Process for the preparation of monofunctionalized cyclic tetramines

Process for the preparation of monofunctionalized cyclic tertramines of formula I ##STR1## in which R denotes a saturated or unsaturated, especially polymerizable, organic radical, characterized in that the corresponding tetraazacycloalkane compound (according to formula II) is prepared, in which three of the four nitrogen atoms are bonded via covalent bonds with a single atom or group of intracyclic atoms A, in that this triprotected compound is reacted with an organic compound RX (of formula III), X denoting a nucleophobic group, and in that the tetraazacycloalkane compound which is tri-protected and monofunctionalized on the unprotected nitrogen (according to formula IV) thus obtained is deprotected.

The present invention, made at the Molecular Chemistry, Electrochemistry 
and Photochemistry Laboratory of the University of Western Brittany, a 
laboratory affiliated to the National Center for Scientific Research, 
relates to a process for the preparation of monofunctionalized cyclic 
tetramines. 
Tetraazamacrorings are macrocyclic ligands which exhibit the characteristic 
of forming extremely stable complexes with ions of transition metals (from 
the manganese column to that of zinc, but also with lead, and the like). 
On the other hand, these molecules do not, or very barely, associate with 
alkali and alkaline-earth metals (see Host Guest Complex Chemistry I, II, 
III. F. Vogtle and E. Weber Edit., Springer Verlag, 1980, 1981 and 1984, 
and Coordination Chemistry of Macrocyclic Compounds, A. Melson Edit., 
Plenum, 1979). 
Many applications are described in the literature in fields as diverse as 
electrochemistry (modified electrodes), catalysis, stabilization of 
unstable oxidation states or, furthermore, nuclear medicine. Each of these 
applications requires a specific modification of the tetranitrogenous 
ligand and therefore a recommencement of its synthesis. 
Equally, the very high affinity of cyclic tetramines for metals which may 
be rare or precious metals (Cu, Ag, Au, Pd, Ru, Rh, Os, and the like) or, 
on the contrary, polluting metals (Zn, Cd, Hg, Pb, and the like) is also a 
potential source of advantageous applications. However, in this case too, 
in order to have the benefit of the properties of these molecules, a 
specific modification of their structure must be carried out for each of 
the envisaged applications. Thus, if it is desired to employ a cyclic 
tetramine to extract an ion from an aqueous phase towards an organic 
phase, a lipophilic group which will increase the solubility of the 
complex in organic solvents must be added to it. Similarly, to make a 
chelating ion exchange resin, the macroring must be attached to a polymer. 
EP-A-0,287,436 illustrates the state of the art considered to be that most 
closely related. The monofunctionalization process described in this prior 
patent has made it possible to prepare known derivatives of cyclam as well 
as other new derivatives, both of cyclam and of other 
tetraazacycloalkanes, symmetrical or otherwise. 
The objective of the present invention is precisely to develop a new method 
of monofunctionalization of this type of tetraazamacrorings, which can be 
applied in less constraining and more economical conditions, and which can 
therefore be exploited better on an industrial scale. 
The new process which is the subject of the present invention is based on 
the blocking of three of the four nitrogen atoms of the ring by engagement 
in covalent bonds with a single intracyclic atom or group of atoms. 
More precisely, the invention is aimed at a process for the preparation of 
monofunctionalized tetramines of formula I 
##STR2## 
in which: m=n=p=q=2, or 
m=n=2 ; p=q=3, or 
m=2 ; n=p=q=3, or 
n=2 ; m=p=q=3, or 
m=n=p=q=3, or 
m=n=3 ; p=q=4, and 
R denotes a saturated or unsaturated, especially polymerizable, organic 
radical, characterized in that a triprotected tetraazacycloalkane compound 
is prepared, of formula II 
##STR3## 
in which: 
x and y denote, independently of each other, 1 or 0, 
at least three of the four nitrogen atoms are bonded, via covalent bonds, 
with a single intracyclic atom or group of atoms A, and 
the broken line denotes a covalent bond which may be formed between the 
fourth nitrogen atom and A; in that the triprotected tetraazacycloalkane 
compound of formula II is reacted with an organic compound of formula III 
EQU R--X (III) 
in which: 
R has the meaning given in connection with formula I, and 
X denotes a nucleophobic group, especially a halogen or a tosylate radical, 
to obtain a triprotected and monofunctionalized tetraazacycloalkane 
compound of formula IV 
##STR4## 
and in that the compound of formula IV is deprotected to obtain the 
corresponding compound of formula I. 
In the above formulae II and IV the symbol A may, in particular, denote a 
boron atom or a metal-carbonyl group M(CO).sub.3 with M chosen from Cr, Mo 
and W, or else a P(O) or P(+) group. In the case where A denotes a P(+) 
group, the broken line of formula II then denotes a covalent bond formed 
between P(+) and the fourth nitrogen atom. 
The first variant of the process according to the invention will be 
illustrated below with the aid of a reaction scheme relating to the 
monoalkylation of cyclam. 
VARIANT A 
The method employed for effecting the monoalkylation of tetraazamacrorings 
in an unambiguous manner turns to good account the property of metal 
carbonyls of the 6th group of forming nitrogenous complexes by reaction 
with amines, by substitution of one, then two, then three C.dbd.O ligands. 
This process of monoalkylation according to the invention is highly 
selective. The monoalkylated compound alone is obtained. This process does 
not, therefore, require any additional purification stage. Furthermore, 
the protection and deprotection stages are quantitative and 
stoichiometric. 
REACTION SCHEME 
a) Protection 
The reaction of a tetraazamacroring with a metal carbonyl of the 6th group 
allows three of the four nitrogen atoms to be blocked: 
##STR5## 
b) Alkylation 
The reaction of alkylation with alkyl halides on the 4th nitrogen atom 
which is left free takes place in conventional SN.sub.2 condition, with 
good yields. 
##STR6## 
c) Deprotection 
The removal of the Cr(CO).sub.3 protecting group is effected simply by air 
oxidation at acidic pH. 
##STR7## 
The second variant of the process according to the invention is also 
illustrated below with the aid of a reaction scheme relating to the 
monoalkylation of cyclam. 
VARIANT B 
This variant is also based on the intracyclic blocking of three of the four 
nitrogen atoms of cyclam. The triprotected intermediate of formula II is 
the phosphorotriamide which can be obtained, for example, according to the 
scheme below, as described by J.E. Richman and J.J. Kubale, J. Am. Chem. 
Soc. 1983, 105, 749: 
##STR8## 
Similarly, the intermediate phosphorotriamides of formula II can be 
prepared in excellent practical conditions by reacting cyclam with 
POCl.sub.3 in the presence of a base. 
##STR9## 
However, in accordance with the present invention, these intermediates are 
obtained in excellent yields according to the reaction scheme below, which 
constitutes a very marked improvement to the operating method described 
above. 
##STR10## 
Intermediate 1 
Intermediate 1 has been studied by J.E. Richman and T.J. Atkins (Tet. Lett. 
1978, 52, 5149) and its characteristics are known; in particular it 
involves two forms in an equilibrium which is more or less displaced. This 
intermediate 1 is readily obtained merely by heating in an organic solvent 
(for example toluene); if the operation is carried out under a stream of 
dry nitrogen, the dimethylamine formed is entrained and the reaction is 
complete after a few hours. The progress of the reaction can be followed 
by the release of the amine formed into a stoichiometric quantity of acid 
containing a small quantity of colored indicator. At the turning point of 
the indicator the reaction is finished. 
Intermediate 1 is treated with excess CCl.sub.4. Intermediate 2 is then 
formed quantitatively: 
##STR11## 
Hydrolysis of this intermediate 2 is carried out using dilute sodium 
hydroxide: 
##STR12## 
This set of operations is quantitative; the macroring triprotected with one 
P(0) is extracted with an organic solvent (dichloromethane) to be 
subsequently employed as in the monoalkylation stage. 
The intermediate phosphorotriamide is alkylated very easily in the 
conventional conditions for the SN.sub.2 reaction. The liberation of the 
tetramine from its protecting group takes place easily in acidic medium 
under reflux for a few hours. The monofunctionalization is thus preferably 
carried out in DMF, in the presence of a base, preferably sodium or 
potassium carbonate. As for the deprotection, this is carried out with 3M 
HCI. 
##STR13## 
Furthermore, when an alcohol functional group is carried by a carbon bonded 
to another unsaturated carbon, this activated alcohol, for example benzl 
alcohol, can react directly with the intermediate 2. 
##STR14## 
The yield from this stage is also quantitative and forms an advantageous 
alternative form of variant B. 
VARIANT C 
The third variant of the process according to the invention consists in 
preparing an intermediate of general formula II, triprotected with an 
intracyclic boron atom. 
This triprotected intermediate can be obtained in various ways. It can be 
obtained, for example, by a transamination reaction with the aid of 
trisdimethylaminoborane. 
##STR15## 
The reaction is conducted in an organic solvent, for example toluene; here 
too, the release of an amine may enable the reaction to be followed. 
In the general operating method the solvent is evaporated off, the residue 
is taken up with a polar solvent for example, THF and an equivalent 
quantity of n-butyllithium is added. The anion thus formed is alkylated in 
excellent conditions. 
##STR16## 
The chief advantage of this variant lies in the deprotection stage, which 
takes place very rapidly in very mild conditions: H.sub.2 O is sufficient; 
nevertheless, a basic medium is adopted to make the extraction of the 
tetraazamacroring easier. 
It will be noted that trisdimethylaminoborane can also be replaced with 
isopropyl or methyl orthoborate B(OCH.sub.3).sub.3. 
To summarize, each of these methods has its own field of application; 
nevertheless, we stress that in all cases stoichiometric methods are 
involved, no excess of ligand being necessary. The examples introduced 
below show that the triprotection is highly efficient; the nitrogen 
remaining free can generally be used in any of the usual alkylation 
reactions of secondary amines. Variant C is wholly original and allows the 
introduction of functional groups which would not withstand a prolonged 
acidic hydrolysis. Thus, the monomeric derivative cyclam--CH.sub.2 
--C.sub.6 H.sub.4 --CH.dbd.CH.sub.2 is prepared by this route alone, in 
superior yields. We also emphasize the rapidity of this latter method, 
which makes it possible to obtain a complete N-monoalkylation within a 
period of a few hours. In all cases, the products are of satisfactory 
quality and do not require any subsequent purification stage.

The process forming the subject of the present invention will be 
illustrated below with the aid of particular examples of use. 
EXAMPLE 1 
All these handling operations are performed with protection from air, under 
nitrogen. 
Preparation of the chromium tricarbonyl complex of cyclam 
1 g of cyclam (5 mmol) and 1.38 g of chromium hexacarbonyl (6 mmol) are 
placed in 50 ml of dry and deaerated dibutyl ether; the mixture is heated 
to the reflux temperature of the solvent for 2-3 hours. The cyclam 
Cr(CO).sub.3 complex precipitates. After cooling to room temperature, the 
solvent is removed by filtration under nitrogen and the solid is rinsed 
with diethyl ether and is then dried under vacuum at 40.degree. C.; the 
excess Cr(CO).sub.6 is thus removed. 
Alkylation and deprotection 
0.278 g of cyclam Cr(CO).sub.3 (0.8 mmol), 96 .mu.l of benzyl bromide (0.8 
mmol) and an excess of sodium carbonate are placed in 5 ml of dry and 
deaerated DMF. The mixture is heated to 100.degree. C. for 2 hours and is 
then cooled to room temperature; the solvent is evaporated off under 
vacuum and this residue is taken up in 20 ml of 6N HCl and is then 
oxidized with air. The mixture becomes green. The mixture is made basic to 
pH=14 by adding potassium hydroxide pellets and is then extracted with 
2.times.25 ml of CH.sub.2 Cl.sub.2 ; after drying of the organic phases 
the solvent is evaporated off; the oily residue is taken up in 5 ml of 10% 
strength sulfuric ethanol; the precipitate is filtered off, taken up in 5 
ml of water, made basic and is then again extracted to give 0.176 g of 
pure N-benzylcyclam (62%). 
Entirely identical results were obtained by replacing chromium hexacarbonyl 
with molybdenum hexacarbonyl. 
EXAMPLE 2 
Preparation of the complex 
200 mg of cyclam (1 mmol) are placed in 40 ml of toluene and 1 mmol of 
tris(dimethylamino)phosphine is added. The mixture is heated to 
100.degree. C. This temperature is maintained until 3 mmol of 
dimethylamine are released. After cooling, 1 ml of dry CCI.sub.4 is added 
slowly. The intermediate precipitates. Hydrolysis with 4M sodium hydroxide 
followed by extraction with dichloromethane allows the cyclam P(0) complex 
to be recovered quantitatively (Y&gt;98%). 
Alkylation and deprotection 
300 mg of sodium carbonate are added to 30 ml of dry DMF containing the 
above compound. The mixture is heated to 100.degree. C. and 130 .mu.l (1 
mmol) of benzyl bromide are added. After one hour's reaction the mixture 
is filtered, the solvent evaporated off, and the residue is then taken up 
with 15 ml of 4M hydrochloric acid. After cooling, the solution is made 
basic by adding sodium hydroxide and the aqueous solution is extracted 
several times with dichloromethane. The organic phases are dried and the 
solvent is stripped off by distillation. N-Benzylcyclam is thus obtained 
in a 95% yield. 
EXAMPLE 3 
The handling operations are performed with protection against air, under 
nitrogen, as far as the deprotection stage. 
Preparation of the complex 
200 mg of cyclam (1 mmol) are placed in 40 ml of toluene and 190 .mu.l of 
tris(dimethylamino)borane are added. The mixture is heated to 100.degree. 
C. This temperature is maintained until 3 mmol of dimethylamine have been 
released. 
Alkylation and deprotection 
The toluene is evaporated off using 30 ml of dry THF. After the complex has 
dissolved, the mixture is cooled to -30.degree. C. and an equivalent 
quantity of n-butyllithium is added. The mixture is kept stirred at 
-30.degree. C. for 15 min. After the addition of 130 .mu.l of benzyl 
bromide (1 mmol), it is allowed to return to room temperature; stirring is 
continued for approximately 2 hours. 
The complex is destroyed by adding a few drops of water. 
The THF is removed by vacuum distillation. The residue is treated with 30% 
strength sodium hydroxide and is then extracted twice with 25 ml of 
CH.sub.2 CI.sub.2. After drying of the organic phases, the solvent is 
evaporated off. The monoalkylation compound is in the form of a yellow 
oil. Yield=95%. 
Each of the variants described in detail in the context of the 
abovementioned Examples 1 to 3 has been successfully employed in a 
satisfactory manner to obtain the following compounds. The halide employed 
may be chosen from the chloride, a bromide, and iodide or else an alkyl, 
aryl or aralkyl tosylate. 
##STR17## 
in which: R=--CH.sub.2 --.phi. 
R=--CH.sub.2 --CH.dbd.CH.sub.2 
R=n--C.sub.12 H.sub.25 
R=--CH.sub.3 
R=--(CH.sub.2).sub.3 --.phi. 
R=CH.sub.2 --ferrocene 
R=CH.sub.2 --C.sub.6 H.sub.4 --CH.dbd.CH.sub.2 (meta+para isomer) 
The compound below was obtained by bringing the complex and the 
corresponding organic dihalide into contact in proportions of 2:1. 
##STR18## 
The results obtained are collected in Table I, introduced below. 
TABLE I 
__________________________________________________________________________ 
COMPOUND YIELD 
VARIANT ALKYLATING AGENT 
__________________________________________________________________________ 
Derivatives of (2222) 95% A: Cr(CO).sub.3 L 
C.sub.6 H.sub.5 CH.sub.2 Br 
##STR19## 75% 70% 90% 50% 
A: Mo(CO).sub.3 L A: W(CO).sub.3 L B 
" " " " 
Derivatives of 2323 
##STR20## 
R = CH.sub.2C.sub.6 H.sub.5 97% A: Cr(CO).sub.3 L 
C.sub.6 H.sub.5 CH.sub.2 Br 
87% A: Mo(CO).sub.3 L 
" 
85% A: W(CO).sub.3 L 
" 
80% B C.sub.6 H.sub.5 CH.sub.2 OH 
95% B C.sub.6 H.sub.5 CH.sub.2 Br 
95% C " 
R = CH.sub.3 30% A: Cr(CO).sub.3 L 
CH.sub.3 I 
30% B CH.sub.3 I 
80% C CH.sub.3OTs 
R = (CH.sub.2).sub.3C.sub.6 H.sub.5 
75% B RBr 
90% C ROTs 
R = C.sub.12 H.sub.25 30% A: Cr(CO).sub.3 L 
RBr 
70% B RBr 
R = CH.sub.2CHCH.sub.2 55% A: Cr(CO).sub.3 L 
RBr 
70% B ROH 
80% B ROH 
80% C RBr 
R = CH.sub.2 -ferrocene 80% A: Cr(CO).sub.3 L 
RCl 
80% B ROH 
80% B RCl 
80% C RCl 
R = CH.sub.2C.sub.6 H.sub.4CHCH.sub.2 
95% C RCl 
commercial mixture of 
meta + para isomers 
Bicylic derivatives 
##STR21## 
Isomer 
ortho 45% B BrCH.sub.2C.sub.6 H.sub.4CH.sub. 
2 Br 
meta 80% B " 
para 90% A: Cr(CO).sub.3 L 
" 
para 90% B " 
Derivative of 3333 90% B C.sub.6 H.sub.5 CH.sub.2 Br 
##STR22## 80% C " 
Derivative of 3434 90% B C.sub.6 H.sub.5 CH.sub.2 Br 
##STR23## 70% C " 
__________________________________________________________________________