One-pot synthesis of N-alkyl substituted phosphoryl guanidines

Article abstract of DOI:10.1080/10426500490459669

This article describes an attractive and one-pot synthesis of the title compound by phosphorylation of just prepared N-substituted guanidines from cyanamide and the desired amine. The method allows a variety of N-substituents to hang on the final phosphoryl guanidine as a function of the wider availability of commercial simple amines.

Full text of DOI:10.1080/10426500490459669

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ONE-POT SYNTHESIS OF N-ALKYL SUBSTITUTED
PHOSPHORYL GUANIDINES
a
a
a
Marcos Costa Souza , William Pires Macedo , Marcelo Campos M. Silva , Guilherme Costa
a
b
de O. Ramos & Helmut G. Alt
a
Universidade Federal Fluminense, Rio de Janeiro, Brazil
Universität Bayreuth, Bayreuth, Germany
b
Version of record first published: 16 Aug 2010
To cite this article: Marcos Costa Souza, William Pires Macedo, Marcelo Campos M. Silva, Guilherme Costa de O. Ramos &
Helmut G. Alt (2004): ONE-POT SYNTHESIS OF N-ALKYL SUBSTITUTED PHOSPHORYL GUANIDINES, Phosphorus, Sulfur, and
Silicon and the Related Elements, 179:6, 1047-1054
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Phosphorus, Sulfur, and Silicon, 179:1047–1054, 2004
Copyright ꢀC Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500490459669
ONE-POT SYNTHESIS OF N-ALKYL SUBSTITUTED
PHOSPHORYL GUANIDINES
∗
∗
Marcos Costa de Souza, William Pires de Macedo,
∗
∗
Marcelo Campos M. da Silva, Guilherme Costa de O. Ramos,
∗
∗
and Helmut G. Alt
Universidade Federal Fluminense, Rio de Janeiro, Brazil;
∗
∗
∗
and Universit a¨ t Bayreuth, Bayreuth, Germany
Received October 1, 2003; accepted October 1, 2003)
(
This article describes an attractive and one-pot synthesis of the title
compound by phosphorylation of just prepared N-substituted guani-
dines from cyanamide and the desired amine. The method allows a
variety of N-substituents to hang on the final phosphoryl guanidine as
a function of the wider availability of commercial simple amines.
Keywords: N-alkyl guanidines; phosphoramidic acid; phosphoryl
guanidines
The well known system phosphoryl guanidine (1) has been investigated
over the last 60 years, initially for its behavior as natural ligand in phys-
iological medium. In this area, phosphoryl guanidines have proven to
1
+2
+2
+2
+2
be efficient in the complexation of ions such as Pb , Ni , Zn , Cu ,
+3
+3
Fe , and Al . Related studies showed that the P(O)N C group serves
as an oncolytic moiety against a sort of cancer as well as osteoporosis
agent. More specific application of phosphoryl guanidine derivatives is
2
found in the new material field, giving rise to many industrial patents
every year. (see Figure 1.)
Nevertheless, such studies are only related to a restrict set of N-
substituted phosphoryl guanidines bearing few N-alkyl groups (R2, R3),
which usually come from one of the two known methods to generate
We are thankful to Conselho Nacional de Pesquisa e Desenvolvimento (CNPq),
Funda c¸ a˜ o de Amparo a` Pesquisa do Estado do Rio de Janeiro (FAPERJ), and Deutscher
Akademischer Austauschdienst (DAAD) for financial support. Additional thanks to Uni-
versidade Estadual de Campinas (UNICAMP) for the mass spectra.
Address correspondence to Marcos Costa de Souza, Universidade Federal Fluminense,
o
Instituto de Qu ´ı mica Organica, Outeiro de S a˜ o Jo a˜ o Batista, s/n , Centro, Niter o´ i, Rio de
Janeiro, Brazil CEP 24020-150. E-mail: gqomarc@vm.uff.br
1
047

1
048
M. C. de Souza et al.
FIGURE 1 N-substituted phosphoryl guanidines.
1
: the direct phosphorylation of scarcely available commercial N-
substituted guanidines (2) (Eq. 1) or the addition-elimination reaction
between amines and phosphoryl-S-ethyl isothioureas (3) (Eq. 2), some-
times disadvantageous because of the unpleasant mercaptan odor that
impregnates the product.3
−7
Herein we describe an attractive and one-pot synthesis of the title
compound by phosphorylation of just prepared N-substituted guani-
dines from cyanamide and the desired amine. The method allows a
variety of N-substituents to hang on the final phosphoryl guanidine as
a function of the wider availability of commercial simple amines.
RESULTS AND DISCUSSION
Phosphorylation of amines easily can be accomplished by using the
3
method of Zhao and Lin, which consists on a two-phase reaction be-
tween dialkyl phosphonate and the amine in alkaline water-carbon
tetrachloride medium. The same condition can be successfully employed
for phosphorylation of commercial guanidines. There are only a few
number of such commercial substituted guanidines, however, limiting
the preparation of final phosphoryl guanidines bearing different sub-
stituents. In this paper we present preliminary results of an alternative

Phosphoryl Guanidines
1049
simple method to synthesize the N-alkyl substituted diisopropyl phos-
phoryl guanidines 1a–d from simple aliphatic amines available in our
laboratory.
SCHEME 1 Phosphoryl guanidines prepared.
The first route we have investigated consists on the condensation of
amines with diisopropyl cyanamidophosphonate (4). This was supposed
to be a very versatile intermediate allowing a sort of aliphatic (and
some aromatic) nucleophilic amines to react with, leading to the desired
∗
phosphoryl guanidine (Eq. 3) . However, we were not able to prepare 4
even after changing the solvent, the base and the phosphorylating agent
(
entries a–e). Only polymerization products and unreacted cyanamide
remained in the reaction bottle.
a) NEt3/acetone; b) pyridine; c) pyridine/acetone; d) NaOH/H2O/CCl4; e) BuLi/THF.
In an alternative route we propose the synthesis of phosphoryl guani-
dines 1a–d by direct phosphorylation of guanidine hydrochlorides using
diisopropyl phosphonate in alkaline medium (Scheme 1). The guanidine
hydrochlorides 2a–d are prepared by condensing cyanamide with the
desired amine in a buffered system (pH 8-9) consisting of amine/amine
hydrochloride.
The whole process is strongly pH dependent. In the first step of the
synthesis we found out that the best pH ranges between 8–9, so that
the amine (HNR2R3) can act as a nucleophile toward the cyanamide
carbon atom. In the next step phosphorylation must take place in alka-
line basic medium in order to abstract the acidic hydrogen atom from

1
050
M. C. de Souza et al.
SCHEME 2 One-pot phosphorylation of guanidine hydrochlorides.
the diisopropyl phosphonate molecule and, at the same time, liberate
the free guanidine from its salt form. Strong pH condition, however, de-
composes the N-substituted guanidine into urea and the initial amine
leading to simple phosphorylamine as the main product.
This methodology was preliminary tested with two primary amines
benzyl amine and 2-phenylethyl amine) and two secondary amines
dimethyl amine and piperidine). These amines provided the guanidine
(
(
hydrochlorides 2a–d as semi-solids which where employed directly in
the phosphorylation step. Guanidines 2a and 2b were phosphorylated
at pH 9 and 11, respectively, giving rise to phosphoryl guanidines 1a and
1
b (Table I). Guanidine 2c decomposes very easily at the pH range be-
tween 9-11 generating the phosphorylamine 5c as the main product and
a small and impure amount of phosphoryl guanidine 1c. One reason for
this behavior would be the sensitivity of N-heterocyclic guanidines un-
der alkaline condition. Employing the N,N-acyclic dimethylguanidine
2
d in turn, the expected phosphoryl guanidine 1d was obtained. Best
result was reached at pH 11 showing that the corresponding guanidine
resisted to strong alkaline medium.
Spectroscopic assignment of the products was carried out by infrared,
3
1
13
1
mass, P, C, and H-NMR techniques (Table II). Presence of C N
13
bond in both infrared and C-NMR spectra as well as P O bond indi-
cated the formation of phosphoryl guanidines 1a, 1b, and 1d. Very weak
signals in the spectra showed that phosphoryl piperidine 5c was pref-
erentially formed instead of the corresponding phosphoryl guanidine

Phosphoryl Guanidines
1051
TABLE I Yield and Optimum pH in the
Phosphorylation of the N-Substituted
Guanidine Hydrochlorides 2a–d
Product
Yield (%)
Optimum pH
1
1
1
1
a
b
c
61
31
—
53
9
11
Not determined
11
d
1
c. Evidence for the formation of 1c, however, was given by mass spec-
troscopy, showing the corresponding molecular pick and a fragmenta-
tion pattern similar to other guanidines.7
EXPERIMENTAL
1H, 13C, and 31P-NMR spectra were recorded on a Varian UP-300 spec-
trometer (300 MHz) with TMS as internal standard or 85% H3PO4 as
external standard; infrared spectra were recorded on a Perkin-Elmer
spectrometer; mass spectra (EI-70 eV) were recorded on a VG Auto Spec
instrument, GC column HP-5 (HP.ULTRA.2), ethyl acetate. Melting
points are uncorrected. Solvents and amines were fractionally distilled
before use. Diisopropyl phosphonate and diisopropyl chlorophospho-
4
8
nate were prepared as described in Lin et al., and McCombie et al. The
amine hydrochlorides were prepared by stirring stoichiometric amount
of hydrochloric acid (37% aqueous solution) and the respective amine.
After evaporation to dryness the salts were stored on a desiccator.
General Procedure to N-Substituted Guanidine
Hydrochlorides 2a--d
To a 1:1 mixture of cyanamide and the appropriate amine hydrochloride
in water some drops of the corresponding amine is added until pH 8-9
is reached. The mixture is refluxed for 3.5 h keeping that pH by adding
more amine if necessary. After cooling down to room temperature the
mixture is acidified to pH 4 with hydrochloric acid. Water is removed
under vacuum to give the guanidine salts as hygroscopic semi-solids
which are ready to use in the following step.
General Procedure to N-Substituted Phosphoryl
Guanidines 1a--d
To a stirred solution of crude guanidine hydrochloride (2a–d) and
sodium hydroxide in water (15 ml) and ethanol (3 ml), recently distilled

1
052

1053

1
054
M. C. de Souza et al.
diisopropyl phosphonate in carbon tetrachloride (15 ml) is added drop-
◦
◦
wise at 0 C. The mixture is then stirred at 65–75 C for 4.5 h keeping pH
or 11 by adding more sodium hydroxide if necessary. The two phases
9
are decanted, the organic layer washed three times with water, dried
with MgSO4, and evaporated under reduced pressure to give the crude
product.
1
a. According to the general procedure, reaction of 4.48 g
(
0.022 mmol) of guanidine hydrochloride 2a, 1.80 g (0.045 mmol) of
sodium hydroxide (enough to keep pH 11), and 3.74 g (0.022 mmol) of
diisopropyl phosphonate gave a yellow oil which was washed several
times with brine to remove the persisting polar residues as showed by
TLC. Such treatment gave a clear yellow oil in 61% yield.
1b. According to the general procedure, reaction of 4.30 g (0.030
mmol) of guanidine hydrochloride 2b, 2.40 g (0.060 mmol) of sodium
hydroxide (enough to keep pH 9), and 4.98 g (0.030 mmol) of diiso-
propyl phosphonate gave a yellow oil which was washed several times
with brine to remove the persisting polar residues as showed by TLC.
Such treatment gave a clear yellow oil in 31% yield.
1c. According to the general procedure, reaction of 3.27 g (0.020
mmol) of guanidine hydrochloride 2c, 1.60 g (0.040 mmol) of sodium
hydroxide (enough to keep pH 9, 10, and 11 in three experiences respec-
tively), and 3.32 g (0.020 mmol) of diisopropyl phosphonate. Phosphoryl
guanidine 5c was obtained as the main product in all cases.
1d. According to the general procedure, reaction of 5.54 g (0.045
mmol) of guanidine hydrochloride 2d, 3.60 g (0.090 mmol) of sodium
hydroxide (enough to keep pH 11), and 7.48 g (0.045 mmol) of diiso-
propyl phosphonate gave a yellow oil which was boiled with active coal
to generate a clear oil in 53% yield.
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[
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[
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(
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[
[
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[
[
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