moreover,
in the case of 18, 22, 24, 27 and 28, which have additional
functionalities, the yields were in the region of 50–90%,
clearly demonstrating the versatility of this method.
The reaction procedure was, however, not as successful
when more extended ring systems such as anthracene,
phenanthroline and methyl-quinoline were used.
Acknowledgement
We thank TCD and Enterprise Ireland for financial
support.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.06.090.
References and notes
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A further investigation was conducted in order to deter-
mine whether the choice of base employed had an affect
on the reaction. Four reactions from the above section,
with a range of yields were chosen. From Table 1, it can
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In summary, we have synthesized a number of a-chloro-
amides by N-acylation of amines under purely aqueous
conditions. Its usefulness stems from the fact that the sol-
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à General experimental procedures for a-chloroamides discussed herein
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