chlorinating agents and the dependence of the completeness of the cyclization reaction on the ratio of compound
2
and 50% aqueous hydrazine.
The chlorination of diethanolamine 1 has been studied in a fairly detailed manner [4-6]. On interacting
compound 1 with gaseous hydrogen chloride at 120°C, with phosgene, and with phosphorus trichloride, the
target product 2 is formed in only trace amounts [4]. The use of thionyl chloride as chlorinating agent leads to
the formation of chloro derivatives in almost quantitative yield (95%) [5, 6]. Regretably there is no systematic
investigation in the literature of the effect of various factors on the yield of the target product, which does not
enable a conclusion to be drawn on the optimal conditions for carrying out the synthesis.
We have investigated experimentally the effect of the solvent on the selectivity of the chlorination
reaction, and have also studied by mathematical planning the dependence of the yield of compound 2 on the
reaction temperature, the concentration of compound 1 in solution, and the molar ratio of SOCl and compound
2
1
. In the course of the investigation we established that chloroform (yield of product 2 95%) is the best of the
solvents used (chloroform, chlorobenzene, trichloroethylene, benzene, toluene). As a result investigation of the
effect of the remaining factors on the yield of chloro derivative 2 was carried out in chloroform. Analysis of the
results of the mathematical treatment of the experiment showed that the yield of compound 2 essentially depends
only on the molar ratio of SOCl and compound 1. The maximum yield of product (95.6%) was observed at
2
SOCl :1 equal to 3:1.
2
It has therefore been established that the chlorination of compound 1 with thionyl chloride proceeds in
the best yield in chloroform at a molar ratio of reactants of 3:1.
Numerous investigations of the conversion of haloalkylamines on interaction with N-nucleophiles in
aqueous alkaline medium or in the nucleophile showed that it proceeds according to a general scheme through
the formation of an aziridinium ion [7]. However, on going over to di(2-haloalkyl)amines competition at ring
closure is possible with the formation of three- and six-membered rings [3].
Although the reaction to obtain nitrogen-containing heterocycles by the interaction of haloalkylamines
1
of general formula RR NCH CH Cl with N-nucleophiles is not new [8], we obtained 1-amino-4-
2
2
methylpiperazine 5 by the reaction of dihaloamine 2 with aqueous hydrazine solution for the first time.
We carried out a series of investigations on the interaction of dichloro derivative 2 with aqueous
hydrazine solution at a substrate 2 ratio to 50% N H of 1:50, 1:10, and 1:5 at 20-30°C. It should be noted that
2
4
the system of dihaloamine 2:aqueous hydrazine was two-phase when using molar ratios of reactants less than
0:1. Visually the reaction mixture becomes homogeneous only after 90% conversion of compound 2. In the
4
case of two media the interaction of dihaloamine 2 with hydrazine is possible both in aqueous and in organic
media. We have investigated the dynamics of the change of chloride ion concentration in the organic layer after
mixing the reactants. The data obtained enable us to assert with a definite degree of probability that the reaction
proceeds only in the aqueous hydrazine medium. Our investigations established that the maximum yield of
cyclization product 5 (87%) was achieved at a ratio of substrate 2 to 50% N H of 1:10.
2
4
1
3
Analysis of the reaction mixture using data of GLC, chromato-mass spectrometry, and C NMR spectra
showed that, in addition to the target product 5, a series of contaminants is formed, which we have identified.
In particular, di(2-hydrazinoethyl)methylamine (6) (up to 2%) was detected by chromato-mass
spectrometry, and at
a
degree of conversion of substrate
2
<80% N-(2-chloroethyl)-N-(2-
hydrazinoethyl)methylamine (4) was established to be present in the reaction mixture (Scheme 1).
Our investigations permit a possible mechanism to be proposed for the cyclization of compound 2 in
aqueous hydrazine through the formation of the reactive intermediate 3. In addition to the identified compounds
4
-6, after distilling off the desired product 5, substances remained in the still which we attribute to quaternary
ammonium bases 7 and 8. The latter are most probably formed by secondary reactions between the target
compound 5 and the reactive compound 3.
1
547