NIS-promoted guanylation of amines

Article abstract of DOI:10.1016/j.tetlet.2009.01.073

An efficient NIS-promoted guanylation reaction is described. This procedure allows the guanylation of primary and secondary amines through the reaction with di-Boc-thiourea and di-Boc-S-methylisothiourea, respectively. We demonstrated that the use of NIS compares favorably with existing methods and is an attractive alternative to heavy metal or Mukayama's reagent activation.

Full text of DOI:10.1016/j.tetlet.2009.01.073

Tetrahedron Letters 50 (2009) 1463–1465
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Tetrahedron Letters
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NIS-promoted guanylation of amines
*
*
Keiichiro Ohara, Jean-Jacques Vasseur , Michael Smietana
Institut des Biomolécules Max Mousseron, UMR 5247 CNRS Université Montpellier 1, Université Montpellier 2, Place Eugène Bataillon, 34095 Montpellier, France
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient NIS-promoted guanylation reaction is described. This procedure allows the guanylation of
primary and secondary amines through the reaction with di-Boc-thiourea and di-Boc-S-methylisothiou-
rea, respectively. We demonstrated that the use of NIS compares favorably with existing methods and is
an attractive alternative to heavy metal or Mukayama’s reagent activation.
Received 1 December 2008
Revised 6 January 2009
Accepted 13 January 2009
Available online 19 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
NIS
Guanidine
Thiourea derivatives
Guanidine-containing molecules display a wide range of biolog-
ically important roles. Many natural metabolites exhibiting biolog-
ical activities possess the guanidine functionality,1 and a number of
synthetic pharmaceuticals incorporate the guanidine framework as
exemplified by the influenza inhibitor zanamivir.2 In addition, in
aqueous media, the protonated guanidine is highly stable and is
at the heart of the formation of selective non-covalent associations
with anionic complementary groups.3 Considering the growing
importance and applications of guanidine derivatives in the field
of medicinal and supramolecular chemistry, a continuous synthetic
interest has been shown for the conversion of amines to the corre-
sponding guanidines.4–6 The most commonly used reagents for this
conversion include pyrazole-1-carboxamidine derivatives,7 dipro-
tected triflylguanidines,8 and protected thioureas as well as S-
methylisothioureas derivatives, which need to be activated by
toxic mercury salts9,10 or by Mukaiyama’s reagent.11 As most of
these methodologies have pro and cons, the choice of a guanylating
reagent usually depends on the synthetic strategy as well as on the
reactivity of the starting amine. In this context, the development of
additional methodologies is of primary importance as it can allow
to increase the chemical flexibility of this usually challenging
reaction.12
standard organic solvents generates a side product commonly
challenging to be removed by chromatography.14 Here, we would
like to report our findings on the conversion of amines into pro-
tected guanidines using N-iodosuccinimide as the promoter.
N-Iodosuccinimide (NIS) is a source of electrophilic iodine,
which allows stereoselective and regioselective reactions on vari-
ous functional groups. It is particularly mentioned in the literature
for regioselective iodination of activated aromatic compounds,15
iodolactonization,16 iodohydroxylation,17 and as a promoter of gly-
cosylation reactions with thioglycosides.18 In analogy to the HgCl2-
promoted guanylation, we reasoned that the thiophilic NIS should
behave as a soft Lewis acid, and thus coordinate the protected thio-
and S-methylisothioureas. Adding Et3N would lead to a carbodiim-
ide intermediate, which should be trapped by the amine to provide
the desired protected guanidine. To test this hypothesis, we re-
acted the commercially available di-Boc-thiourea (1 equiv) with
benzylamine (1.2 equiv) in the presence of NIS (1 equiv) and trieth-
ylamine (2 equiv) in dichloromethane. After 3 h at room tempera-
ture (TLC monitoring) the protected guanidine (Table 1, entry 1)
was obtained in 85% yield without any noticeable undesirable side
product. To investigate the scope and limitations of this original
use of NIS, a series of structurally diverse amines were subjected
to the reaction conditions.
The results are illustrated in Table 1. From these data, several
conclusions can be reached. First, unhindered primary amines
(entries 1–4) can generally be guanylated in high yields (>80%)
demonstrating, therefore, the ability of NIS to act as an efficient
carbodiimide promoter. Second, hindered or unreactive primary
amines appeared to react somewhat slower, nevertheless good
yields could still be obtained after longer reaction times and high-
er temperatures (entries 5 and 6). It should be noted that NIS
worked solely for activation of the sulfur-leaving group as no
iodinated by-products was formed during the process. Although
During our ongoing project that aimed at the synthesis and the
evaluation of guanidino derivatives designed for their ability to
complex polyanionic biomolecules,13 we were interested in replac-
ing the traditional promoters (HgCl2 and Mukaiyama’s reagent)
used for the guanylation of thio- and S-methylisothioureas. The
problems associated with the use of toxic metal salts are well doc-
umented and Mukaiyama’s reagent that is rather insoluble in most
* Corresponding authors. Tel.: +33 4 67143837; fax: +33 467042029 (M.S.).
E-mail addresses: vasseur@univ-montp2.fr (J.-J. Vasseur), msmietana@
univ-montp2.fr (M. Smietana).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.073

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K. Ohara et al. / Tetrahedron Letters 50 (2009) 1463–1465
Table 1
Guanylation of amines using di-Boc-thiourea and NIS
Entry
Amine
Product
Yield (%)a
85
Time (h)
3
NBoc
NH2
1
N
H
NHBoc
NBoc
2
3
80
88
2
NH2
N
H
NHBoc
H
N
NH2
NHBoc
14
NBoc
O
N
O
NH
NH
H
N
4
H2N
N
O
BocHN
O
75
15
O
O
NBoc
OH
OH
NBoc
5
6
66
71
10b
16
N
H
NHBoc
NH2
H
N
NH2
NHBoc
NBoc
H
N
NH2
NHBoc
7
8
15
22b
NBoc
O2N
O2N
N
N
H
38
25
6
BocN
NHBoc
N
S
NHBoc
NBoc
a
Isolated yields.
Refluxing dichloromethane.
b
it was not investigated, the reaction is, however, expected to pro-
duce iodinated by-products with substrates bearing reactive dou-
ble bonds.17 Interestingly, in the case of N,N-dibutylamine, we
were able to isolate along with the expected guanidine a second-
ary product, which corresponds to the S-aminoisothiourea in 25%
yield (entry 8, Supplementary data). This compound likely results
from a competitive nucleophilic attack of the amine on the S-
iodoisothiourea intermediate.19 To circumvent this setback, we
decided to evaluate the use of di-Boc-S-methylisothiourea in the
presence of NIS. While these conditions could not be applied for
the guanylation of primary amines as poor yields are obtained,
they significantly facilitated the guanylation of secondary amines.
In a typical reaction, NIS (1 equiv) and a slight excess of the S-
methylisothiourea (1.5 equiv) were added to a solution of the
amine (1 equiv) in DMF in the presence of 2 equiv of Et3N. Under
these reaction conditions, secondary amines were readily guany-
lated while no S-aminoisothiourea by-product could be detected
(Table 2). As an example of a highly hindered secondary amine,
Table 2
Guanylation of secondary amines using di-Boc-S-methylisothiourea and NIS
Entry
1
Amine
Product
Yielda (%)
N
N
H
72
BocN
NHBoc
N
2
75
65
N
H
BocN
NHBoc
NBoc
NH
3
N
NHBoc
a
Isolated yields.

K. Ohara et al. / Tetrahedron Letters 50 (2009) 1463–1465
1465
diisopropylamine was guanylated in 75% yield, which compared
References and notes
favorably with all the other methods reported in the literature
(entry 2).4,8,11
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Although the precise reaction mechanism has not been clarified
yet, we assume that a carbodiimide is the key intermediate, which
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along with triethylamine iodide and succinimide derivatives.20
In conclusion, we demonstrated the ability of the thiophilic NIS
to promote the conversion of amines into protected guanidines.
This reaction was shown to easily tolerate a diversity of substitu-
tion patterns on the amines. Thioureas and S-methylisothioureas
are common reagents for the synthesis of guanidines, and this con-
version requires usually initial activation by heavy metal or the use
of Mukaiyama’s reagent. Guanylation with NIS eliminates without
perceptible loss of yield the use of toxic heavy metals and the prob-
lem associated with their elimination. Moreover, it is an attractive
alternative to Mukaiyama’s reagent, especially when solubility and
purification issues are encountered.
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We gratefully acknowledge l’Université de Montpellier 2 for
financial support. K.O. thanks ‘l’Association pour la Recherche sur
le Cancer’ (ARC) for a doctoral fellowship.
Supplementary data
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Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.01.073.